Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment

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TOX/2012/26 Annex 1

COMMITTEE ON TOXICITY OF CHEMICALS IN FOOD, CONSUMER PRODUCTS AND THE ENVIRONMENT

Table 1 DATABASE SEARCH TERMS

1. (organophosphate* OR organophosphorus*) OR 2. (diazinon*) OR 3. (propetamphos*) OR 4. (sheep dip*) OR 5. (parathion*)

Table 2 REVIEW INCLUSION AND EXCLUSION CRITERIA

Inclusion Criteria

Health outcomes relating to the nervous system: • neuropsychological abnormalities • electroencephalographic (EEG) abnormalities • peripheral neuropathy and neuromuscular dysfunction • psychiatric illness • effects on the autonomic nervous system • focus on chronic, low-level exposure in relation to the above health outcomes • acute poisoning with persistent chronic effects, in particular memory and psychiatric illness • PON1 and polymorphism studies, if they are associated with OP related chronic neurological ill-health • Alzheimer’s Disease (AD) • Parkinson’s Disease (PD) • Parkinsonism • chronic effects of Gulf War incident with low exposure at Khamisiyah, Iraq • health effects arising from the Tokyo subway sarin episode • Chronic Organophosphate Induced Neuropsychiatric Disorder (COPIND), which includes the symptoms: personality changes, impulsive suicidal thoughts, cognitive impairment, language disorder, alcohol intolerance, heightened sense of smell, handwriting deterioration, sensitivity to OPs, decreased exercise tolerance, and exacerbation of “dipper’s flu” in sheep dippers • symptoms most frequently mentioned by individuals who believe they suffer long- term ill-health from exposure to OPs, which, besides those comprising COPIND, include: anxiety, confusion, depression, headache, fatigue, impaired concentration, incoordination, irritability, memory loss, muscular pains and/or spasms, nausea, nightmares, numbness of the extremities, respiratory disease, sleep disorders • peer-reviewed case reports • relevant reviews

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Exclusion Criteria

• studies reporting animal or in vitro data • studies not reporting original results: meta-analyses, comments, letters, editorials, abstracts, and most of the retrieved reviews (a few reviews thought to be particularly relevant will be included) • papers concerned only with methodology • papers dealing with exposure or exposure monitoring only • papers reporting on monitoring the activity of acetylcholinesterase in absence of any other health outcomes identified in the inclusion criteria • studies dealing with health outcomes other than those relating to the nervous system, for example, immunological or reproductive effects, mutagenicity, carcinogenicity • studies dealing with neurodevelopmental defects in children aged 0-15 years • papers reporting poisonings or only the acute effects of exposure to OPs • cabin air reports previously reviewed by COT • papers relating to medical treatment of poisoning with OPs • acute poisoning giving rise to intermediate syndrome or polyneuropathy • Gulf War Veteran studies other than those relating to the incident at Khamisiyah, Iraq • mortality studies • Creutzfeldt-Jakob disease

2 TOX/2012/26 Annex 2

COMMITTEE ON TOXICITY OF CHEMICALS IN FOOD, CONSUMER PRODUCTS AND THE ENVIRONMENT

STUDY SUMMARY NOTES (TABLE 3)

HPA COT Secretariat

August 2012

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TOX/2012/26 Annex 2

COMMITTEE ON TOXICITY OF CHEMICALS IN FOOD, CONSUMER PRODUCTS AND THE ENVIRONMENT

Table 3 STUDY SUMMARY NOTES

AUTHOR: Abdel Rasoul et al 2008

TITLE: Effects of occupational pesticide exposure on children applying pesticides

HYPOTHESIS: Increasing exposure to OP pesticides is associated with progressively larger neurobehavioural deficits

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date of Study Reference Measure Other risk factors / Outcome Narrative description Statistical study collectio study population population of bias / confounders variables of basic results methods n period exposure Egypt Cross- June to 2008 Male children Children who Serum or Neurobehavioural Neurobehaviou Applicator groups had SPSS Version (Shebin sectional August aged 9 to 18 had never plasma performance was ral significantly impaired 14.0 used, Elkom) 2005 years, working worked in the AChE: adjusted for effects performance; neurobehavioural t- test for as seasonal cotton fields, only one of age and neurological performance on all differences workers in selected from measure education; the symptoms; measures of the between cotton fields friends and taken, no partial correlation correlation of Wechsler Adult means,χ²- test for and spraying relatives of baseline of neurobehaviour Intelligence Scale (p differences pesticides with the applicator measure neurobehavioural al performance values <0.05), between backpack children. of AChE performance with with AChE, significantly more percentages, applicators. There were days worked this duration of neurological multiple linear There were 30 30 control season, years work symptoms (p <0.05), regression to children in the children in the worked, and and evidence for a DR estimate Younger (9-15) Younger age AChE, was relationship between difference in age group, and group and 20 controlled for age days worked in the average 20 in the Older in the Older and its interaction season, and years performance (16-18) age age group with all these worked as pesticide between control group variables. applicators, and AChE and applicator BMI was included level and groups (p values as a covariate in neurobehavioural reported, see the analysis performance description of results)

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AUTHOR: Alarcon et al 2011 (Abstract evaluated, poster presented at a Conference)

TITLE: Characterisation of poly neuropathologies in Almeria providence in regions with differing pesticide levels

HYPOTHESIS: (Not clear in abstract) A descriptive study of polyneuropathy arising in areas of high and low pesticide use

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure of Other risk Outcome Narrative description of basic Statistical study collection of population population exposure factors / bias variables results methods period study / confounders Spain Cross- 2006- 2011 Individuals Individuals The authors note Not specified Polyneuropathy Risk of polyneuropathy was ORs and (Almeria) sectional 2008 living in living in that different almost two times higher in 95% CI, p (descriptive) areas of areas of low geographical areas people living in areas of high value high pesticide were selected pesticide use (rate pesticide use based on the 43.2/100,000 population) use number of hectares compared to those living in devoted to intensive areas of low pesticide use agriculture (22.3/100,000) (OR=1.94 95% CI[1.53-2.45]; p < 0.001)

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AUTHOR: Albers et al 2004a

TITLE: The effects of occupational exposure to chlorpyrifos on the peripheral nervous system: a prospective cohort study

HYPOTHESIS: Chronic occupational exposure to chlorpyrifos at levels associated with various aspects of manufacturing produces a clinically evident or subclinical peripheral neuropathy

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data collection Date Study Reference Measure of Other risk Outcome Narrative Statistical study period of population population exposure factors / bias / variables description of methods study confounders basic results US Cohort Eligible Dow 2004 53 chlorpyrifos 60 workers Historic and Age, sex, Nerve No support for SAS version 8.2; (Michigan) Chemical manufacturing involved in ambient height, weight, conduction the hypothesis t test for Company workers with manufacturing chlorpyrifos BMI (body studies (NCS) that workers difference in workers were known and Saran (clear exposure mass index), were with chronic means and those employed measurable plastic film based on skin performed on occupational comparison of on 1 September exposure to wrapping personal air temperature the dominant exposure to nerve conduction 1999 in chlorpyrifos, but material) with sampling data; over nerve side sensory chlorpyrifos study results, p buildings not no occupational urinary TCP being tested; and motor develop values given; involved either occupational exposure to excretion smoking in nerves: clinically Fisher’s exact in chlorpyrifos exposure to chlorpyrifos or divided by pack-years, sensory evident or and χ² tests to production or in other OPs or to suspected creatinine socio- negative peak subclinical compare Saran other neurotoxicants concentration; economic amplitude and peripheral neurological production; neurotoxicants; monthly plasma status, onset latency neuropathy, symptoms, p baseline 1-year BuChE education were and no values given; evaluation evaluations activities; level, anxiety recorded, and evidence of logistic performed on completed on red blood cell motor deterioration regression each worker on 111 of the 113 AChE activities response over 1 year of calculating OR inclusion in the subjects at baseline and amplitude and chlorpyrifos for chlorpyrifos study, and then evaluated at 1-year onset latency. exposure workers a 1-year baseline examination Subclinical or among developing evaluation clinically subjects peripheral approximately evident compared to neuropathy at one year later neuropathy the referent either was defined group examination using compared to symptoms, referent group at signs and baseline NCS results

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AUTHOR: Albers et al 2004b

TITLE: The effects of occupational exposure to chlorpyrifos on the neurologic examination of central nervous system function: a prospective cohort study

HYPOTHESIS: Chronic exposure to chlorpyrifos at levels usually associated with various aspects of the manufacturing process produces clinical neurologic examination evidence of CNS dysfunction

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data collection Date of Study Reference Measure of Other risk Outcome Narrative Statistical study period study population population exposure factors / bias / variables description of methods confounders basic results US Cohort Eligible Dow 2004 53 chlorpyrifos 60 workers Historic and No CNS neurologic No clinically t test for (Michigan) Chemical manufacturing involved in ambient adjustment outcome apparent difference in Company workers with manufacturing chlorpyrifos was made for variables of: adverse CNS means, workers were known and Saran (clear exposure multiple encephalopathy, effects were Fisher exact those employed measurable plastic film based on comparisons pyramidal tract evident under test or χ² test on 1 September exposure to wrapping personal air dysfunction, the conditions for 1999 in chlorpyrifos, material) with sampling extrapyramidal of the study associations; buildings but not no data; dysfunction involving p values involved either occupational occupational urinary TCP Clinical chronic, low- given for in chlorpyrifos exposure to exposure to excretion assessment of level neurologic production or in other OPs or chlorpyrifos or divided by cognitive occupational ratings Saran other to suspected creatinine functions exposure to production; neurotoxicants; neurotoxicants concentration; including Mini- chlorpyrifos baseline 1-year monthly Mental State- evaluation evaluations plasma Examination No cognitive performed on completed on BuChE (MMSE) effects each worker on 111 of the 113 activities; reported inclusion in the subjects red blood cell using MMSE. study, and then evaluated at AChE a 1-year baseline activities at evaluation baseline and approximately 1-year one year later examination

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AUTHOR: Albers et al 2004c

TITLE: Absence of sensory neuropathy among workers with occupational exposure to chlorpyrifos

HYPOTHESIS: Workers with long-term occupational exposure to chlorpyrifos develop dose-related subclinical or clinically evident adverse effects, including peripheral neuropathy

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure of Other risk Outcome Narrative Statistical study collection of population population exposure factors / bias variables description of methods period study / basic results confounders US Cross- 2 month 2004 53 chlorpyrifos 60 workers Historic and Study and Subclinical or A few subjects with SAS (Michigan) sectional period for manufacturing involved in ambient referent clinically clinical or version clinical workers with manufacturin chlorpyrifos groups were evident electrodiagnostic 8.2used, t examinations; known and g Saran exposure comparable in neuropathy, findings suggestive test for 4 month study measurable (clear plastic based on age, gender, defined using of neuropathy were difference period for exposure to film wrapping personal air anthropometric combination of equally divided in means biological chlorpyrifos, material) with sampling data; features, abnormalities between exposed between measurement but not no urinary TCP alcohol use, from the and unexposed chlorpyrifos s; occupational occupational excretion smoking categories of groups; mean group and eligible Dow exposure to exposure to divided by history, and symptoms nerve conduction referent Chemical other OPs or chlorpyrifos creatinine medication (identified in study results did group, Company other or to concentration; use clinical not differ Fisher workers were neurotoxicants suspected monthly interview), significantly exact test, those neurotoxican plasma BuChE signs between groups; or χ² test employed on ts activities (identified by overall, no support for 1 September averaged over neurological for hypothesis that association 1999 in 4 month study examination), sensory neuropathy s, p values buildings period; and nerve or other isolated reported involved red blood cell conduction peripheral either in AChE on day testing abnormalities are chlorpyrifos of examination related to production or chlorpyrifos in Saran exposure production

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AUTHOR: Albers et al 2007

TITLE: Dose-effect analyses of occupational chlorpyrifos exposure and peripheral nerve electrophysiology

HYPOTHESIS: Chronic chlorpyrifos exposures at levels in the range associated with appreciable inhibition of B-esterases produce adverse dose effects on peripheral nerve electrophysiology suggestive of sub-clinical neuropathy

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data collection Date Study Reference Measure of Other risk Outcome Narrative description Statistical study period of population population exposure factors / bias / variables of basic results methods study confounders US Cohort Eligible Dow 2007 53 chlorpyrifos 60 workers Historic and Sex, BMI, Nerve A few significant or SAS version (Michigan) Chemical manufacturing involved in ambient temperature conduction borderline-significant 8.2 used; Company workers with manufacturing chlorpyrifos over nerve studies were associations were nerve workers were known and Saran (clear exposure being tested, performed found, but gave conduction those employed measurable plastic film based on estimated on sensory conflicting results or measures on 1 September exposure to wrapping personal air general ability, and motor findings not were modelled 1999 in chlorpyrifos, material) with sampling data; education nerves, and explained by a in regression buildings but not no occupational urinary TCP level, anxiety the change neurotoxic effect, so models using involved either occupational exposure to excretion level, alcohol in a nerve authors were historic in chlorpyrifos exposure to chlorpyrifos or divided by use conduction cautious in the chlorpyrifos production or in other OPs or to suspected creatinine (drinks/day), measure per interpretation. They exposure, Saran other neurotoxicants concentration; alcohol-related unit change conclude that the interim (over production; neurotoxicants; plasma behaviours, in findings from the the 1-year baseline 1-year BuChE smoking pack- chlorpyrifos study were not study period) evaluation evaluations activity; years exposure suggestive of causal chlorpyrifos performed on completed on red blood cell was relationships exposure or each worker on 111 of the 113 AChE activity calculated between exposure to interim inclusion in the subjects chlorpyrifos over TCP/Cr level. study, and then evaluated at many years during 95% CIs and a 1-year baseline the manufacturing p values evaluation process and reported for approximately subclinical parameter one year later neuropathy estimates

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AUTHOR: Al-Shehab et al 2000 (Abstract evaluated, original article unobtainable)

TITLE: Peripheral neuropathies complicating chronic low-level exposure to organophosphate, carbamates and pyrethroid pesticides

HYPOTHESIS: Nerve conduction studies are a sensitive test for the detection of changes induced by chronic low-level exposure to OPs

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AUTHOR: Androutsopoulous et al 2011

TITLE: Role of paraoxonase 1 (PON1) in organophosphate metabolism: Implications in neurodegenerative diseases

Date of Review 2011

Aim To summarize the involvement of PON1 genotypes in the occurrence of Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis

Topics covered OP pesticide metabolism by PON1 and disease PON1 and Parkinson’s disease PON1 and Alzheimer’s disease PON1 and amyotrophic lateral sclerosis Mechanistic link between PS-AD pathology and paraoxonase status Health Parkinson’s disease Alzheimer’s disease outcomes Amyotrophic Lateral Sclerosis considered

Original studies Studies referenced in this review did not meet inclusion criteria (i.e. pre-dated 1999, animal, biomarker, or mechanistic studies or did not provide OP specific data) not identified in literature search

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AUTHOR: Araki et al 2005

TITLE: Association between lower P300 amplitude and smaller anterior cingulate cortex volume in patients with posttraumatic stress disorder: a study of victims of Tokyo subway sarin attack

HYPOTHESIS: There is an association between the lower amplitude of the P300 wave on EEG recording and brain morphological abnormalities in patients with post-traumatic stress disorder (PTSD) following the Tokyo subway sarin attack

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date of Study population Reference Measure of Other risk factors / Outcome Narrative Statistical study collection study population exposure bias / confounders variables description of methods period basic results Japan Cross- Between 2005 47 subjects who 13 subjects Record of Victims who had Unequivocal Victims with Student’s t tests (Tokyo) sectional 2000 and were victims of out of the 47 having been had any psychiatric PTSD related to PTSD showed for group 2001, 5-6 the Tokyo who did not involved in treatment or the subway sarin significantly lower differences in years after subway sarin have PTSD the subway medication, or attack; amplitudes of reaction times; the subway attack treated for sarin attack, history of an ERP (event- P300 compared ANOVA for group sarin attack acute sarin and hospital neurological related potential) to victims without differences in intoxication, and treatment illness, were not recording of PTSD, and the P300 amplitude with a follow up, for the included; IES-R response to P300 amplitudes and latency; at St Luke’s intoxication (impact of event auditory stimuli showed a trend Spearman’s International scale-revised) showing lower towards a correlations for Hospital in scores, STAI (trait P300 wave significant P300 amplitudes Tokyo; and state anxiety amplitude; positive and IES-R, STAI 8 victims scores), and smaller anterior correlation with a and diagnosed as concentrations of cingulate cortex smaller volume of cholinesterase having serum- volume in the anterior cingulate concentrations. unequivocal cholinesterase brain, recorded cortex grey P values are PTSD, with no were considered to by MRI (magnetic matter reported other psychiatric test for their resonance comorbidity, were possible imaging) scan chosen for the confounding study effects

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AUTHOR: Araoud et al 2011

TITLE: Factors influencing plasma butyrylcholinesterase activity in agricultural workers

HYPOTHESIS: To determine the factors that must be considered for occupational BChE monitoring of workers exposed to pesticides

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study population Reference Measure of Other risk Outcome Narrative description of Statistical methods study collection of population exposure factors / bias / variables basic results period study confounders Tunisia Cross- Not 2011 110 agricultural 97 sex and Questionnaire Sex, age, Neurological Agricultural workers Mean ± SD, sectional reported workers from the age-matched to obtain info weight and reported several Students t-test, Sahel region of controls on smoking neuropsychiatric neurological and Pearson’s analysis Tunisia chronically without occupational habits, alcohol symptoms i.e. neuropsychiatric or Spearman rank exposed to a previous history, date of consumption, headache, symptoms. Among the correlation mixture of occupational last exposure, education tremor, 44% of farmworkers pesticides (i.e. exposure to etc. level, medical asthenia, that reported at least OPs, carbamates, pesticides or Plasma BChE history irritability, one toxic neurological pyrethroids, any other activity paraesthesia, or neuropsychiatric thiocarbamates) industrial anxiousness, symptom, 29% had chemicals limb numbness, BChE activity lower sleep than 6000 IU/L. disturbance and Headache was vertigo observed in 20% of (assessed via workers, numbness or questionnaire paraesthesia of limbs and clinical (14%) as well as examination) asthenia (13%). Factors considered relevant to reduced BChE activity and toxic effects included 10 or more years exposure to OP-carbamate mixtures, that was for 2 days or more per week, exceeding 150 h per year with the last exposure being up to 60 days

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AUTHOR: Arima et al 2003

TITLE: Transient and reversible Parkinsonism after acute organophosphate poisoning

HYPOTHESIS: Parkinsonism is a rare complication in patients with OP poisoning, and the authors believe that this was the third case to be reported in the literature to date

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AUTHOR: Aubeneau et al 2008 (Abstract evaluated, article in French)

TITLE: Chronic parkinsonian syndrome after 10 years of repeated insecticide spraying

HYPOTHESIS: Pesticides are suspected to be one risk factor responsible for parkinsonism; the case presented supports this environmental hypothesis

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study population Reference Measure of Other risk Outcome Narrative description of Statistical study collection of population exposure factors / bias / variables basic results methods period study confounders France Case Not specified 2008 One case of N/a Report by N/a Parkinsonism Acute and reversible N/a report in abstract atypical patient of parkinsonism is usually parkinsonian repeated daily described after massive disorder following spraying; ingestion of OPs, repeated authors whereas acute spraying with an consider he intoxications occurring aerosol had a daily after pesticide spraying insecticide massive dermal are rare; this case containing and respiratory illustrates that pyrethrum and exposure to parkinsonian syndrome OP these can also occur with pesticides, for repeated spraying where 10 years there is a sufficiently large dose over a prolonged period of time

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AUTHOR: Baldi et al 2001

TITLE: Neuropsychologic Effects of Long-Term Exposure to Pesticides: Results from the French Phytoner Study

HYPOTHESIS: To assess the cognitive effects of long-term exposure to pesticides in vineyard workers in the Bordeaux area

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure of Other risk factors / Outcome variables Narrative Statistical study collection of population population exposure bias / confounders description of methods period study basic results France Cross- Feb 1997 2001 Bordeaux 216 workers Lifelong Educational level, Neuropsychological Exposed Chi square, sectional to Aug vineyard employed in occupational age, sex, alcohol tests wrt: memory, subjects had ANOVA, 1998 workers: (528 forestry or exposure to consumption, abstraction, attention higher risk of Univariate directly agricultural co- pesticides e.g. 20 smoking, and speed of scoring a low analysis, exposed and operatives years or more (as environmental information processing performance multivariate 173 indirectly (considered to determined via exposures, on the tests logistic exposed to have a low questionnaires) depressive regressions pesticides) probability of symptoms, exposure) psychoactive drugs

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AUTHOR: Bayrami et al 2012

TITLE: Electroencephalogram, cognitive state, psychological disorders, clinical symptoms, and oxidative stress in horticulture farmers exposed to organophosphate pesticides

HYPOTHESIS: OP pesticides may cause electroencephalography, cognitive state and psychological disorders, clinical symptoms, oxidative stress, AChE and DNA damage in exposed horticulture farmers

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure of Other risk Outcome variables Narrative Statistical study collection of population population exposure factors / bias / description of basic methods period study confounders results Iran (Arak) Cross- Not 2012 40 male 40 workers Oxidative stress Control group Levels of oxidative There were Two sample t sectional specified horticulture from the same markers were of 40 workers stress markers and ndications of test used for farmers, age village who assayed: matched on AChE levels reported, oxidative stress and statistical range 15-80, were not activity of age, sex and and certain AChE inhibition in comparisons, from the engaged in superoxide education biochemical and farmers compared Pearson village of any dismutase, level haematological to controls, but no correlation Hafte in agricultural catalase, 8- parameters; effects on significant coefficient for Arak, Iran work, and with hydroxy-2- cognitive function differences in association no history of deoxy examined through the cognitive function between job-related guanosine, Mini Mental State were seen; for variables; exposure to glutathione Examination (MMSE); psychological all data OPs peroxidase; psychological distress, only presented as plasma AChE symptoms and somatisation was mean ±SD, activity distress evaluated significantly higher with p values of measured through Symptom in farmers less than 0.05 Checklist-90-Revised considered (SCL-90-R) statistically significant

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AUTHOR: Bazylewicz-Walczak et al 1999

TITLE: Behavioral Effects of Occupational Exposure to Organophoshorous Pesticides in Female Greenhouse Planting Workers

HYPOTHESIS: To assess the behavioural effects of chronic exposure to organophosphorous pesticides at the gardening enterprises

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure of Other risk factors / Outcome variables Narrative Statistical methods study collection of population population exposure bias / confounders description of period study basic results Poland Cross- Not 1999 26 women 25 women Estimated Matched cases and Neurobehavioural Psychological Two Way ANOVA sectional specified. performing employed concentrations of controls including effects via Polish test results did (to identify OP Authors standard in most frequently for age, education adaptation of the not reveal exposure effects note that gardening canteens, used OPs (i.e. level (recognised Neurobehavioural effects of dictated by a single study was jobs kitchens Dichlorvos, confounders for Core Test Battery exposure after spraying season or conducted /greenhouse and admin Methamidophos, neuropsychological (NCTB) (e.g. single spraying long term effects of between workers jobs Methidathion, testing) and place of cognitive and season; exposure, or Jan – Pirimiphos-Methyl) habitation psychomotor exposed interaction between June in greenhouse air, functions, mood females had short and long term on clothes and states and longer reaction effects of skin. Exposure subjective symptom times and exposure); mean assessment questionnaires). reduced motor values and SDs for conducted via Psychological steadiness cf. the NCTB tests Durhan & Welfe examinations unexposed reported method (Takes conducted before workers, plus (significance level into account and after spraying increased α=10 used to dermal and season (Jan/Feb tension, greater determine respiratory and June depression and neurobehavioural absorption routes) respectively) fatigue and effects Peripheral more frequent neurological symptoms of symptoms also CNS assessed disturbance

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AUTHOR: Beard et al 2011

TITLE: Suicide and pesticide use among pesticide applicators and their spouses in the Agricultural Health Study

HYPOTHESIS: There may be an association between pesticide use and suicide among licensed pesticide applicators and their spouses enrolled in the Agricultural Health Study (AHS)

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure of Other risk factors / Outcome Narrative Statistical methods study collection of population population exposure bias / confounders variables description of basic period study results US Cohort 2009 2011 110 suicides 81,998 Self-reported Age, sex, state of Suicide Findings of study Cox proportional identified cohort information in residence, do not support the hazards regression through state members questionnaire on race/ethnicity, hypothesis that models to estimate mortality files pesticide use, education level, pesticide use may hazard ratios (HR) and the including years marital status, increase suicide and 95% CIs for National Death of use and number of children in risk in pesticide the association of Index occurring average days of family as a measure applicators and suicide with each in AHS use per year. of social connection, their spouses measure of participants Information size of farm worked pesticide use between elicited on 10 last year, alcohol enrolment in pesticide consumption during the AHS (from categories, past 12 months, 1993 to 1997) including OPs, smoking status, ever and 31 May and on ever use diagnosed with heart 2009 of 50 specific disease or diabetes pesticides as measures of chronic disease

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AUTHOR: Beckman, 2009

TITLE: OP sheep dips – new study sheds light on an old problem

Date of 2009 Commentary

Aim Report on a study by Mackenzie Ross et al (2009) investigating the relationship between low-level exposure to OPs in sheep dip and permanent/long term neurological damage in UK farmers

Topics covered Background to research Measurable neurological impacts (i.e. effects on attention, touch perception and manual dexterity) Healthy worker effect Genetic susceptibility to OP toxicity/PON polymorphisms Study findings, conclusions and implications

Health outcomes Flu-like illnesses Chronic, debilitating physical and mental symptoms i.e. neuropsychological impairments (ranging from fatigue and weakness to short-term memory considered loss and depression)

Original studies not Studies referenced in this review did not meet inclusion criteria (i.e. pre-dated 1999) identified in literature search/ (not included in selected refs)

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AUTHOR: Beseler et al 2006

TITLE: Depression and Pesticide Exposures in Female Spouses of Licensed Pesticide Applicators in the Agricultural Health Study Cohort

HYPOTHESIS: To study pesticide exposures occurring in the course of farm work undertaken by women and evaluate whether cumulative pesticide exposure, or a history of acute pesticide poisoning, was associated with physician-diagnosed depression

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study population Reference Measure of Other risk factors Outcome Narrative description of Statistical study collection of population exposure / bias / variables basic results methods period study confounders US (Iowa, Nested 1993- 2006 2051 female 27023 Lifetime pesticide State, age, race, Depression Depression significantly Univariate North case- 1997 spouses of never use categorised education, off- associated with a history analysis via Carolina) control private pesticide exposed as low (up to 225 farm work, of pesticide poisoning logistic (from applicators with female days); or high alcohol, cigarette (OR=3.26[1.72-6.19] but regression; AHS) physician spouses (>225 days) and smoking, not low or high cumulative multiple diagnosed history of physician visits pesticide exposure logistic depression diagnosed and solvent (OR=1.09[0.91-1.31] and regression requiring pesticide exposure OR=1.09[0.91-1.31] analysis treatment poisoning respectively)

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AUTHOR: Beseler and Stallones, 2008

TITLE: A Cohort Study of Pesticide Poisoning and Depression in Colorado Farm Residents

HYPOTHESIS: To describe the associations between pesticide poisoning and depressive symptoms in a cohort of farm residents

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure of Other risk Outcome Narrative description of basic Statistical study collection of population population exposure factors / bias / variables results methods period study confounders US Cohort 1993 - 2008 617 farm Year 1 Baseline Age, gender and Depression Pesticide poisoning was T-test, chi- (Colorado) (3 year 1996 operators self- marital status (evaluated via use significantly associated with square test, follow- living in rural reported and health of The Center for depression (OR=2.59[1.20- non-parametric up) farm pesticide decreased Epidemiologic 5.58]). Authors suggest this Kruskal-Wallis residences poisoning income, and Studies- was largely due to significant test, ANOVA (annual follow increased debt, Depression scale) associations with the (weighted least- up) education symptoms of being bothered by squares things and feeling that regression) everything was an effort (OR=3.29[1.95-5.55] and OR=1.93[1.14-3.27] respectively)

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AUTHOR: Beseler et al 2008

TITLE: Depression and Pesticide Exposures among Private Pesticide Applicators Enrolled in the Agricultural Health Study

HYPOTHESIS: To evaluate the relationship between pesticide exposure and physician-diagnosed depression in a cohort of farmer applicators enrolled in the Agricultural Health Study (AHS)

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure of exposure Other risk factors / Outcome Narrative Statistical study collection of population population bias / confounders variables description of basic methods period study results US Cross- 1993- 2008 534 private 17,051 controls Self reported State, age, Depression OP specific results: Logistic (Iowa, sectional 1997 pesticide who reported pesticide use lifetime education, marital Ever use of OPs regression; North study applicators never having been pesticide exposure status, doctor associated with univariate and Carolina) (from who self- diagnosed with categories were: visits, alcohol use, diagnosed multivariable AHS) reported a depression/feel Low (<226 days), smoking, solvent depression in both models physician depressed > once median 225 days is exposure, not adjusted and diagnosed a week in past reference group); currently having unadjusted models depression year Intermediate (226- crops/animals, ever OR=1.7[1.22-2.38] 752 days); High (> working a job off and OR=1.78[1.27- 752 days above the the farm 2.50] respectively 90th centile). Also, acute high-intensity pesticide exposures (i.e. High Pesticide Exposure Event (HPEE) or physician diagnosed pesticide poisoning)

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AUTHOR: Bhatt et al 1999

TITLE: Acute and reversible parkinsonism due to organophosphate pesticide intoxication: Five cases

HYPOTHESIS: To describe five patients who developed acute and reversible parkinsonism following organophosphate (OP) pesticide exposure and to consider whether this syndrome represents a rare sequela of such exposure in genetically susceptible individuals

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type Data Date Study population Reference Measure of Other risk Outcome Narrative description of basic Statistical of collection of population exposure factors / bias / variables results methods study period study confounders India Case No 1999 5 patients n/a Self report of OP Possible Parkinsonism All patients developed None series information presenting with poisoning exposure to parkinsonism. Three patients provided recent OP (deliberate and other pesticide were exposed to pesticides exposure and accidental via oral compounds before onset of parkinsonism. symptoms of an or respiratory/ during Patients either recovered acute akinetic- dermal exposure application completely without treatment or rigid syndrome respectively) experienced repeated episodes of parkinsonism upon re- exposure to pesticide contaminated environment

21 THIS IS A DRAFT PAPER FOR DISCUSSION. IT SHOULD NOT BE QUOTED, CITED OR REPRODUCED

AUTHOR: Browne et al 2006

TITLE: Coding region paraoxonase polymorphisms dictate accentuated neuronal reactions in chronic, sub-threshold pesticide exposure

HYPOTHESIS: To reveal the relationship between environmental exposure and inherited sensitivity to OPs in an exposed population

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure of Other risk Outcome Narrative description of Statistical study collection of population population exposure factors / variables basic results methods period study bias / confounders Israel Cross- No 2006 291 male and No. of individuals Airborne spread of History of Neuro- [Neurophysiologic N=19; Students t- sectional information female rural / from urban areas pesticides, (to CNS related physiologic control =9]: Decreased test, non- provided agricultural with no history of provide diseases; (includes theta activity in various parametric workers from a exposure to anti- environmental history of EEG brain regions of exposed t-test; P rural community cholinesterases; exposure level data) acute analysis), individuals i.e. values where OPs are biochemical tested via use of pesticide neuro- hippocampus, routinely used analyses (n=91); litmus type test intoxication, psychological, parahippocampal regions e.g. fenitrothion, electro- impregnanted with age, sex, biochemical and cingulated cortex chlorpyrifos, encephalography cholinesterase education and genetic (known to play a role in monocrotophos, (EEG) analysis enzyme (screens for effects (via cholinergic-associated ethion, and (n=9); presence of genotyping cognitive functions). azinphos- neuropsychological cholinesterase for PON1 Increased beta activity in methyl test (n=24) inhibitors e.g. OPs); Q192R and prefrontal cortex of plasma PON1 L55M exposed individuals paraoxonase activity poly- (which is known to play a (as a marker* of OP morphisms) role in cholinergic- exposure); plasma associated cognitive cholinesterase functions); activity i.e. for AChE [Neuropsychological and BChE N=23; control =23]: (butylcholinesterase) Significant deficit in the delayed visual recall in exposed individuals; [Biochemical]: Increases in paraoxonase and arylesterase activities and reduced serum AChE activity in chronically exposed individuals

22 THIS IS A DRAFT PAPER FOR DISCUSSION. IT SHOULD NOT BE QUOTED, CITED OR REPRODUCED

AUTHOR: Buchanan et al 2002

TITLE: Clinical validation of methods of diagnosis of neuropathy in a field study of United Kingdom sheep dippers

HYPOTHESIS: To investigate the reproducibility (and hence reliability) of measured indices of chronic peripheral neuropathy from a field study of sheep dippers when compared with similar measurements carried out in a clinical setting

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data collection Date Study Reference Measure Other risk Outcome variables Narrative description of basic Statistical study period of population population of factors / bias results methods study exposure / confounders UK Clinical Field study: 2002 79 sheep n/a Reported Acute effects Neuropathy Half of subjects were assigned Cross sub- (winter farmers/ exposure from recent (measured in both similar classifications in the field tabulation; x2 study months); workers to sheep dipping the field and at the and clinic based on neuropathy tests of clinical exposed to dip clinic via symptoms scoring system. Grouped association, assessment: sheep dip questionnaire, symptom scores (i.e. grouped k-statistics (between 7 and sensory threshold into three categories that 18 months after tests - data corresponded to how it was used field study) subsequently scored) within the overall neuropathy scoring system) proved more reproducible than quantitative sensory test indicators

23 THIS IS A DRAFT PAPER FOR DISCUSSION. IT SHOULD NOT BE QUOTED, CITED OR REPRODUCED

AUTHOR: Burstyn et al 2009

TITLE: The virtues of a deliberately mis-specified disease model in demonstrating a gene-environment interaction

HYPOTHESIS: Fitting a deliberately mis-specified model that uses a Mendelian randomisation approach gives us a better chance of detecting biologically meaningful gene-environment interactions than a correct disease model

24 THIS IS A DRAFT PAPER FOR DISCUSSION. IT SHOULD NOT BE QUOTED, CITED OR REPRODUCED

AUTHOR: Camarinha et al 2011 (Abstract evaluated, Article in Portuguese)

TITLE: Auditory temporal processing assessment in rural workers exposed to organophosphate pesticides

HYPOTHESIS: To evaluate auditory temporal processing in workers occupationally exposed to OP pesticides

25 THIS IS A DRAFT PAPER FOR DISCUSSION. IT SHOULD NOT BE QUOTED, CITED OR REPRODUCED

AUTHOR: Carod-Artal and Speck-Martins, 1999 (Abstract evaluated, article in Spanish)

TITLE: Late onset polyneuropathy due to exposure to organophosphates

HYPOTHESIS: The risk of developing late onset neuropathy is not necessarily related to a history of acute intoxication

26 THIS IS A DRAFT PAPER FOR DISCUSSION. IT SHOULD NOT BE QUOTED, CITED OR REPRODUCED

AUTHOR: Catano et al 2008

TITLE: Plasma cholinesterase levels and health symptoms in Peruvian farm workers exposed to organophosphate pesticides

HYPOTHESIS: There are plasma cholinesterase changes and reported adverse health effects, largely associated with acute exposure, in a Peruvian agricultural population

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure of Other risk Outcome Narrative description Statistical study collection of population population exposure factors / bias / variables of basic results methods period study confounders Peru Preliminary Not 2008 213 78 healthy Self-reported Age, gender, Pesticide- PChE activity is a Mean levels of cross- specified agricultural volunteers exposure to body mass related useful indicator of PChE compared sectional workers without pesticides and any index (BMI), symptoms OP exposure in by Student t-test; study occupational incidence of years of work associated Peruvian agricultural mean levels and exposure to pesticide as an with acute workers; 15% of the SD of PChE and pesticides, poisoning, and agricultural exposure exposed population pesticide-related mainly bus report of using worker who reported a past symptoms, and conductors personal poisoning by past poisoning and teachers, protective pesticides had by pesticides; p recruited from equipment (PPE); significantly lower values reported the same rural blood samples to PChE levels; 61% areas as the check plasma who reported farm workers cholinesterase pesticide-related activity (PChE) symptoms did not have a significant difference in PChE, and use of PPE was significantly associated with higher PChE levels

27 THIS IS A DRAFT PAPER FOR DISCUSSION. IT SHOULD NOT BE QUOTED, CITED OR REPRODUCED

AUTHOR: Chao et al 2010

TITLE: Effects of low-level exposure to sarin and cyclosarin during the 1991 Gulf War on brain function and brain structure in US veterans

HYPOTHESIS: Veterans exposed to sarin/cyclosarin would show deficits on measures of short-term memory, attention, visuospatial abilities, and manual dexterity relative to their unexposed peers. Exposed veterans would also have reduced white matter and increased ventricular cerebral spinal fluid volumes compared to unexposed peers, and there may also be smaller hippocampal volumes in veterans with exposure

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure Other risk Outcome Narrative description Statistical study collection of population population of factors / bias / variables of basic results methods period stud exposure confounders y Iraq, Cross- Exposure 2010 40 Gulf War 40 veterans Plume Age, sex and Performance Exposed veterans had SPSS (Statistical (Khamisiya sectional occurred veterans selected modelling intracranial on neuro- reduced total grey Package for h)/US from 10 to drawn from from the of volume for MRI psychological matter volume, not Social Sciences), 13 March 230 veterans 190 estimated brain measures; test battery; white matter as version 17, used; 1991; who remaining release and gender, age, volumetric hypothesised; Kruskal-Wallis veterans participated in unexposed dispersion education, measurements they had smaller tests, chi square participated the study in veterans, of sarin and handedness, using MRI hippocampal volumes; tests, Spearman’s in the study San Fransisco matched to cyclosarin clinicially scans of brain exposure NOT correlation of effects of between 2002 the 40 around the assessed post- grey matter, associated with deficits coefficients, Gulf War and 2007; exposed Khamisyah traumatic stress white matter, of attention, memory, ANCOVA illness these 40 site disorder, major hippocampus, visuospatial abilities, or analyses of between veterans were depression, and manual dexterity; covariance; p 2002 and identified as chronic multi- cerebrospinal positive association values reported 2007 potentially symptom illness; fluid between total white for measures of having been also 6 “factor matter volume and brain volume and exposed to analysis-derived lower performance on neuropsychologic sarin/cyclosari syndromes”, for some al test n example neuropsychological performance and ‘confusion- tests. exposure and ataxia’ Marginal effect on neuropsychologic visuo-spatial memory al test not significant after performance exclusion of subjects testing positive for malingering

28 THIS IS A DRAFT PAPER FOR DISCUSSION. IT SHOULD NOT BE QUOTED, CITED OR REPRODUCED

AUTHOR: Chatterjee and Sarma, 2003

TITLE: Unusual neurological complications in a case of organophosphate poisoning

HYPOTHESIS: A rare combination of intermediate syndrome and delayed polyneuropathy may be present in a single patient

29 THIS IS A DRAFT PAPER FOR DISCUSSION. IT SHOULD NOT BE QUOTED, CITED OR REPRODUCED

AUTHOR: Cherry et al 2002

TITLE: Paraoxonase (PON1) polymorphisms in farmers attributing ill health to sheep dip

HYPOTHESIS: Organophosphates contribute to the reported ill health of people who dip sheep

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Locatio Type of Data Date of Study Reference Measure of Other risk Outcome Narrative Statistical n study collection study population population exposure factors / bias / variables description of basic methods period confounders results UK Case- July 1999 to 2002 175 cases of 234 farmers Self-reported Sex, region, Presence of Cases were more Odds Ratios referent May 2000 farmers with ill nominated by the dipping activity date of first polymorphisms likely than referents reported for study health that they cases as people in questionnaire dipping, age at position 192, to have at least one case status for attributed to who dipped and interview; position 55, and R allele at position polymorphism sheep dip sheep and were blood sample both positions 192, both alleles of s at positions not blood taken for PON1 192 and 55 of type LL, and to 192 and 55 of relatives, who genotyping and PON1 and have diazoxonase PON1; Odds they thought to to check reported ill activity below Ratios for be in good diazoxonase health in normal median; diazinonoxon health, who lived activity farmers results support the activity below near them, were hypothesis that the median, within 10 years of OPs contribute to and adjusted age of them, and the reported ill for position with similar health of sheep 192 and 55 sheep dipping dippers and activity to their diazinonoxon own activity

30 THIS IS A DRAFT PAPER FOR DISCUSSION. IT SHOULD NOT BE QUOTED, CITED OR REPRODUCED

AUTHOR: Cherry et al 2010

TITLE: ‘Dippers’ flu’ and its relationship to PON1 polymorphisms

HYPOTHESIS: Subjects carrying R alleles of the PON1 enzyme are more likely to report dippers’ flu, and there is an interaction between handling diazinon concentrate and genotype in the reporting of flu-like symptoms

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure of Other risk factors Outcome Narrative Statistical methods study collection of population population exposure / bias / variables description of period study confounders basic results UK case- dipping 2010 175 cases of 234 farmers Self-report of Bias - Presence of Farmers with the Mean exposures referen practices farmers with nominated by the ‘dippers’ flu’; no systematic polymorphisms 192R allele on compared by t tests, t study and ill health that cases as people self-reported study of features at positions 192 PON1 were more presence or absence symptoms they attributed who dipped dipping activity of dippers’ flu; and 55 and likely to complain of susceptibility recorded to sheep dip sheep and were in questionnaire problems with diazinon of dippers’ flu polymorphisms by for each from the not blood and interview, recall of hydrolysis; (DF); having the logistic regression, p year from original 2002 relatives, who to create symptoms over interaction 192R allele values for exposure 1970 to study, here they thought to cumulative 30 years; between increased the risk indices and dippers’ 2000 called the be in good exposure exposure genotype and of DF in those flu; univariate and ‘chronically health, who lived indices; blood misclassification handling handling diazinon multivariable unwell’ or near them, were sample for of diazinon or diazinon concentrate; analyses only for ‘chronic’ within 10 years of typing PON1 non-diazinon; concentrate those with the those who had group age of them, and polymorphisms referent group 192R allele in the handled diazinon with similar not group without concentrate, ORs for sheep dipping representative of chronic illness association of activity to their cohort of farmers developed DF dippers’ flu with own, here called who began symptoms in a genotype, handling the ‘not chronic’ dipping years shorter time concentrate, and series previously their interaction

31 THIS IS A DRAFT PAPER FOR DISCUSSION. IT SHOULD NOT BE QUOTED, CITED OR REPRODUCED

AUTHOR: Chuang et al 2002

TITLE: Delayed neuropathy and myelopathy after organophosphate intoxication

HYPOTHESIS: In a classic acute cholinergic crisis after poisoning the patient develops delayed neuropathy

32 THIS IS A DRAFT PAPER FOR DISCUSSION. IT SHOULD NOT BE QUOTED, CITED OR REPRODUCED

AUTHOR: Colosio et al 2009

TITLE: Neurobehavioural effects of pesticides with special focus on organophosphorus compounds: Which is the real size of the problem?

Date of Review 2009

Aim To report on the risk of neurobehavioural impairment as a consequence of a prolonged, low dose exposure to neurotoxic pesticides

Topics covered Review of 24 papers published up to May 1st 2008 on human neurobehavioural effects of organophosphorus and/or carbamate pesticides

Health Functional areas considered are cognitive, sensory-motor, psychological and psychomotor outcomes considered

Original studies All relevant studies identified; other studies did not meet inclusion criteria (pre-dated 1999, or were reviews) not identified in literature search

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AUTHOR: Cox et al 2005

TITLE: Evaluation of potential adverse health effects resulting from chronic domestic exposure to the organophosphate insecticide methyl parathion (MP)

HYPOTHESIS: Residents whose homes were illegally sprayed with MP may suffer adverse health effects, and if adverse health effects are found, an attempt is made to determine at what exposure levels these occurred

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure of Other risk Outcome Narrative Statistical methods study collection of population population exposure factors / bias / variables description of basic period study confounders results US Case 1996 2005 121 subjects Ccontrol 10cm-square Comparison of Respiratory, No differences ANOVA and t tests (Mississippi) series from 49 homes group of 170 wipe samples sex distribution, gastrointestinal found in symptom to compare in the state of subjects from taken of flat mean age and and reporting, continuous data; Mississippi with 56 homes in surfaces in age distribution neuropsychiatri cholinesterase Bonferonni test to high levels of state of different rooms in the 2 groups; c symptoms (53 levels or physician determine methyl Mississippi in each house, exposure to different evaluation for sub- significance in parathion (MP), with non- and results tobacco smoke, symptoms) as a acute or chronic multiple groups; >150μg/100cm² detectable or averaged; second hand result of MP toxicity between logistic regression very low- samples tobacco smoke, being sprayed subjects in to compare levels of MP, analysed for number of in the house; exposure and findings for groups, <15μg/100cm MP using gas hours spent in cholinesterase control group; p values reported ² chromatograph homes, number activity in blood subjects in homes for frequency of y and mass of times homes samples with very high symptoms between spectrometry were sprayed levels of MP may groups, and OR of and how long have increased increased ago incidence of frequency of chronic symptoms, symptoms in primarily homes with highest neuropsychological levels of MP

34 THIS IS A DRAFT PAPER FOR DISCUSSION. IT SHOULD NOT BE QUOTED, CITED OR REPRODUCED

AUTHOR: Crawford et al 2008

TITLE: Hearing Loss among Licensed Pesticide Applicators in the Agricultural Health Study

HYPOTHESIS: To investigate the association between pesticide exposures and self-reported hearing loss among private pesticide applicators in the Agricultural Health Study (AHS), and to determine whether exposures to pesticides in general, to classes of pesticide, and to individual pesticides were associated with hearing loss among cohort members

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure of exposure Other risk Outcome Narrative description of basic Statistical methods study collection of population population factors / bias variables results period study / confounders US Case- 1993- 2008 4926 9303 Lifetime days of State, age, Hearing Compared to no exposure the Logistic regression control 1997 licensed subjects pesticide use via exposure to loss OR for the highest quartile of using hearing loss (nested) private who questionnaire. This noise, exposure (i.e. >129.5 (based on as the dependent pesticide answered was further classified/ solvents and reported non-intensity-adjusted variable; odd ratios applicators no to categorised into non-farm cumulative lifetime days of use) and 95% CIs are with self hearing functional groups i.e. metals was 1.17(1.03-1.31) for OP reported; p-values reported loss insecticides (10 being insecticides. Other exposure (2-sided) for trend hearing loss question OPs); exposed quartiles yielded non-significant for cumulative days subjects categorised mildly increased odd ratios; of pesticide use in tertiles with ref OPs showed the strongest calculated; two- category = those associations with hearing loss as stage hierarchical reporting zero a class of insecticide; results of logistic regression exposure thereby individual OP analyses used to increase resulting in 4 (intensity-weighted days of use) precision when exposure categories showed that associations with evaluating multiple hearing loss were elevated individual (ORs > 1.2 for at least one pesticides category of use) for various OPs (malathion, fonofos, diazinon, phorate and parathion) with significant trends (p<0.05) noted for others (i.e. diazinon, fonofos, phorate and terbufos)

35 THIS IS A DRAFT PAPER FOR DISCUSSION. IT SHOULD NOT BE QUOTED, CITED OR REPRODUCED

AUTHOR: Dahlgren et al 2004

TITLE: Health Effects of Diazinon on a Family

HYPOTHESIS: To report on a family (specifically the children) who experienced an acute overexposure to diazinon followed by permanent sequelae

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type Data Date Study Reference Measure of Other risk Outcome variables Narrative description of basic Statistical of collection of population population exposure factors / bias results methods study period study / confounders US Case June 2004 Family of n/a Acute diazonin No Neurological, Chronic neurological symptoms No series 1999 seven (2 exposure and information neurophysiological evident after 3 year follow-up: information (with 3 parents and 5 clinical poisoning provided and persistent neurological effects provided mo/ 3 children) NB. Authors were neuropsychological (e.g. memory loss, decreased year exposed to unable to deficits concentration, irritability, follow-up) diazinon determine the personality changes, impaired following quantity of balance, reaction time, colour mistaken diazinon applied vision and slotted pegboards application to in the home. The and trials making) and interior by diazinon was neuropsychological effects pesticide diluted; the family (e.g.cognitive disorder and company left the home 2 psychomotor dysfunction) days after exposure; exposure assessed via wipe, air and bulk sampling

36 THIS IS A DRAFT PAPER FOR DISCUSSION. IT SHOULD NOT BE QUOTED, CITED OR REPRODUCED

AUTHOR: Das et al 2011

TITLE: Role of familial, environmental and occupational factors in the development of Parkinson’s Disease

HYPOTHESIS: Genetic, environmental and occupational factors may play a role in the development of Parkinson’s Disease, with the following risk factors examined in detail: place of living, family history of PD and tremor, source of drinking water, exposure to insecticides, pesticides, herbicides and industrial toxins, acute OP poisoning, CNS infections and head injury

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure of Other risk Outcome Narrative Statistical methods study collection of population population exposure factors / bias / variables description of period study confounders basic results India (W. Case- January 2011 345 cases of 370 controls (220 Self-reported Multiple factors Parkinson’s The factors Logistic regression Bengal) control 2003 to idiopathic males, 150 exposure to were included Disease found to be analysis January Parkinson’s females, mean environmental in the study, associated with considering an 2008 Disease (215 age 62±3 years), risk factors; with each the association males, 130 age-matched±3 PD diagnosis factor analysed development of between PD and females, years and sex- clinically separately. A PD in this region multiple factors; mean age matched, confirmed by history of of India were estimated 62±2 years) selected from neurologist addiction family history of coefficient values in persons factors was PD and familial the logistic accompanying included, which tremor, regression equation the cases, considered exposure to are reported, p patients attending smoking insecticides and values, and the general neurology habits, alcohol pesticides, well 95% CI for the or medicine intake, and water use for difference of department of the coffee and tea drinking proportion hospital, or intake purposes, relatives of cases. Japanese B Controls had encephalitis, neither significant and acute OP neurological or poisoning medical illness

37 THIS IS A DRAFT PAPER FOR DISCUSSION. IT SHOULD NOT BE QUOTED, CITED OR REPRODUCED

AUTHOR: Dassanayake et al 2007

TITLE: Cognitive processing of visual stimuli in patients with organophosphate insecticide poisoning

HYPOTHESIS: To determine the effect of OP insecticide poisoning on cognitive processing time (CPT) of visual stimuli

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type Data Date Study population Reference Measure Other risk Outcome variables Narrative description of Statistical of collection of population of factors / bias / basic results methods study period study exposure confounders Sri Case- May 2007 33 patients who 33 age and Clinically Alcohol, Psychomotor CPT of simple visual Mean and Lanka control 2004 to recovered from sex-matched diagnosed tobacco and abnormalities detected reactions and SD; non- Feb 2006 cholinergic phase controls of OP coffee via calculation of CPT – recognition visual paired t-test of OP insecticide similar social patients consumption, defined as the time reactions were (two sided) poisoning (via background lack of sleep taken from the initial significantly prolonged assessed at ingestion). with no acute cortical perception of a in patients, e.g. mean the 5% Recovery was poisoning stimulus to initiation of difference (ms) being significance approx 15 days history or the descending motor 29.2(5.33-53.01) and level after poisoning chronic OP impulse. CPT is 59.97(18.96-100.97) (range from 4 to exposure Calculated indirectly by respectively. (Also 47 days) subtracting sum of P100 corroborated by the depending on time and the Total Motor reaction time results). to recovery from Conduction Time NB. P100 latency and the acute stage of (TMCT) from the visual TMCT were not poisoning reaction time significantly different between groups

38 THIS IS A DRAFT PAPER FOR DISCUSSION. IT SHOULD NOT BE QUOTED, CITED OR REPRODUCED

AUTHOR: Dassanayake et al 2008

TITLE: Long-term event-related potential changes following organophophorus insecticide poisoning

HYPOTHESIS: To determine prolonged effects of OP insecticide poisoning on cognitive event-related potentials (ERPs)

STUDY DESCRIPTION EXPOSURE & HEALTH RESULTS OUTCOME Location Type Data Date Study Reference population Measure of Other risk Outcome Narrative description of Statistical of collection of population exposure factors / bias / variables basic results methods study period study confounders Sri Case- Jan 2005 2008 32 patients Two control groups (matched Clinical Alcohol, Cognitive OP patients showed Students non- Lanka control to Sept recovered for age and sex): a) 32 healthy diagnosis of tobacco and event – highly significant paired t-test, 2006 from volunteers; b) 9 patients acute OP coffee related prolongation of P300 One way (with 6 cholinergic hospitalised with paracetomol insecticide consumption, potentials latency cf. controls (e.g. ANOVA, month phase of OP overdose (to match the general poisoning lack of sleep (ERPs) healthy controls Bonferroni test, follow-up) insecticide wellbeing and psychological p=0.003) mean paired t-test. All poisoning status of the test group at time difference (ms) (and two-sided and of neurophysiological 95% CI) = 39.9(13.7 to assessed at the assessment). NB. 66.0); follow-up ERP 5% significance Paracetamol was chosen due findings (in 21 patients, level to its lack of direct action on 6 months after OP cognitive function intoxication) revealed that the impairment remained unchanged

39 THIS IS A DRAFT PAPER FOR DISCUSSION. IT SHOULD NOT BE QUOTED, CITED OR REPRODUCED

AUTHOR: Dassanayake et al 2009

TITLE: Auditory event-related potential changes in chronic occupational exposure to organophosphate pesticides

HYPOTHESIS: To determine whether chronic occupational exposure to OPs leads to cognitive impairment using event-related potentials (ERPs)

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure of Other risk factors Outcome variables Narrative description Statistical methods study collection of population population exposure / bias / of basic results period study confounders Sri Cross- Sept 2009 35 35 controls Long-term Alcohol, coffee, Neurocognitive Farmers made Mixed model ANOVA Lanka sectional 2007 – vegetable (male hospital occupational tobacco, lack of impairment significantly more (to initially compare Feb 2008 farmers labourers who exposure to sleep, recent (interpreted from counting errors cf. ERP component (male) do not handle OP pesticides handling of auditory oddball controls in the latencies between applying any (> 5years). agrochemicals; ERPs, which oddball task. groups) with OP agrochemicals) Formulations history of acute provide a Farmers also had a subsequent pesticides used by the OP poisoning neurophysiological greater delay in later comparisons of farmers requiring medical correlate of ERP components group differences of included care, hearing cognitive e.g. mean difference latencies of each dimethoate, impairment, pre- processing of in counting errors component made chlorpyrifos, existing illness/ information) (and 95% CI) using Students t-test; quinalphos, medication that between farmers Stepwise Bonferonni profenophos, may predispose and control for the correction procedure phenthoate, to cognitive following ERP for multiple fenitrothion dysfunction, components were comparisons; and fenthion random blood as: P200 = 8(1.4- analysis of glucose levels 17.4); covariance N200=14.2(2.4-25.9) (ANCOVA) to partial and P300 latency out variance in the =32.1(14.1-50.0) component of interest associated with variance in the immediately preceding component

40 THIS IS A DRAFT PAPER FOR DISCUSSION. IT SHOULD NOT BE QUOTED, CITED OR REPRODUCED

AUTHOR: Davies et al 1999

TITLE: Chronic organophosphate induced neuropsychiatric disorder (COPIND): Results of two postal questionnaire surveys.

HYPOTHESIS: To address the anecdotal nature of evidence obtained in studies investigating COPIND in particular the lack of controls

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study population Reference population Measure Other risk factors Outcome Narrative description Statistical study collection of of / bias / variables of basic results methods period study exposure confounders UK Cross- Information 1999 Study 1: 130 Study 1: 45 randomly Self Use of different Neuropsychiatric Study 1: Highly Chi- sectional not randomly selected selected farmers not reported questionnaires, symptomology significant difference squared provided farmers exposed exposed to OPs (i.e. OP patients with (as assessed via in reporting of test (to to OPs (i.e. answered ‘No’ to exposure medically symptom scores) symptoms compare answered ‘Yes’ to whether they were unexplained exposed whether they exposed to OPs over symptoms more Study 2: Significant and non- were exposed to 10 years prior to likely to return similarities in exposed OPs over 10 receipt of questionnaire symptom profiles symptom years prior to questionnaire) between individuals scores) receipt of from disparate questionnaire) Study 2: 32 farmers/ occupational COPIND concerned backgrounds whose Study 2: 179 individuals registered common factor is COPIND on OPIN who had had organophosphate concerned no involvement with exposure individuals sheep dipping (but registered on exposed via other OPIN who had ways) i.e. arable been exposed farmers, market through sheep gardeners, pest dipping control workers, pet enthusiasts (flea treatment), delivery drivers, Gulf War veterans and water from a OP contaminated well)

41 THIS IS A DRAFT PAPER FOR DISCUSSION. IT SHOULD NOT BE QUOTED, CITED OR REPRODUCED

AUTHOR: de Araujo et al 2007 (Abstract evaluated, article in Portugese)

TITLE: Multiple exposure to pesticides and impacts on health: a cross-section study of 102 rural workers

HYPOTHESIS: Farmers have multiple exposures to different pesticides, giving rise to delayed neuropathy or neurobehavioural or psychiatric outcomes in a percentage of workers

42 THIS IS A DRAFT PAPER FOR DISCUSSION. IT SHOULD NOT BE QUOTED, CITED OR REPRODUCED

AUTHOR: Delgado et al 2004 (Scand J Work)

TITLE: Central nervous system effects of acute organophosphate poisoning in a two-year follow-up

HYPOTHESIS: To follow-up a cohort of patients hospitalised for acute OP poisoning to test the hypothesis of chronic CNS damage from overexposure to OP (i.e. high enough to result in clinical poisoning) and provide information on the evolution of CNS changes and their resolution over time

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type Data Date Study Reference Measure of Other risk factors / Outcome Narrative description Statistical methods of collection of population population exposure bias / confounders variables of basic results study period study Nicaragua Cohort July 1992 to 2004 53 persons 28 Low Age, education, Immediate verbal Immediate verbal Longitudinal Dec 1996 hospitalised persons (moderate lifestyle, general memory, visual memory: deficits in confounder Follow-up I: for acute OP never occupational), health and other motor high exposure group adjusted between at time of poisoning poisoned Med (severe previous neurotoxic performance and (esp at time of category discharge; occupational), exposures, alcohol neuropsychiatric discharge); visual comparisons and Follow-up II: High (severe consumption, loss symptoms motor performance: longitudinal 7 weeks via oral route) of consciousness deficit at 7 weeks in analysis of variance post for over 30 mins medium exposure and covariance poisoning and diagnosed by a group improving after used to assess and Follow- physician, 2 years; effects of exposure up III: 2 occupational neuropsychiatric i.e. two-way years post exposure to symptoms: in excess analyses of poisoning vibrating machinery, of 2 years in low and variance and of history of chronic medium exposure covariance and diseases groups linear regression analyses; mean values and SD reported and mean differences in the changes and their 95% CIs

43 THIS IS A DRAFT PAPER FOR DISCUSSION. IT SHOULD NOT BE QUOTED, CITED OR REPRODUCED

AUTHOR: Dick et al 2001

TITLE: Evaluation of acute sensory-motor effects and test sensitivity using termiticide workers exposed to chlorpyrifos

HYPOTHESIS: To evaluate the sensitivity of several specifically selected measures of sensory and motor functions using urinary TCP (3,5,6- trichloro-2-pyridinol) as a measure of current exposure to chlorpyrifos

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure of Other risk factors Outcome variables Narrative Statistical study collection of population population exposure / bias / description of methods period study confounders basic results US Cross- May – 2001 106 termiticide 52 non- Urinary Age, gender, Acute sensory and Limited acute Correlation (North sectional Jun 1998 workers (65 exposed concentrations of education, race, motor effects e.g. effects from analysis, Carolina) current and participants TCP (as a smoking and olfactory dysfunction, exposure to Bonferroni former) (same gender measure current alcohol visual acuity, contrast chlorpyrifos; Correction , primarily using friends and exposure). NB. consumption, sensitivity, colour other tests failed P≤ 0.05, chlorpyrifos blue collar TCP levels were medical history vision, vibrotactile to show any MADD, containing worker) measured on day esp. chronic sensitivity, tremor, evidence of products of sensory and sensory/motor manual dexterity, eye acute exposure motor testing ailments hand co-ordination, effects; visual postural stability. NB. measures were Tests used are not significant considered appropriate to detect both acute and chronic, sensory and motor effects from pesticide exposures

44 THIS IS A DRAFT PAPER FOR DISCUSSION. IT SHOULD NOT BE QUOTED, CITED OR REPRODUCED

AUTHOR: Dunn, 2002 (abstracted from the reference list of a review paper by Povey, 2010)

TITLE: Analytical study of sheep dip reports

HYPOTHESIS: To explore patterns of exposure and clinical presentation in the database of all suspected adverse reactions (SARS) reports reported to the Veterinary Medicines Directorate (VMD)

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure of Other risk Outcome variables Narrative description of basic Statistical study collection of population population exposure factors / bias results methods period study / confounders UK Analytical Not 2002 646 reports n/a Quantitative Age, onset of Commonly reported Only 95 reports were Pearson’s chi- (descriptive specified of SARs to levels of both ill-health, symptoms (in order of supported with a consultant’s square statistic; and OP sheep short-term year of decreasing diagnosis, of which by far one degree of exploratory) dip held on and long-term report, prevalence) were the most common diagnosis freedom chi the SARs exposures missing data nervous disorders (e.g. was depression (29 cases) square test of database determined on explicit headache, dizziness, with 5 cases of chronic trend; from exposures paraesthesia), general fatigue syndrome and 5 Spearman’s database info disorders (e.g. fatigue, cases of anxiety; cessation rank (via algorithm influenza and of exposure was found to be correlation; suggested by lethargy), associated with either logistic Dr John gastrointestinal improvement or recovery; regression; Cherrie) disorders (e.g. nausea levels of co-morbidity for Pearson’s and diarrhoea), individual pairs of symptoms product- psychiatric disorders were not very high, although moment (e.g. depression and reports of nausea and correlation; amnesia), dizziness, and those for Principal musculoskeletal depression and memory-loss component disorders (e.g. were associated; psychiatric analysis arthralgia and disorders (particularly myalgia), respiratory depression) and disorders (e.g. musculoskeletal disorders dyspnoea), skin (particularly myalgia) had disorders, infections highly statistically significant and infestations, and associations with both short eye disorders and long term exposures

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AUTHOR: Elbaz et al 2009

TITLE: Professional exposure to pesticides and Parkinson Disease (PD)

HYPOTHESIS: There may be an association between Parkinson’s Disease and professional exposure to pesticides in a population with a high prevalence of exposure, and that association may be with specific pesticide families or with specific pesticides

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Locatio Type of Data Date Study Reference Measure of Other risk Outcome Narrative description Statistical methods n study collection of population population exposure factors / bias / variables of basic results period study confounders France Community Patients with 2009 224 cases 557 controls Self-reported Analyses were PD The study reports an Complete-case -based PD had from the who were exposure on stratified by association between analyses conducted case- applied for Mutualité affiliates of the questionnaire sex, median PD and overall using conditional control healthcare Sociale same health and in age at onset/ professional logistic regression; from Agricole in insurance, free interview index age, and pesticide use in multiple imputation February France who of PD, ahd who median men, and also a analysis also 1998 to had applied had requested disease positive association performed, with August 1999; for reimbursement duration; all with professional missing values controls had healthcare for health- analyses were exposure to replaced by plausible applied for for PD from related adjusted for insecticides; for values based on health- February expenses from gicatette exposure specifically observed data for that related 1998 to February 1998 smoking to OP insecticides, variable,using logistic expenses August 1999 to February (pack-years) ORs are more than regression model; from 2000 and for the 1, but 95% CIs all ORs and 95% CIs February results of the include 1 reported, and p value 1998 to Mini Mental for trend in exposure February State to categories of 2000 Examination pesticides (MMSE), a test (insecticides/ used to assess fungicides/ cognitive herbicides) impairment

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AUTHOR: Engel et al 2001

TITLE: Parkinsonism and occupational exposure to pesticides

HYPOTHESIS: There is a potential risk of parkinsonism related to lifetime occupational exposure to pesticides among a cohort of men, mostly orchardists, in Washington State

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure of Other risk Outcome Narrative description Statistical methods study collection of population population exposure factors / bias / variables of basic results period study confounders US Cohort Original 2001 238 exposed 72 non-exposed Self- Adjustments parkinsonism A significant PR A generalised linear (Washing cohort subjects from subjects reported made for age (Prevalence Ratio) model with binomial ton State), members the original identified from a exposure and pack- was found for distribution was enrolled cohort, whose City Directory, years of subjects in the used to estimate 1972-76; occupations frequency smoking highest tertile of prevalence ratios subjects in were: matched with years of exposure to (PRs) with 95% CIs current orchardists, exposed pesticides, but a study professional subjects by age, trend test did not invited to pesticide race, and show a significant participate applicators, degree of exposure-response in summer pesticide occupational relation, and no 1997 formulation physical activity; increased risks were plant workers, occupations found associated other farm or included with specific agricultural construction pesticides or workers workers, lorry pesticide classes drivers, road workers, roofers, salesmen

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AUTHOR: Farahat et al 2003

TITLE: Neurobehavioural effects among workers occupationally exposed to organophosphorus pesticides

HYPOTHESIS: To identify neurobehavioural deficits among workers exposed to OP pesticides in their occupation

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study population Reference Measure of Other risk Outcome Narrative Statistical methods study collection of population exposure factors / variables description of basic period study bias / results confounders Egypt Cross- June to 2003 52 occupationally 50 unexposed Questionnaire; Age, Neurobehavioral Exposed subjects SEM; multiple sectional Sept 2000 exposed male male controls AChE activity education and personality exhibit significantly regression analysis (time workers (exposed (clerks and (used to provide deficits which lower performance (of neurobehavioural when to either one or a administrators) a marker for OP included than controls on performance by pesticides combination of exposure, assessment of neurobehavioural duration of were two or three of although limited neurological tests including exposure); applied to the OP by fact that sensory and motor visuomotor speed, prevalence (%) and function cotton carbamate or carbamates verbal abstraction, odd ratios of crops in pyrethroid also inhibit attention and symptoms and sign the field) insecticides). AChE) memory in exposed and Pesticides used control participants for spraying p- values < 0.05 cotton crops considered included the significant; 95% CI following OPs: (for differences profenofos, between means) chlorpyrifos, triaziphos and phorate

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AUTHOR: Finkelstein Y et al 2010

TITLE: Peaceful use of disastrous neurotoxicants

HYPOTHESIS: Low-level OP exposure is associated with neuropsychological deficits.

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AUTHOR: Firestone et al 2005

TITLE: Pesticides and Risk of Parkinson Disease

HYPOTHESIS: To investigate associations between pesticide exposures and idiopathic Parkinson’s Disease (PD)

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AUTHOR: Fletcher et al 2005

TITLE: SHAPE: Survey of Health and Pesticide Exposure Telephone Survey

HYPOTHESIS: Sheep farmers and others exposed to OP formulations have experienced chronic illness as a result of their exposure

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study population Reference Measure of Other risk Outcome Narrative Statistical methods study collection of population exposure factors / bias / variables description of period study confounders basic results UK Cross- Telephone 2005 367 individuals who No suitable Self-reported Limitation that Descriptive Overall, people SPSS procedure sectional interviews had reported being control exposure on study overview of who reported “HOMALS” used to from July to exposed to OPs to group questionnaire, participants reported ill- having had an do multiple November 4 support groups: identified including report were self- health: overall acute response to correspondence 2001 Action on Pesticide of having had selected; health status, OPs reported analysis (MCA), a Exposure, Northern an acute OP possible and list of 32 more symptoms review of multiple Ireland OP exposure confounders reported than those who pair-wise Sufferers episode in 4 out gender, age, physical and did not. associations Association, OP of 5 cases; ever mental For most between symptoms; Information report of experienced symptoms variables, there ORs of associations Network, and OP exposure to acute was no evidence between symptoms Users Support sheep dip or to response to of an association from the same Group. Many of the other OP OP exposure, with sheep dip OP group in the neuro- individuals were exposure smoking, age exposure behavioural, sheep dippers or at which neuropathological exposed to finished full- and autonomic agricultural time symptom groups; chemicals education, logistic regression alcohol use and ORs of reporting any symptoms in those reporting ever having had an acute response

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AUTHOR: Fonseka et al 2003

TITLE: Self-limiting cerebellar ataxia following organophosphate poisoning

HYPOTHESIS: A cerebellar disorder can develop after OP poisoning

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AUTHOR: Friedman et al 2003

TITLE: Creatine phosphate kinase elevations signalling muscle damage following exposure to anticholinesterases: 2 sentinel patients

HYPOTHESIS: Elevations in creatine phosphate kinase (CPK), detected more than a decade following the first acute exposure, in 2 workers who experienced exposure to anticholinesterases that commenced in the 1970s, were sentinel events for impending muscle damage and necrosis

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study population Reference Measure of exposure Other risk Outcome Narrative description Statistical study collection of population factors / bias / variables of basic results methods period study confounders US Case 1998 2003 Patient 1 was a 42- N/a Both patients were N/a N/a Elevations in CPK N/a reports year old male hospitalised in 1982 and myopathy in the reporting muscle after acute inhalation 2 patients indicated aches and pains, exposure to IMPF muscle damage and muscle weakness (isopropyl impending necrosis and chronic fatigue methylphosphono- from past exposures in 1998; fluoridate); only patient to anti- patient 2 was a co- 1 also had intermittent cholinesterases; worker referred by exposure to OP findings lend support patient 1, with insecticides over 10 to the hypothesis myalgia, nonspecific years through that nonspecific myopathy and agricultural spraying; myopathy in Gulf depression blood tests between War veterans is a 1993 and 1997 revealed prodromal state prior high CPK levels to the appearance of CPK

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AUTHOR: Friedman et al 2007

TITLE: Latency: An important consideration in gulf war syndrome

Date of Letter 2007

Aim To respond to a study by Heaton et al 2007 reporting latent anatomical changes in brains of US soldiers years after sarin exposure

Topics covered Limitations of Gulf War Syndrome (GWS) research especially the use of plume models Potentiation of Sarin effects by pyridostygmine Association between chemical agent exposure and lasting neuromyopathic deficits in GWS in US veterans Health outcomes Neuromyopathic deficits considered

Original studies Studies referenced in this letter did not meet inclusion criteria (i.e. focus on exposure, mechanism/biomarker, clinical experience or general GW health) not identified in literature search/ (not included in selected refs)

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AUTHOR: Garcia-Martin et al 2010

TITLE: Paraoxonase 1 (PON1) polymorphisms and risk for essential tremor

HYPOTHESIS: PON1 genotype and allelic variants of the polymorphisms Leu55Met and Glu192Arg increases the risk of essential tremor

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AUTHOR: Gatto et al 2009

TITLE: Well-water consumption and Parkinson’s Disease in rural California

HYPOTHESIS: Consumption of water from private wells, located in areas with documented historical agricultural pesticide use, is associated with an increased risk of Parkinson’s Disease (PD) among residents of the Central Valley of California

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure of Other risk Outcome Narrative Statistical methods study collection of population population exposure factors / bias / variables description of period study confounders basic results US Case- Subjects 2009 368 cases 341 population Geographic Age, race, sex, Parkinson’s Cases were more SAS version 9.1 (California) control recruited diagnosed controls who information system education, Disease likely to have used; multivariable between as clinically were at least (GIS)-based model family history of consumed private unconditional January probable or 35 years of using geocoded PD, smoking; in well water, and on logistic regression 2001 and possible PD age, residing residential historical some models, average 4.3 years to calculate ORs January who lived in primarily in addresses (all adjustment for longer than between possible 2007; years Fresno, one of the 3 addressed ambient controls (p value exposure to 6 covered Tulare or counties, and inhabited between exposure to a given). High individual pesticides were 1974 to Kern had lived in 1974 and 1999), given pesticide levels of possible (including the OPs 1999, the County, and California for information of well-water diazinon, period had lived in at least 5 application to cotamination with chlorpyrifos and covered by California for years before agricultural crops chlorpyrifos dimethoate) from PUR at least 5 the screening from California increased the risk well water (pesticide years pesticide use of PD (OR consumption and use report) reports (PURs) for reported). PD; data for 1974-1999 and Exposure to for OPs as a group, California land-use maps, and higher number of p-values for trend data on well-water water-soluble and reported consumption from to OP pesticides interviews with also increased subjects risk of PD

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AUTHOR: Gauthier et al 2001

TITLE: Environmental pesticide exposure as a risk factor for Alzheimer’s Disease: a case-control study

HYPOTHESIS: Pesticide exposure has an influence on the development of Alzheimer’s Disease (AD)

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data collection Date Study population Reference Measure of Other risk Outcome Narrative Statistical study period of population exposure factors / bias / variables description of methods study confounders basic results Canada Case- Not specified; 2001 68 cases drawn 68 paired non- Environmental Education Diagnosed Results failed logistic (Quebec) control data from from 1924 study demented exposure based on level, AD, based on to show a regression Agricultural participants, controls, data from presence of screening for significant risk using SAS Census of who were matched for age Agricultural Census family cases, cognitive of AD with an software, Statistics randomly +/- 2years and of Statistics Canada ApoE ε4 allele, impairment, exposure to ORs and Canada used selected from sex and from the occupational determination herbicides, 95% CIs for the years files of the Quebec Department exposure whether insecticides reported for 1971-1991 provincial health of Forestry for each subject had and pesticides risk of AD plan of Quebec municipality, to dementia, and and establish areas using criteria exposure to sprayed with for probable herbicides, herbicides and and possible insecticides insecticides; AD to identify and subject’s residential the disease pesticides history; self- responsible for reported the dementia occupational exposure on questionnaire

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AUTHOR: Goel et al 2006

TITLE: Magnetic resonance imaging changes in a case of extra-pyramidal syndrome after acute organophosphate poisoning

HYPOTHESIS: An uncommon intermediate neurological complication of extra-pyramidal syndrome, with features of Parkinsonism and dystonia (muscle spasms), can develop after OP poisoning

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date of Study Reference Measure of Other risk Outcome variables Narrative description of Statistical study collection study population population exposure factors / bias / basic results methods period confounders India Case Date of 2006 21-year old N/a Clinical signs N/a Symptoms of Patient developed N/a report poisoning female who and symptoms acute OP Parkinsonism on 10th day not given, ingested reported by poisoning; of acute poisoning with though pesticide hospital Parkinsonism novel MRI abnormality in symptoms containing developed on 10th striatal nuclei; this is an are dichlorvos day of poisoning; uncommon intermediate described MRI abnormality in syndrome complication. over a 10- striatal nuclei Patient had fast clinical week observed recovery with treatment, period though some mild limb dyskinesia (difficulty performing voluntary movements) persisted after 10 weeks

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AUTHOR: Gomez et al 2010 (Abstract evaluated, Article in Spanish)

TITLE: Toxicity by organophosphate insecticides of fumigators working on the dengue control campaign in Aragua state, Venezuela

HYPOTHESIS: (Not clear) A descriptive study of the health of fumigators exposed to pesticides in dengue control operations

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AUTHOR: Hancock et al 2008

TITLE: Pesticide exposure and risk of Parkinson’s disease: A family-based case-control study

HYPOTHESIS: There is an association between self-reported direct pesticide application and Parkinson’s Disease (PD)

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of study Data Date Study Reference Measure of Other risk Outcome Narrative Statistical collection of population population exposure factors / bias / variables description of methods period study confounders basic results US Family based 2000 to 2008 319 cases 252 relative Self-reported Age-at- PD Direct application SAS version 8e case-control 2006 recruited by the controls from the direct pesticide examination, of OP used, to model Udall PD 308 families with application; sex, cigarette compounds was associations Research at least one recalled smoking, found to be between Center, from case, and 44 pesticide caffeine significantly pesticide 308 families spouse or other products were consumption associated with exposure and PD unrelated classified into PD using population- controls, or functional averaged relative controls types and generalised in families with chemical estimating no environmental classes, equations (GEE); risk factor data including OPs OR reported for available on the association of case – 296 childhood and controls in all adulthood direct application of OPs with PD

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AUTHOR: Hanna et al 1999

TITLE: Multiple system atrophy

HYPOTHESIS: There is a possible role of environmental toxins in multiple system atrophy

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AUTHOR: Hashim et al 2011

TITLE: Parkinsonism complicating acute organophosphate insecticide poisoning

HYPOTHESIS: Parkinsonism may be an uncommon sequel following OP poisoning

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AUTHOR: Hayden et al 2010

TITLE: Occupational exposure to pesticides increases the risk of incident AD

HYPOTHESIS: Occupational pesticide exposure increases the risk of incident dementia and Alzheimer’s Disease (AD) in later life

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data collection Date Study population Reference Measure of Other risk Outcome Narrative Statistical study period of population exposure factors / bias / variables description of methods study confounders basic results US (Utah) Cohort Baseline was 2010 3,084 residents 2,512 of the Self-report on Baseline age Dementia OP exposure SAS software January 1995, of Cache County 3,084 structured centred at 65, and AD was used; Cox follow-up after aged 65 or older residents questionnaire sex, education associated proportional 3, 7 and 10 in 1995, without who were about level in years, with an hazard ratios years dementia at unexposed to occupational APOE ε4 status, increased risk calculated to baseline, who pesticides exposure and baseline of dementia assess provided self- associated Modified Mini- and AD, relationship report exposures to Mental State although the between prior information pesticides; Examination risk of pesticide/OP about pesticide exposure to OPs score dementia did exposure and the exposures; as a group was not reach risk of incident 572 were considered significance dementia and AD, exposed to and for AD using unexposed pesticides was only participants as the marginally reference group. significant Hazard Ratio (HR) (lower bound and 95% CI of 95% CI was reported 1.05)

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AUTHOR: Heaton et al 2007

TITLE: Quantitative magnetic resonance brain imaging in US army veterans of the 1991 Gulf War potentially exposed to sarin and cyclosarin

HYPOTHESIS: There is an association between modelled estimates of sarin/cyclosarin exposure levels and volumetric measurements of gross neuroanatomical structures in 1991 Gulf War veterans with varying degrees of possible low-level sarin/cyclosarin exposure

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study population Reference Measure of Other risk factors Outcome Narrative Statistical study collection of population exposure / bias / variables description of methods period study confounders basic results Iraq Cross- Exposure 2007 13 “exposed” 13 Plume Age, post- Volume of No differences in SPSS version 14 (Khamisiyah sectional occurred in Gulf War- “unexposed” modelling of traumatic stress discrete brain volumetric and SAS version )/ US March 1991; deployed veterans estimated disorder tissues: white measurements of 8 used; binary participants veterans recruited release and symptomatology matter, grey discrete brain comparisons in the study recruited from from the dispersion matter, left tissues seen between recruited the Devens Devens of sarin and and right between exposed exposure level between Cohort Study; the Cohort cyclosarin lateral and unexposed estimates and 1999 and Devens Cohort Study Time around the ventricles, veterans; volumetric brain 2001 consisted of Gulf 3 Khamisyah and however, linear measurements; War veterans assessment site cerebrospinal trend analysis ANOVAs to from the New fluid showed a compare England area, significant volumetric and a subset association measurements in (Time 3 between higher exposed and assessment) was levels of estimated unexposed recruited from sarin/cyclosarin groups; p values 1994 to 1996 exposure and reported for using stratified reduced white measures of random sampling matter, and brain volume, to produce a increased right and and p values for balanced sample left lateral test for trend of high and low ventricles health symptom reporters

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AUTHOR: Hong et al 2009

TITLE: The estimation of pesticide exposure in depression scores: in case of Korean orchard farmers

HYPOTHESIS: To investigate depression in farmers chronically exposed to pesticides

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure of exposure Other risk Outcome Narrative description of Statistical study collection of population population factors / bias / variables basic results methods period study confounders South Cross- Not 2009 46 m/f 36 m/f Self reports of Smoking, Depression No significant difference Mean ± SD, Korea sectional specified orchard orchard pesticide alcohol (measured via between farmer groups of χ2 test, farmers living farmers exposure/poisoning consumption, the Beck in-residence and out- Students t- in residence living out- (OPs among one of age, history of Depression residence in both the BDI test, (houses residence regularly used intoxication, Inventory (BDI) and MMPI1-D scores; correlation located (houses insecticides) depression and Minnesota frequency of pesticide analysis, inside located in scores, farming Multiphasic spraying per year and no. statistical orchard in villages duration, Personality of years of farming significance close outside the frequency of Inventory 2- showed no significant p< 0.05 proximity to orchards) spraying Depression difference in the in- and fruit grove) (MMPI-D) out-residence; positive scale) correlation observed between MMPI-D score and alcohol consumption, years of farming, and annual frequency of pesticide spraying

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AUTHOR: Horowitz et al 1999

TITLE: A Multi-Modality Assessment of Peripheral Nerve Function in Organophosphate-Pesticide Applicators

HYPOTHESIS: To re-evaluate findings of an original study conducted in male pesticide applicators and determine whether any of these findings could be indicative of organophosphate-induced peripheral neurologic deficits

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure of Other risk Outcome variables Narrative description Statistical study collection of population population exposure factors / bias of basic results methods period study / confounders US Cross- Not 1999 9 male There was no ref OP exposure for Diabetes Peripheral 4 subjects showed 95% sectional specified. pesticide group for this approx 20 years mellitus, neurologic deficits clinical evidence of confidence (NB. applicators / study. NB. This is to methyl neurological (as determined by peripheral limits States fruit growers because this parathion, disorders or clinical, neuropathic (established subjects (from a cohort study aims to tetraethyl alcohol electrophysiologic dysfunction i.e. in age/sex studied of 90). determine the pyrophosphate consumption and quantitative reduced sensations matched off- Selected on the nature and extent (TEPP) and motor and sensory in lower extremities; controls). NB. season) basis that they of abnormalities azinphos-methyl examination) one subject showed Data had (generally) in a small sub (guthion). NB. electrophysiologic analyses > 20 years of group of the May need to refer abnormalities; used is not OP exposure original study to original study unremarkable results clear. and had population. In the for further details. in remaining 4 highest original study subjects peripheral age-matched Subjects also neurologic controls were exposed to other deficits (as drawn from non-OP determined by general chemicals albeit vibration population to a lesser degree threshold e.g. fungicides sensitivity)

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AUTHOR: Hoshino et al 2008

TITLE: Ototoxicity study in workers exposed to organophosphate

HYPOTHESIS: To characterise vestibular test results from rural workers occupationally and environmentally exposed to organophosphates used in agricultural pesticides

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure of Other risk Outcome Narrative Statistical methods study collection of population population exposure factors / bias variables description of basic period study / results confounders Brazil Cross- No info 2008 18 rural There was no Based on no. of Smoking, Vestibular 16 workers had % subjects (to describe sectional provided workers (5 ref group for years workers were alcohol and system peripheral irritative relationships/correlations male and 13 this study. (This active and whether drug abuse, alterations vestibular between examination female) who is because this subjects had metabolic, syndrome/body result and complained of study sought to occupational hormonal balance disorder, of health/exposure variable dizziness and characterise exposure to OP and neck which 11 cases had disorders in (obtained via disorders were due to altered occupational hearing and questionnaires). nystagmus test exposure to vestibular NB. Most broadly results and/or OP systems of used pesticides positional vertigo compounds. subjects). NB. were manzate and 9 cases due to NB. Over half Hearing (carbamate), hyperreflexia working > 21 normality followed by 2 OPs (overactive/ over years criteria was (parathion, responsive reflex); used to methamidophos) 2 subjects had characterise and paraquat normal vestibular subjects results displaying normal values

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AUTHOR: Hsieh et al 2001

TITLE: Acetylcholinesterase Inhibition and the Extrapyramidal Syndrome: A Review of the Neurotoxicity of Organophosphate

HYPOTHESIS: To report the presentation of atypical neurological manifestations (other than delayed peripheral neuropathy) in patients admitted to a Taiwanese hospital with organophosphate poisoning

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AUTHOR: Jalali et al 2011

TITLE: Electrophysiological Changes in Patients with Acute Organophosphorus Pesticide Poisoning

HYPOTHESIS: To study electrophysiological changes in patients with OP poisoning

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AUTHOR: Jamal et al 2001

TITLE: Peripheral nerve dysfunction in farmers using organophosphate sheep dip

HYPOTHESIS: To identify the pattern of nervous system dysfunction (if any) experienced by farmers reporting chronic effects with previous acute OP intoxication, and to investigate chronic conditions arising from low-level OP exposure (encompassing peripheral and/or CNS dysfunction) in exposed farmers not reporting acute intoxication

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type Data Date Study Reference Measure of exposure Other risk Outcome variables Narrative description Statistical of collection of population population factors / bias / of basic results methods study period study confounders UK Case- No info 2001 Group 1: 16 16 healthy Biochemical markers Age, Neuropathy Median clinical scores ANOVA control provided OP exposed age/sex- of recent OP excessive assessed via clinical for symptoms, (to assess the farmers matched exposure: blood AChE alcohol symptoms, and reflexes and presence of regularly controls of and serum intake, taking neurophysiological sensation significantly statistical involved in mixed office- cholinesterase activity; medication techniques e.g. abnormal in Group 1, differences dipping based detailed exposure with motor and sensory and to lesser extent between sheep with occupations levels/history not neurotoxic conduction studies, Group 2 cf. controls. groups); 95% long term ill available; time since effects, and multi-modality Also significant CI of mean health last exposure to sheep occupation evoked potential increases in mean difference following dip in excess of 4 studies vibration and cold between each episodes of months; OP perception threshold farmer group mild- compounds used by in both groups; mean and control; moderate farmers: diazinon, heat perception pooled acute OP propetamphos, or threshold significantly standard error; poisoning clorfenvinphos. NB. increased in Group 1 p-value via All subjects in both only; most farmers in double-sided Group 2: 16 groups had 4 or more both groups showed student t-test, OP exposed years exposure to OPs motor conduction Mann-Whitney farmers abnormalities (more regularly pronounced in both involved in groups); there were dipping no differences in sheep with enzyme activities no history of between farmer symptoms of groups and control acute poisoning

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AUTHOR: Jamal et al 2002a

TITLE: A clinical neurological, neurophysiological, neuropsychological study of sheep farmers and dippers exposed to organophosphate pesticides

HYPOTHESIS: To facilitate clinical interpretation of associations found in the second phase epidemiological study and refine relationships and compare neuropsychological with neurological status and OP exposure

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study population Reference Measure of Other risk factors / Outcome variables Narrative Statistical study collection of population exposure bias / confounders description of methods period study basic results UK Nested Jan– 2002 a) 23 sheep 15 farmers Mean Alcohol consumption; Peripheral Incidence of Scoring for case- May farmers and exposed to cumulative inherent neuropathy as clinical neuropathy symptoms, control 1998 dippers with OPs but exposure via neuropsychological determined via increased from no Quantitative (within definite or almost exposure characteristics; deficits in: to probable/ Sensory Test cross probable certainly history abnormal cold neurological signs, definite group; (QST) and section of neuropathy without assessment threshold responses; motor and sensory sensory neuropathy 685 (determined from neuropathy questionnaire taking medication e.g. nerve conduction abnormalities outcome; subjects) neuropathy in second for hypertension; electromyography, found more often number of questionnaire phase diagnosed with quantitative sensory than motor subjects and and sensory rheumatoid arthritis, testing; deficits. percentage tests from the family history of high neuropsychological Details of experiencing second phase foot arches, carpal abnormalities neuropsychology neurological study of a cross- tunnel syndrome and tests too limited symptoms is sectional study radioculopathy for assessment reported of sheep farmers); b) an intermediate group comprising of 34 farmers with possible neuropathy

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AUTHOR: Jamal et al 2002b

TITLE: Low-level exposures organophosphorus esters may cause neurotoxicity

Date of Review 2002

Aim To report on evidence supporting the claim that low-level exposure to OP esters may cause neurotoxicity

Topics covered Findings of studies investigating Chronic Organophosphate Induced Neuropsychiatric Disorder (COPIND) arising from a) acute clinical cholinergic episodes and b) without such preceding attacks (e.g. experimental studies, case series and case-control) Health outcomes COPIND considered

Original studies Pilkington et al 1999. Epidemiological study of the relationships between exposure to organophosphate pesticides and indices of chronic peripheral neuropathy and neurophysiological abnormalities in sheep farmers and dippers. Phase 3; Clinical neurological, neurophysiological and neuropsychological not identified in study. Official report to British HSE, DoH and MAFF, May; p1-205. NB. This was previously considered by the COT in its review of OPs in 1999 and literature search/ subsequently published as Jamal et al 2002 (Occup Environ Med). (not included in NB. Other studies referenced in this review did not meet inclusion criteria (i.e. pre-dated 1999, non-OP related or mechanistic study) or are already selected refs) included in the screening process

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AUTHOR: Jayasinghe & Pathirana, 2011

TITLE: Effects of Deliberate Ingestion of Organophosphate or Paraquat on Brain Stem Auditory-Evoked Potentials

HYPOTHESIS: To identify the effects of deliberate ingestion of OP or PQ on brain stem auditory-evoked potentials (BAEPs)

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type Data Date Study population Reference Measure of Other risk Outcome Narrative Statistical of collection of population exposure factors / bias / variables description of methods study period study confounders basic results Sri Lanka Cohort Not 2011 Male and female 70 age, gender Cholinergic Subjects Ototoxicity Interpeak ANOVA and (Southern specified patients with and occupation features of excluded if they (assessed via latencies were not post-hoc Province) deliberate ingestion matched healthy patients had history of brain stem statistically comparisons; of OP (70) admitted volunteers (who treated in diabetes, auditory different from mean to a secondary and accompanied hospitals with neuropathies, evoked controls in either differences and tertiary care hospital. patients to the atropine was head injury and potentials assessment. No 95% CIs Subjects were tertiary care used to ear infections (BAEPs) significant lesions reported followed up twice: 1 hospital), with no confirm OP conducted at in the auditory and 6 weeks after acute history of ingestion week 1 and 6 pathway of OP exposure. 53 pesticide exposure after the patients were patients attended the exposure) observed clinic for second assessment. NB. Study group also included 28 patients who ingested PQ

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AUTHOR: Jin et al 2008

TITLE: Isolated bilateral vocal cord paralysis with intermediate syndrome after organophosphate poisoning

HYPOTHESIS: To report a case of bilateral vocal cord paralysis (BVCP) arising during clinical recovery from acute cholinergic crisis in OP poisoning

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type Data Date Study population Reference Measure of Other risk factors Outcome Narrative description of Statistical of collection of population exposure / bias / variables basic results methods study period study confounders Korea Case No info 2008 Patient attempted n/a Case history/ n/a Bilateral vocal Patient displayed symptoms n/a report provided suicide after clinical cord paralysis of BVCP from day 5 which consuming symptoms (BVCP) lasted for 15 days and dichlorvos resolved over time

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AUTHOR: Julu et al 2007

TITLE: Clinical Evaluation of a Sample of Participants in the SHAPE Survey of Health and Pesticides Exposure

HYPOTHESIS: To validate (in general terms) self reported health status of farmers/ members of support groups (OPIN, PEX, OPUS and NIOPSA) reporting exposure to sheep dip during the course of their work

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure Other risk factors / Outcome variables Narrative Statistical methods study collection of population population of bias / confounders description of period study exposure basic results UK Cross- No info 2007 43 (m/f) farmers/ n/a Self Medical/therapeutic Peripheral neuropathy 28 classified as OR and 95% CI sectional provided members of reported risk factors for (assessed via clinical neuropathy given for an support groups exposure neurological damage examination) i.e. positive (19 association between (OPIN, PEX, to OPs structured history, beside reporting acute a clinical neuropathy OPUS and /sheep dip neurological examination, cholinergic diagnosis and NIOPSA) taken electrodiagnostics (nerve episode and 9 reporting an acute from SHAPE conduction studies) and not reporting cholinergic episode ; survey of which quantitative sensory tests an acute significance level 28 reported an (thermal and vibration cholinergic not specified; acute reaction to thresholds) episode) authors report mean OPs, 15 values and SDs and reporting none range for nerve conduction velocity data

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AUTHOR: Kamel et al 2000

TITLE: Retinal Degeneration in Licensed Pesticide Applicators

HYPOTHESIS: To compare pesticide use in applicators reporting retinal degeneration

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date of Study Reference Measure of Other risk Outcome Narrative description of basic Statistical study collection study population population exposure factors / bias / variables results methods period confounders US Cross- 1994- 2000 154 pesticide 17.8K Lifetime Age, sex, Retinal Data combined from two sites OR (P value sectional 1996 applicators pesticide use of education, degeneration (to increase sample sizes) for trend); (taken providing self applicators pesticides; host (RD) showed nonsignificant Logistic from the reports of a who answered ever use of characteristics marginal association between regression Agricultural physician ‘No’ to the 29 OP (e.g. eye RD and use of OP. Health diagnosis of question: “Has insecticides colour, skin No dose-response relationship Study) retinal/macular a doctor ever (among damage); for increasing total lifetime degeneration told you that others); lifestyle and days of OP use and RD; an you had Cumulative medical association was observed retinal/macular days of use history; between ever use of 7 of 21 degeneration?” evaluated multiple specific OPs (i.e. dichlorvos, for only a exposures to cygon, guthion, imidan, subset of different malathion, orthene, and OPs (two pesticides/ prolate) and RD (no of which neurotoxic confidence data provided); included agents dose response relationships dichlorvos for cumulative days of use and were found for only two of nine diazinon) OP evaluated i.e. dichlorvos and diazinon (data not shown)

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AUTHOR: Kamel et al 2003

TITLE: Neurobehavioural performance and work experience in Florida farm workers

HYPOTHESIS: There is a relationship between long-term experience of farm work and deficits in neurobehavioural performance

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AUTHOR: Kamel et al 2005

TITLE: Neurologic Symptoms in Licensed Private Pesticide Applicators in the Agricultural Health Study

HYPOTHESIS: To analyse the relationship between neurologic symptoms and several measures of pesticide exposure

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure of exposure Other risk Outcome Narrative Statistical study collection of population population factors / bias variables description of methods period study / basic results confounders US Cross- 1993-97 2005 18,782 white “Controls” = the Self-reported Age, state, 23 neurologic Significant dose OR (95% sectional male licensed 80% of applicators exposure; education, symptoms response for CI) (from the private who experienced < cumulative use of smoking and reported, which cumulative and Linear Agricultural pesticide 10 symptoms in the OPs (lifetime days, alcohol use included use of pesticides, regression; Health applicators; year before without or with use in headaches, particularly Logistic Study) these were enrolment, past year) was numbness in insecticides; regression grouped into whenevaluating the calculated ranging hands or feet, greater symptom “Cases” and association of from 1 to > 500 days depression, poor count also “Controls in an summary measures use in past year. balance, loss of associated with evaluation of of neurologic Cumulative use also consciousness cumulative use. the association symptom calculated for other An association of summary prevalence with chemical classes was also measures of pesticide use and including observed neurologic exposure organochlorines, between each of symptom carbamates, the listed prevalence with pyrethoids symptoms and pesticide use OP exposure and exposure. “Cases” were the 20% of applicators who experienced ≥10 symptoms in the year before enrolment

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AUTHOR: Kamel et al 2007a

TITLE: Pesticide exposure and self-reported Parkinson’s Disease in the Agricultural Health Study

HYPOTHESIS: Parkinson’s Disease (PD) is associated with pesticide exposure, and with exposure to some specific pesticides, including individual OPs

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Locatio Type of Data Date Study population Reference Measure of Other risk factors Outcome Narrative description Statistical n study collection of population exposure / bias / variables of basic results methods period study confounders US Cohort Enrollment 2007 83 participants who 79,557 cohort Self-reported Adjustments PD Incident PD was Logistic in the reported physician- members who duration (years) made for: age at associated with regression to cohort diagnosed PD at did not report PD and frequency enrollment, using cumulative days of evaluate the took place enrollment, were at enrollment (days per year) a 4-level pesticide use at relation of either from 1993- defined as were the of use of any categorical enrolment; no prevalent PD or 1997; “prevalent cases”; comparison pesticide, and variable with significant incident PD to follow-up 78 participants who population for the ever use of 50 persons aged 51- association was general pesticide took place reported physician- 83 prevalent commonly used 60 years as the found for 10 specific variables; two- in 1999- diagnosed PD at cases; pesticides, referent group; OPs stage hierarchical 2003 follow-up were 55,931 cohort including State (Iowa or logistic regression defined as members who specific OPs North Carolina); used when “incident cases” did not report PD type of evaluating at follow-up were participant multiple specific the comparison (applicator or pesticides; ORs population for the spouse) in and 95% CIs 78 incident cases models that reported included both. Race and education were also considered as possible confounders

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AUTHOR: Kamel et al 2007b

TITLE: Neurologic symptoms in licensed pesticide applicators in the Agricultural Health Study

HYPOTHESIS: Neurological symptoms are associated with exposure/cumulative exposure to moderate levels of pesticide exposure

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of study Data Date of Study Reference Measure of Other risk Outcome Narrative Statistical methods collection study population population exposure factors / bias / variables description of period confounders basic results US (Iowa Cross- 1993 to 2007 18,782 Controls are Self-reported Age, state, 23 Neurological Logistic regression; and sectional 1997 licensed drawn from exposure on education, neurological symptoms are ORs and 95% CI North analysis from applicators the same questionnaire of cigarette symptoms associated with calculated for Carolina) information enrolled in the cohort as duration and smoking, typically cumulative relative risk of given in the Agricultural the cases frequency of use alcohol use associated exposure to experiencing 10 or Agricultural Health Study; of pesticides, with pesticide moderate levels more neurological Health Study Caucasian including use of intoxication of OP symptoms in the males aged chemical groups insecticides, year before 18-75 of insecticides, regardless of enrolment among them OPs recent exposure or history of poisoning

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AUTHOR: Kara-Peketi et al 2009 (Abstract evaluated, article in French)

TITLE: Chemical risk assessment and preventive procedure among cotton growers in Togo. Longitudinal survey between 2003 and 2008

HYPOTHESIS: Pesticides used by cotton producers in Togo have an impact on their health, and preventive measures and hygiene adopted by the workers also have an impact

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study population Reference Measure of Other risk factors / Outcome Narrative Statistical study collection of population exposure bias / confounders variables description of methods period study basic results Togo Longitudinal 2003 and 2009 Cotton growers N/a Not given Not given Dermatological, There was a Prevalence of 2008 (numbers in neurological and higher dermatological, study not given digestive prevalence of neurological and in abstract) symptoms dermatological, digestive neurological and symptoms in digestive 2003 and 2008 symptoms in compared and 2008 than in expressed as 2003. There was percentages a decrease in good personal and environmental hygiene measures from 2003 to 2008

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AUTHOR: Kawada et al 2005

TITLE: Insomnia as a sequela of sarin toxicity several years after exposure in Tokyo subway trains

HYPOTHESIS: Sarin exposure has an effect on insomnia

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure of Other risk Outcome Narrative description of Statistical methods study collection of population population exposure factors / bias variables basic results period study / confounders Japan Cross- October 2005 75 women Control Problems Not analysed Poor sleep in the In the younger exposed Chi square test (Tokyo) sectiona and aged 30 to 69 female related to preceding month, group (under 50), there carried out to l November years (n=61 subjects lived insomnia and the presence was a significantly compare the 2003 aged 30 to 49, along Route were of one or more of higher prevalence of distribution of and n=14 aged 17 of reported on a the following poor sleep, difficulty frequencies of 50-69) who Maebachi self- symptoms: falling asleep, insomnia or had been City, Gunma administered difficulty falling intermittent awakening, insomnia-related victims of the Prefecture, questionnaire asleep, early morning factors between Tokyo subway Japan: intermittent awakening, a feeling of exposed and sarin attack in n=186 awakening, early light overnight sleep and control subjects; 1995 controls aged morning insomnia; in older SPSS package 30 to 49, and awakening, exposed group, there used, version n=145 feeling of light was significantly higher 11.5J. controls aged overnight sleep, prevalence of poor Prevalence of 50-69 occurring one or sleep, feeling of light insomnia is more times a overnight sleep, and reported as week early morning percentages, and p awakening. values are given for presence of insomnia in cases compared to controls

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AUTHOR: Kawana et al 2001

TITLE: Psycho-physiological effects of the terrorist sarin attack on the Tokyo subway system

HYPOTHESIS: Victims of the 1995 Tokyo sarin attack continue to suffer physical and psychological symptoms 5 years after the terrorist incident

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type Data collection Date Study Reference population Measure of Other risk Outcome Narrative Statistical of period of population exposure factors / bias variables description of basic methods study study / results confounders Japan Cohort Questionnaire 2001 582 sarin Two other groups Symptoms Not Physical, eye- Victims of the 1995 Frequency and (Tokyo) data collected patients exposed to sarin were reported on considered related and Tokyo sarin attack percentage of in 1997, 1998 treated at St included in a questionnaire; psychological continue to suffer symptoms in and 2000 – 2,3, Luke’s comparative exposure was symptoms from physical and the St Luke’s and 5 years International subanalysis of to the 1995 arising after psychological Hospital sarin after the attack Hospital, symptom incidence sarin attack on the 1995 sarin symptoms 5 years patients is listed Tokyo, on the i.e. 655 victims the subway attack after the terrorist for 1997, 1998 day of the Victims of the Tokyo system incident; and 2000, and attack (20 sarin attack studied psychological Fisher’s exact March, 1995). by a non- symptoms did not test used to governmental decrease compare 1997 organisation, victims significantly over vs. 1998, and of the 1994 the 5 years of the 1998 vs. 2000, Matsumoto sarin study, except for p values attack, and 87 depressed mood, reported; Matsumoto controls of which significantly symptom the 1994 Matsumoto decreased in 1998 incidence (%) sarin attack were compared in 3 used for a groups exposed comparative to sarin, and subanalysis of one control symptom incidence group

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AUTHOR: Keifer et al 2000

TITLE: Neurological effects of organophosphates on farm workers

HYPOTHESIS: Exposure to OPs in the process of apple thinning has a detectable effect on neurobehavioural performance and neurological function, and years of historical exposure to orchard thinning show an effect on the same functions after recovery from any acute effects

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure of Other risk Outcome Narrative description Statistical study collection of population population exposure factors / bias variables of basic results methods period study / confounders US Cross- April to 2000 137 farm For each worker Self-reported Peabody Sensory and No consistent SPSS or SAS (Washington sectional August 1994, workers of recruited from an work history, and Picture motor nerve significant effect of a statistical State) during the both sexes orchard, a worker reported home Vocabulary conduction; season of orchard packages thinning recruited was recruited pesticide score, age, results for thinning in OP- used; multiple season, from several from a non- exposure, in gender, repetitive sprayed orchards on linear when recent orchards in agricultural questionnaire; haemoglobin stimulation neurobehavioural or regression exposure the workplace, blood taken for electro- neurophysio-logical performed and would be at Wenatchee including testing AChE myography; parameters was logistic a cumulative area; garment levels; testing performance found, and no effect regression for peak, and 90 workers manufacturing, also done for on neuro- of recent exposure some binomial again after 6- were tested hotels and paraoxonase, behavioural or past history of variables; 9 month a second restaurants chlorpyrifos test battery thinning was seen coefficients for exposure time oxonase and effect reported respite diazinon oxonase and delta score on most for difference participants between Year 2 and Year 1 scores, with p value for the model

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AUTHOR: Kesavachandran et al 2009

TITLE: Health risks of employees working in pesticide retail shops: an exploratory study

HYPOTHESIS: In this exploratory health study, it was hypothesised that shopkeepers selling pesticides suffer health effects from their exposure

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AUTHOR: Kesavachandran & Mudiam., 2010

TITLE: Adverse sub-clinical health effects in pesticide-exposed population: challenges and need for developing non-invasive clinical biomarkers

Date of Letter 2010

Aim To introduce results of epidemiological study (Pathak 2011) and discuss the limitations associated with current biomarkers of exposure to OP pesticides

Topics covered Advantages of hair analysis cf. current biomarkers

Health outcomes Subclinical effects in relation to haematology, cholinesterase activity, lung function and nerve conduction tests considered

Original studies Studies referenced in this letter did not meet inclusion criteria (i.e. pre-1998, non-neurological health outcomes) not identified in literature search/ (not included in selected refs)

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AUTHOR: Kilburn, 1999

TITLE: Evidence for chronic neurobehavioural impairment from chlorpyrifos, an organophosphate insecticide (Dursban) used indoors

HYPOTHESIS: There are possible neurobehavioural effects of assumed low-levels of chlorpyrifos sprayed indoors

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type Data Date Study population Reference Measure of Other risk Outcome Narrative Statistical of collection of population exposure factors / bias variables description of basic methods study period study / confounders results US Cros 1991 to 1999 22 chlorpyrifos- 264 men and Self-reported Age, Neurobehaviour Exposed subjects Neurobehaviour s- 1997 exposed women aged 18- exposure on education, al impairment, had significantly al test scores secti subjects, aged 83 years, questionnaire, gender, assessed impaired balance, and standard onal 34-77 years, out unexposed to although height, family through tests of visual fields, colour deviations of 384 patients neurotoxic schedules of income, balance, simple discrimination, reported for from 8 US states chemicals, pesticide hours of and choice simple and choice exposed and evaluated for recruited at application general reaction time, reaction time, and unexposed; possible random from were found for anaesthesia, blink reflex hearing; they also also symptom neurobehavioura voter registration offices of 6 weight, latency, visual had psychological frequencies, as l effects of rolls in patients, so POMS field impairment of means with chemicals at a Wickenburg, AZ concentrations (Profile of performance, verbal recall and standard neurotoxicology and Smithfield, of applied Mood States) hearing, colour cognitive function, deviations; both clinic at LA. chlorpyrifos score discrimination embedded memory compared by University of were known, and grip strength and perceptual analysis of Southern and 4 patients motor performance. variance, and California had personal Mean Depression p values School of clothing or score higher in reported Medicine rugs analysed exposed. for chlorpyrifos

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AUTHOR: Kimura et al 2005 (abstracted from the reference list of a review paper by Yokoyama (2006))

TITLE: Effects of Pesticides on the Peripheral and Central Nervous System in Tobacco Farmers in Malaysia: Studies on Peripheral Nerve Conduction, Brain-Evoked Potentials and Computerised Posturography

HYPOTHESIS: To examine the effects of pesticides on the central and peripheral nervous system in tobacco farmers and determine the most sensitive neurological test method

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study population Reference Measure of exposure Other risk Outcome variables Narrative Statistical study collection of population factors / bias description of methods period study / confounders basic results Malaysia Cross- 8th – 30th 2005 76 male tobacco 38 male Questionnaire to Existing Neurophysiological The power of Students t test (Kentalan) sectional Aug farmers exposed to officers determine years illnesses, abnormalities e.g. postural sway (to examine 2001 pesticides registered working with age, height, slowed nerve of 0-1 Hz was differences in (randomly selected on the NTB tobacco, names of weight conduction velocity significantly P300, P100, from National who did not pesticides used and smoking and (NCV), prolonged larger in NCV, blood Tobacco Board handle use of protective alcohol latencies of brain Tamaron level of (NTB) from pesticides equipment; serum consumption evoked potentials (e.g. users than cholinesterase Kentalan). NB. or wet cholinesterase event-related evoked that of activities, age, Tamaron tobacco activity. NB. Most potentials (ERP), controls in height and skin (methamidophos) leaves farmers used two or pattern reversal visual the anterior- temperature), p used by 26 farmers more pesticides. evoked potential posterior values reported Other pesticides (VEP)) and abnormal direction with used included, pattern or postural eyes open (p organochlorines, sway < 0.05) pyrethroids, dithiocarbamates and dinitroanilines

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AUTHOR: Konieczny et al 1999

TITLE: Impaired respiratory muscle function in chemical plant workers producing chlorfenvinphos

HYPOTHESIS: Impaired respiratory muscle function might play a role in the development of ventilatory dysfunction in workers employed in the production of chlorfenvinphos

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure of Other risk Outcome variables Narrative Statistical study collection of population population exposure factors / bias / description of basic methods period study confounders results Poland Cross- Not 1999 All staff Spirometric Air chlorphen- Duration of The following Study shows Mean and (Katowice) sectional specified members of a tests: 22 vinphos employment, parameters from weakness of SD of chemical plant healthy men concentration in smoking in spirometry: vital respiratory muscles spirometry producing aged 20-62 production area pack-years, capacity (VC), forced in workers indices; chlorfenvinphos years, without estimated in chronic expiratory volume in compared to absolute : 35 males occupational factory laboratory bronchitis, one second (FEV1), controls, but air values of aged 25-55 exposure to using Gas Liquid atopic airways FEV1/VC ratio concentration of maximal years, with chemicals. Chromatography; disease (FEV1 %), maximal chlorfenvinphos inspiratory duration of Repetitive 8-hour weighted expiratory flow at was not excessive, and employment 1- nerve average was 25% VC (MEF 25%), and AChE activity expiratory 15 years stimulation 0.0008-0.0018 peak expiratory flow similar to that in pressure test: 30 mg/m³, did not (PEF), gas transfer control group; (MIP and healthy males exceed maximum factor (TLCO), muscle weakness MEP) in aged 35-52 allowable specific airways may be due to workers and years who concentration of conductance (sGaw), pathological controls, p were residents 0.01 mg/m³. intrathoracic gas changes in the values given of the region. AChE and volume (ITGV), ratio muscles RBC AChE plasma AChE of residual volume to themselves, and and plasma determined total lung capacity not due to cholinesterase (RV/TLC) impairments of the activity: 33 nervous system healthy males aged 20-55 years

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AUTHOR: Lawlor et al 2007

TITLE: The association of the paraoxonase (PON1) Q192R polymorphism with depression in older women: findings from the British Women’s Heart and Health Study

HYPOTHESIS: The association of PON1 Q192R with symptoms of depression in occupationally exposed groups to OPs (sheep dippers, Gulf War veterans) may be driven by exposure to toxins that everyone in the general population is exposed to, or other mechanisms underlie the association

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study population Reference Measure of Other risk factors / Outcome Narrative Statistical methods study collection of population exposure bias / confounders variables description of basic period study results UK Cohort 1999 to 2007 Data used from None Presumed No adjustments Depression Study findings Genetic frequencies 2001 the British exposure to made; suggest that PON1 tested for Hardy- Women’s Heart low-levels of findings may not be Q192R is Weinberg equilibrium; and Health Study: OPs in generalisable to associated with logistic regression used participants were general other populations, depression in older to calculate the odds of 3,266 ‘white’ household including men; British women, and ever being diagnosed British women insecticides there may be authors therefore with depression; aged 60-79 years measurement error question whether OR and 95% CI selected randomly from the fact that associations of reported for odds of from 23 British depression outcome PON1 with ever being diagnosed towns is based on depressive-type with depression with retrospective self- symptoms in sheep each additional R allele report of ever being dippers and Gulf (QQ, QR, RR) diagnosed by a War veterans can doctor be used as strong evidence for the biological basis of symptoms

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AUTHOR: Lee et al 2003

TITLE: Association Between Human Paraoxonase Gene Polymorphism and Chronic Symptoms in Pesticide Workers

HYPOTHESIS: Among farm workers exposed to OPs, those with a slower PON activity would have a higher risk of pesticide toxicity compared to those with faster PON activity

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure of exposure Other risk Outcome Narrative description Statistical study collection of population population factors / bias / variables of basic results methods period study confounders South Cross- 1983 2003 100 farm From the 73 Plasma and erythrocyte Age, number of Abdominal pain, Proportion of 2-tailed t- Africa sectional workers participating cholinesterase (marker years on job, nausea, subjects with toxic test for selected from farms, one of acute OP exposure/ smoking and rhinorrhea, symptoms unpaired 347 subjects non-applicator toxicity respectively); alcohol history, dizziness, significantly higher data, from 73 from the same self-reported pesticide education level, headache, among applicators Wilcoxon participating farm was applicator history. NB. plasma or red somnolence than non- rank sum farms in selected for The authors briefly blood cell (i.e. applicators; test and Western Cape, every two allude to the fact that cholinesterase drowsiness/ proportion of Fisher exact South Africa; applicators of farm workers were level or sleepiness), subjects with toxic test, Mantel- subjects pesticides, exposed to OPs, and previous history fatigue, gait symptoms increased Haenszel genotyped for matched for direct readers to of acute OP disturbance, in a stepwise test for polymorphism age within 2 London et al 1998. poisoning limb numbness, manner: from trend; Multi- of the PON years and Cross-referencing paresthesias, nonapplicator-fast variable gene at position education confirmed that the limb pain, limb genotype, non- logistic 192; genotype within 1 year, in exposure assessment weakness applicator slow and regression information was the original was based on an OP applicator-slow analysis available for survey of 347 job exposure matrix that genotype; OR (95% CI) only 82 of subjects included measures of independent P<0.1 these. direct/indirect OP predictors of chronic 49 of the exposures toxicity were subjects in the characterised as previous history of study were cumulative and average head injury, slow pesticide intensity of exposure. genotype (Gln/Gln) applicators Non-occupational and history of being exposure to OPs was a pesticide also considered applicator

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AUTHOR: Little et al 2010

TITLE: Sensory ataxia associated with chronic organophosphate pesticide exposure

HYPOTHESIS: To describe a novel case of sensory ataxia in a patient occupationally exposed to a variety of OP pesticides

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type Data Date Study Reference Measure of exposure Other risk factors / Outcome Narrative description of basic Statistical of collection of population population bias / confounders variables results methods study period study UK Case No info 2010 52 year old n/a Case history report of Medical history of Imbalance, Patient diagnosed with n/a report provided farmer exposed sheep dipping; an anterior C5/6 falls, sensory ataxia combined with to various inappropriate protection discectomy for tremors postural tremor); authors note pesticides over and use of personal right sided that the patient had an 30-year period protective equipment in brachialgia abnormal phenotype of with 2 year recent decade; plasma resulting in plasma cholinesterase history of and erythrocyte resolution; (heterozygous for the usual worsening cholinesterase activity. possible acute and the fluoride resistant imbalance and NB. OP among poisoning week butyrylcholinestase variants), falls and 6 year commonest product used before attending which confers lower activity of tremor e.g. chlorpyrifos and, clinic the enzyme diazinon or propetamphos and possibly carbamates

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AUTHOR: Loh et al 2010

TITLE: Case report: Long-term cognitive sequelae of sarin exposure

HYPOTHESIS: To describe the neurocognitive sequelae of one of two incipient cases of exposure in Iraq

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type Data Date Study population Reference Measure of Other risk Outcome Narrative description of basic Statistical of collection of population exposure factors / bias / variables results methods study period study confounders US/Iraq Case 2004 2010 34 year old male n/a Erythrocyte Sinus, Neurocognitive Patient had a 39% reduction in n/a report army explosive cholinesterase arthroposcopic sequelae erythrocyte cholinesterase activity sergeant exposed activity; case knee surgery which returned to normal month to sarin while report of IED later; patient also displayed short deployed in Iraq inspection term memory loss, imbalance and whilst attempting to episodic discoordination, disarm an headaches, difficultly with rapid unexploded and alternative finger tapping; leaking improvised neuropsychological testing explosive device demonstrated mild cluster of (IED) in an impairments e.g. reduced speed of enclosed area information processing, poor focused and divided attention, Subsequent acute difficult in speeded, bilateral symptoms reported manual motor coordination 8-10 minutes later months after exposure

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AUTHOR: London et al 2004

TITLE: Guillain-Barre syndrome in a rural farming district in South Africa: A possible relationship to environmental organophosphate exposure

HYPOTHESIS: Aerial OP insecticide application is related to a raised incidence of Guillain-Barre syndrome (GBS) in an isolated farming region of Northern Cape Province of South Africa

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of study Data Date Study population Reference Measure of Other risk Outcome Narrative Statistical collection of population exposure factors / bias variables description of basic methods period study / results confounders South Retrospective 1993 2004 7 White cases of White Self report from Acute OP GBS (a Progression of Poisson Africa cohort (11-year GBS in an isolated population of occupational poisoning demyelinating illness ceased in 7 distribution follow-up since farming area subject magisterial and syndrome) cases by week 2; (to compare 1980) to intensive aerial district of environmental /Motor symptoms were no. of application of OP Hartswater history polyneuropathy minimally present; observed vs. insecticides (rural (approx 6000 one patient expected White population of people) remained on cases) Hartswater ventilator for no. of magisterial district – months and approx 3000 people). reported residual NB. GBS survivors hearing deficit traced back over an although not clear 11-year period since as to cause 1980

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AUTHOR: London et al 2005

TITLE: Suicide and exposure to organophosphate insecticides: cause or effect?

Date of Review 2005

Aim To review the literature of mortality and morbidity studies related to suicide among pesticide-exposed populations

Topics covered Global epidemiology of pesticide poisoning and patterns of causation; relationship between suicide and exposure to pesticides; evidence from animal data for link between OP exposure and serotonin levels in the brain; evidence from human studies of association between chronic exposure and affective disorders; symptoms in neurobehavioural studies Health Suicide and exposure to OP pesticides outcomes considered

Original studies All relevant studies identified; other studies did not meet inclusion criteria , or pre-dated 1999, or were reviews, or are already covered by the COT 1999 not identified in Report on Organophosphates literature search

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AUTHOR: Lotti, 2002 (Muscle Nerve)

TITLE: Low-level exposures to organophosphorus esters and peripheral nerve function

Date of Review 2002

Aim To evaluate the evidence (epidemiological and clinical) linking low-level and prolonged exposures to OPs to peripheral nerve dysfunction

Topics covered Clinical effects Acute neurotoxicities of OPs Long-term low-level exposures to OPs (wrt. Peripheral Nerve Function and Current Exposures to OPs; Peripheral Nerve Function and Past/Current Exposures to OPs; Studies in Animals)

Health outcomes Cholinergic syndrome, Intermediate syndrome considered Delayed polyneuropathy Peripheral nerve dysfunction

Original studies Pilkington et al . Epidemiological study of the relationships between exposure to organophosphate pesticides and indices of chronic peripheral neuropathy and neurophysiological abnormalities in sheep farmers and dippers. IOM Technical Memorandum Series TM/99/02c. Edinburgh: Institute of Occupational not identified in Medicine. 1999. NB. This was previously considered by the COT in its review of OPs in 1999 and subsequently published as Jamal et al 2002 (Occup literature search/ Environ Med). (not included in selected refs) NB. Other studies referenced in this review did not meet inclusion criteria (i.e. pre-dated 1999, non-OP epi related or mechanistic study) or are already included in the screening process

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AUTHOR: Lotti & Moretto, 2005

TITLE: Organophosphate-induced delayed polyneuropathy

Date of Review 2005

Aim To describe the clinical features of organophosphate-induced delayed polyneuropathy (OPIDP) in humans and critically discuss reported cases

Topics covered OPIDP mechanisms Pesticide poisoning caused by several OPs/carbamates Case reports of neuropathies attributed to OP exposures Observational studies on long-term, low-level exposures to OPs

Health outcomes OPIDP considered

Original studies Pilkington et al . Epidemiological study of the relationships between exposure to organophosphate pesticides and indices of chronic peripheral neuropathy and neurophysiological abnormalities in sheep farmers and dippers. IOM Technical Memorandum Series TM/99/02c. Edinburgh: Institute of Occupational not identified in Medicine. 1999. NB. This was previously considered by the COT in its review of OPs in 1999 and subsequently published as Jamal et al 2002 (Occup literature search/ Environ Med). (not included in selected refs) NB. Other studies referenced in this review did not meet inclusion criteria (i.e. pre-dated 1999, non-OP epi related or mechanistic/in-vivo study, provided general textbook info, methodological) or are already included in the screening process

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AUTHOR: Lubis et al 2008 (Abstract evaluated - Paper unobtainable)

TITLE: A biomarker for exposure to organophosphate and carbamate pesticides

HYPOTHESIS: To investigate the effects of pesticide exposure (organophosphate and carbamate)

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure Other risk Outcome variables Narrative description Statistical study collection of population population of factors / bias / of basic results methods period study exposure confounders Not Cross- June 2006 2008 64 paddy 22 fisherman Not clear Not reported in Not clear from abstract. CPT values were Not stated in sectional farmers with 5- (NB. This is an from abstract However, the following significantly elevated reported in abstract 20 years of assumption and abstract techniques were used: among farmers on abstract pesticide needs to be nerve conduction both the medial and exposure verified) velocity and current peroneal nerves (P< perception threshold 0.002) (CPT)

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AUTHOR: Mackenzie Ross et al 2009

TITLE: Neuropsychological and Psychiatric Functioning in Sheep Farmers Exposed to Organophosphate Pesticides (VM02302)

HYPOTHESIS: To establish whether low-level exposure to organophosphate pesticides (OPs) is associated with neuropsychological impairment and psychiatric disorder in UK sheep farmers; to determine the nature and extent of neurobehavioural problems following low-level exposure to organophosphate pesticides; to investigate whether some individuals are more vulnerable to the effects of OPs than others

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Locatio Type of Data Date Study Reference Measure of Other risk Outcome variables Narrative description of basic Statistical methods n study collectio of populatio population exposure factors / bias / results n period stud n confounders y UK Cross- Not 2009 Cross- Cross- Exposure History of acute Neuropsychologica Cross-sectional: Agricultural 2-factor ANOVA (to sectiona specified sectional: sectional: 40 history via intoxication, l deficits with workers obtained lower scores compare exposure l and 79 rural police semi- substance respect to. on tests of response speed, groups and working case- working workers with structured abuse cognition (i.e. working, verbal and visual status); MANOVA control sheep no OP interview (e.g. (including intellectual ability, memory, mental flexibility and (to minimise any study farmers exposure level of alcohol), memory, response fine motor control, than non- potential Type I exposed history and exposure with retirement on speed, mental exposed controls (which error); unrelated t- to OPs; no farm respect to. non-ill health flexibility, verbal remained after controlling for tests or Mann Case- working duration and grounds e.g. for fluency, fine motor confounders); Case-control: Whitney U (to control: history; frequency, age or skill and Retired farmers reported analyse differences 65 sheep Case- use of economic effort/malingering); higher rates of emotional in mean scores and farmers control: 42 protective reasons, history mood deficits with distress and physical SDs); p values who rural police clothing, of psychiatric respect to. anxiety symptoms cf. working farmers. reported; chi retired on workers who involvement problems prior and depression; However, few differences were squared test; grounds retired on ill- in high risk to exposure or physical health; found on objective measures Spearman’s of ill- health activity i.e. neurological or and PON1 status of cognitive function or correlation (to health grounds diluting serious medical potential vulnerability factors establish whether matched for concentrate); conditions that such as PON1 status; weak there was a age, gender, two exposure could account significant correlations were relationship education indexes for cognitive/ observed between duration of between cognitive level, etc calculated i.e. emotional exposure and verbal and visual function and lifetime problems memory, verbal ability, strategy exposure history) exposure making and fine motor control index and the Esk exposure metric

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AUTHOR: Mackenzie Ross et al 2010

TITLE: Neuropsychological and psychiatric functioning in sheep farmers exposed to low-levels of organophosphate pesticides

HYPOTHESIS: Low-level exposure to OPs causes neuropsychological or psychiatric impairment in UK sheep farmers, and affected individuals show deficits on tests of working and general memory, response speed and mental flexibility, with preserved reasoning and general intellectual functioning farmers

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data collection Date Study Reference Measure Other risk Outcome Narrative description of Statistical methods study period of population population of factors / bias / variables basic results study exposure confounders UK Cross- Not specified; 2010 127UK 78 controls Self- Sample of Cognitive Relationship may exist 2 factor ANOVAS (England) sectional previous pilot sheep who were reported venous blood domains of between low-level used to compare (exposed study reported farmers rural police exposure taken for working exposure to OPs and Exposure Groups and on in 2007, so exposed to workers in analysis of memory, impaired (exposed vs. control) unexposed this study done OPs (67 and who interview PON1 visual neurobehavioural and Working Status compared) subsequently. working, had never through polymorphisms memory, functioning: exposed (farmers vs. and case- Subjects had to 60 retired) worked in current and activity auditory subjects performed controls); MANOVA control have exposure the farming work and level; memory, significantly worse than and MANCOVA (working to OP pesticides industry (38 exposure variables were response controls on tests of multivariate tests and retired for a minimum of working, 40 history age-scaled, or speed, fine memory, response used where farmers 5 years prior to retired) (number of age added as motor control, speed, fine motor appropriate. F values compared) 1991 (before days or covariate if not; mental control, mental reported for implementation years flexibility, flexibility and strategy performance in of safety spent strategy making, and over 40% cognitive domains, regulations in working making, of exposed subjects with p values of 1992) with OPs) verbal ability, reported clinically significance. visuo-spatial significant levels of Spearman’s skills, verbal anxiety and depression correlations to and visual indicate association reasoning; between cognitive depression function and duration and anxiety of exposure

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AUTHOR: Mackness et al 2003

TITLE: Paraoxonase and susceptibility to organophosphorus poisoning in farmers dipping sheep

HYPOTHESIS: Individuals inheriting low activity isoforms of PON1 would be more liable to report symptoms of OP toxicity (wrt. investigating the relationship between PON1 genetic polymorphisms and PON1 activity in OP-exposed farmers reporting chronic ill health)

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type Data Date Study Reference Measure of Other risk Outcome Narrative description of Statistical methods of collection of population population exposure factors / bias / variables basic results study period study confounders UK Case- No info 2003 175 farmers 234 farmers Self-reported Age, location, Risk of Cases more likely to Students unpaired t- control provided reporting carrying out similar exposures being a have R192 and L55 test, Mann-Whitney chronic ill activities reporting from case (i.e. allele than control; R U test, chi-squared health that they no ill-health questionnaire reporting ill and L genotypes test, ANOVA, attribute to OP (nominated by health) associated with lower multiple regression exposure while cases). Age- PON1 activity towards analysis, sheep dipping matched, living in diazoxon; farmers with probabilities of ≤ similar locality, with lowest rate of serum OP 0.05 considered similar pattern of (diazoxon) hydrolysis significant dipping had greater risk of being OR and 95% CIs, P a case value

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AUTHOR: Manthripragada et al 2010

TITLE: Paraoxonase 1, Agricultural Organophosphate Exposure, and Parkinson Disease

HYPOTHESIS: To examine associations between Parkinson’s disease (PD) and OPs and the influence of a functional polymorphism at position 55 in the coding region of the PON1 gene (PON1-55).

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure of exposure Other risk Outcome Narrative description Statistical study collection of population population factors / bias / variables of basic results methods period study confounders US Case- 1 Jan 2010 351 clinically 363 controls Residential OP Sex, smoking Parkinson’s OP- exposed (low Chi-squared control 2001 – 1 diagnosed PD from same exposure to agricultural status, age, Disease and high categories test, (part of a Jan 2008 cases in rural tri-county OP applications i.e. education, merged) carriers of unconditional larger population of (Fresno, diazinon, chlorpyrifos county, race, MM PON1-55 logistic population Central Valley Tualre and and parathion occupational genotype exhibited > regression to based (California) who Kern) with (estimated via pesticide pesticide 2-fold (diazonin) or 3- calculate ORs case- live close to no PD usage reports, land-use exposure fold (chlorpyrifos) (95% CI) to control areas of diagnosis maps and geographic increase in risk of PD assess the main study) extensive information system cf. to wildtype or effects of both agricultural (GIS) approach); heterozygous genes and pesticide subjects categorised genotype and no pesticides application into either zero, low or exposure. NB. For (particularly high residential OP those highly exposed OPs) exposure (via 1974- to diazonin the risk of 1999 average pesticide- PD was over 5-fold specific pounds per for MM carriers acre); occupational pesticide exposure also estimated based on lifetime work history/self reports of agricultural pesticide applications and specific job tasks

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AUTHOR: Matmurodov et al 2011 (Abstract evaluated because this is a Conference Publication presented at a Congress in Budapest, Hungary, and the whole publication is not available)

TITLE: Polymorphism of the genes GSTM1, GSTT1, and environmental factors in the development of Parkinson’s Disease among representatives of the Uzbek nationality

HYPOTHESIS: Subjects with genetic polymorphisms of the GSTT1 and GSTM1 genes may develop PD after exposure to environmental factors such as OP pesticides

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date of Study Reference Measure of Other risk Outcome Narrative Statistical methods study collection study population population exposure factors / bias / variables description of period confounders basic results Uzbekistan Cross- Not 2011 180 PD 100 healthy Not clarified Not reported PD The proportion p values are sectional specified patients Uzbek individuals of patients with reported for the from the null genotypes main risk factors Uzbek of the GSTT1 examined population gene was 49.8%higher than in healthy individuals, and the GSTM1 gener is 20.8% higher in patients than in healthy individuals

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AUTHOR: McCauley et al 2001

TITLE: Symptoms of Gulf War veterans possibly exposed to organophosphate chemical warfare agents at Khamisiyah, Iraq

HYPOTHESIS: Health effects may have persisted in Gulf War veterans who participated in, or witnessed, the destruction of Iraqi munitions at Khamisiyah in March 1991, where they were potentially exposed to sarin/cyclosarin

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study population Reference Measure of Other risk Outcome Narrative Statistical study collection of population exposure factors / bias / variables description of methods period study confounders basic results Iraq Cross- October 2001 653 Khamisiyah 610 Non- No direct ORs and 95% Acute The veterans ORs and 95% (Khamisiyah sectional 1998 to veterans who Khamisiyah military measure, but CIs adjusted for symptoms who had taken CIs of current )/US April were operating personnel who were exposure potential known to be part in or neuro- 1999 between March 1 deployed in the Gulf was confounders of associated witnessed the behavioural and March 15 in during the Gulf War, assumed for age, gender, with demolition in symptoms if 1991 within a 50 but were outside the troops within and region of exposure to 1991 were Khamisiyah km radius of the 50 km radius and a 50 km residence. sarin; more likely to Witness vs. Khamisiyah had no known radius of the Selection bias psychiatric, report Non- Ammunition exposure to nerve detonated possible neurological, historical or Khamisiyah Storage Point agents; chemical because sample and extant Witness, where the 516 Non-Deployed warfare limited to neuro- symptoms, in Khamisiyah munitions were personnel who had agents persons whose behavioural particular 5 group vs. Non- destroyed; been on active duty telephone health neurological Khamisiyah a subgroup of at the time of the numbers could symptoms symptoms, group, and 162 individuals Gulf War, but not be tracked down present at than were deployed vs. had been involved deployed to the by common time of data veterans from non-deployed in or watched the Gulf; search collection 8-9 other military group Khamisiyah participants were mechanisms, years after units detonation, and also residents of and the the exposure 405 had not been one of the 5 states Khamisiyah involved, and the of OR, WA, CA, NC population of remainder were or GA veterans was unsure; not evenly veterans had to distributed be resident in one throughout the of the 5 states of US, so there OR, WA, CA, NC may be bias due or GA to location

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AUTHOR: McCauley et al 2002

TITLE: Illness experience of Gulf War veterans possibly exposed to chemical warfare agents

HYPOTHESIS: To evaluate the prevalence of self-reported medical diagnoses and hospitalisations among a potentially exposed population of GW veterans from Oregon, Washington, California, North Carolina and Georgia and among comparison groups of veterans deploted and nondeployed to the SW Asia theater of operations

STUDY DESCRIPTION EXPOSURE & HEALTH RESULTS OUTCOME Location Type of Data Date Study population Reference Measure of Other risk Outcome Narrative description of Statistical study collection of population exposure factors / bias variables basic results methods period study / confounders Iraq Cross- October 2001 653 Desert Storm 610 Desert storm Exposure Region of Medical Troops within 50km of Factor (Khamisiyah sectional 1998 to veterans present Non-Khamisiyah history residence, conditions Khamisyah site did not analysis of /US April within a 50 km military personnel taken from gender and diagnosed differ from other deployed self-reported 1999 radius of who were telephone age by a troops on reports of any health symptoms. Khamisiyah, deployed in the questionnair physician medical conditions or ORs were Coalition-Occupied Gulf during the e interview hospitalisations in the 9 reported for a Iraq who may have Gulf War, but were years following the GW. study group to been exposed to outside the 50 km Deployed troops were report being sarin /cyclosarin radius and had no significantly more likely to diagnosed during first 2 weeks known exposure to report diagnosis of several with a of Mar 1991. NB. nerve agents; symptoms that included particular The authors do not 516 Non-Deployed high blood pressure health outcome provide additional personnel who had (OR=1.7); slipped dick or

information on the been on active pinched nerve (OR=1.5); rationale or method duty at the time of PTSD (OR=14.9); used to estimate the Gulf War, but hospitalisation for 50km radius ; not deployed to the depression (OR=5.1) veterans had to be Gulf; (among other symptoms) resident in one of Participants from compared to non-deployed the 5 states of OR, both groups were troops WA, CA, NC or GA also residents of one of the 5 states of OR, WA, CA, NC or GA

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AUTHOR: Miranda et al 2002a This was identified via cross-referencing of Delgado et al (2004) (Scand J Work)

TITLE: Onset of grip- and pinch-strength impairment after acute poisonings with organophosphate insecticides

HYPOTHESIS: To evaluate motor neurologic impairment after OP poisoning

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type Data Date Study Reference Measure of exposure Other risk Outcome Narrative Statistical methods of collection of population population factors / bias / variables description of basic study period study confounders results Nicaragua Cohort July 1992- 2002 59 men 39 cattle Pesticide used for Age, Motor Grip and pinch Multiple linear Dec 1996 hospitalised for ranchers and poisoning confirmed in education, neurologic strength were regression acute OP fisherman 38 patients. Authors lifetime OP impairment impaired among all analysis; where a Follow-up poisoning who had categorise pesticides pesticide (assessed OP-poisoned regression conducted between 1992 never according to whether exposure via hand subjects at both coefficient with a p at hospital and 1996 (8 experienced they were neuropathic history, grip and examinations (esp. value < 0.05 discharge intentional, pesticide (e.g. methamidophos, alcohol pinch among those considered and 7 and 51 poisoning chlorpyrifos and consumption, strength) poisoned with statistically weeks after occupational) (although fenthion) or non- body mass neuropathic OPs) significant; poisoning some had neuropathic (methyl index when compared Jonckheere- been exposed parathion, malathion, with controls; Terpstra test used to pesticides) terbufos, phorate, among severe to evaluate trends ediphenfos and poisonings with for means for metofox). Exposure neuropathic OPs, ordered categories; was categorised as impairments were paired-samples t- being either mild, more marked test to evaulate moderate and severe. among intentional intra-individaul Exposure was further than among mean change categorised as either occupational between first and moderate and severe poisonings, which second non-neuropathic worsened at examinations for poisonings and second every hand- moderate and severe examination strength test neuropathic

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AUTHOR: Miranda et al 2002b This was identified via cross-referencing of Delgado et al (2004) (Scand J Work)

TITLE: Tactile vibration thresholds after acute poisonings with organophosphate insecticides

HYPOTHESIS: To determine whether organophosphate poisonings cause persistent large-diameter myelinated sensory fibre impairment and evaluate the incidence and severity of impairment

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type Data Date Study Reference Measure of exposure Other risk Outcome Narrative Statistical of collection of population population factors / bias / variables description of methods study period study confounders basic results Nicaragua Cohort July 1992 2002 56 men 38 male Pesticide used for Callus, age, Large- Threshold of big Multiple linear to Dec hospitalised for members of poisoning confirmed in height, diameter toes of men with regression; 1996 acute poisoning fishing and 32 patients. Authors education, myelinated severe intentional vibrotactile with OPs (6 cattle co- categorise pesticides alcohol sensory fibre poisonings due to thresholds were Follow-up intentional and operatives who according to whether consumption, impairment neuropathic OPs used as the conducted 50 non- had never they were neuropathic days between via increased outcome at hospital intentional i.e. experienced (e.g. methamidophos, poisoning and cutaneous between the first variables as well discharge occupational pesticide chlorpyrifos and the quantitative and second as mean and approx overexposure) poisoning. NB. fenthion) or non- examination, tactile examinations as changes in index 7 weeks Of these 11 neuropathic (methyl examiner and vibration compared with finger and toe later were cattle parathion, malathion, OPs thresholds in controls; vibrotactile farmers, some terbufos, phorate, cumulative the dominant significant thresholds of whom had ediphenfos and exposure, time index finger threshold (difference in occassionally metofox). Exposure and great toe impairment was vibration been exposed was categorised as not detected in thresholds to pesticides being either mild, the index finger between the two moderate and severe. (regardless of evaluations). A Exposure was further poisoning agent regression categorised as either or severity) coefficient with a moderate and severe p value < 0.05 non-neuropathic considered poisonings and statistically moderate and severe significant neuropathic

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AUTHOR: Miranda et al 2004 This was identified via cross-referencing of Delgado et al (2004) (Scand J Work)

TITLE: Muscular strength and vibration thresholds during two years after acute poisoning with organophosphate insecticides

HYPOTHESIS: To evaluate the association of acute OP poisoning with chronic sensory and motor neurological impairment

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type Data Date Study population Reference Measure of Other risk Outcome Narrative Statistical methods of collection of population exposure factors / bias / variables description of study period study confounders basic results Nicaragua Cohort July 1992 2004 48 men (from an 28 healthy male Patient report on Age, education, Sensory and Men poisoned Vibration threshold – Dec original group of cattle ranchers hospital examination lifetime motor with OP distributions 1996 71) admitted to and fishermen, (confirmed by field exposure to abnormalities insecticides had normalised with log hospital for acute (from an visits) OPs, alcohol (obtained from persistent transformation; Follow- OP poisoning original group consumption, clinical reduced hand linear multiple up at two (either intentional of 74), who had Exposure categories body mass examination strength; Index regressions; years or occupational); never were moderate and index, lead and interview) finger and toe comparisons severity of experienced severe poisonings exposure, vibration expressed as poisoning classed pesticide caused by non- neurological thresholds were mean and SD, age as mild, moderate poisoning. NB. neuropathic OPs side effects of slightly increased adjusted or severe Some had been (e.g. medicinal at the end of the regression according to a exposed to methamidophos, drugs two year period coefficient with predefined list of pesticides but chlorpyrifos and among men with 95% CI; a signs and none reported fenthion) and OP poisonings in regression symptoms ever having neuropathic OPs all categories, but coefficient with been poisoned (e.g. edifenphos, patterns of onset p<0.05 was methyl parathion, and evolvement considered phorate, malathion of impairment of significant and terbufos) vibration sensitivity were less clear than with grip and pinch strength

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AUTHOR: Misra et al 1994

TITLE: A study of cognitive functions and event related potentials following organophosphate exposure.

HYPOTHESIS: Auditory Event Related Potentials altered in pesticide workers applying fenthion.

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AUTHOR: Mittal et al 2011

TITLE: Correlation of defects in regional cerebral blood flow determined by 99mTc SPECT with residual neurocognitive testing abnormalities during and 3 months post exposure in acutely poisoned patients with organophosphates

HYPOTHESIS: To determine regional cerebral blood flow (rCBF) abnormalities in the brain using a brain SPECT, and then correlate these abnormalities with neurocognitive deficits observed both during initial admission and at 3 months post exposure

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date of Study Reference Measure of Other risk Outcome variables Narrative description Statistical study collection study population population exposure factors / of basic results methods period bias / confounders India Cross- Jul 2009 2011 28 patients 20 adults Patient history; Not reported Neurocognitive Patients presented Data sectional to Dec with acute matched for age, serum AChE function assessed with a range of expressed as 2010 OP sex (from a activity via the following cholinergic mean ± SD. poisoning previous study) tests: trailmaking A symptoms. At Chi square admitted who were either and B; PGI discharge there were test, Student’s between hospital memory scale reduced performance t-test, p<0.05 July 2009 employees or (modification of in Trail B, verbal and healthy Weschler memory fluency, visual December attendants of the scale); retention, visual 2010 patients Verbal fluency test recognition, and (test of mental verbal retention (and flexibility) BVMG). At 3 months Bender-Visual follow-up there was Motor Gestalt test significant impaired (BVMG) (a test of performance in verbal visual-motor fluency, visual coordination. recognition and verbal retention (and BVMG) PGI had subtests, visual retention, visual recognition, verbal retention

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AUTHOR: Miyaki et al 2005

TITLE: Effects of sarin on the nervous system of subway workers seven years after the Tokyo subway sarin attack

HYPOTHESIS: There are chronic effects of sarin exposure on neurobehavioural function in subway workers 7 years after the exposure

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date of Study population Reference Measure of Other risk Outcome Narrative Statistical study collection study population exposure factors / bias / variables description of methods period confounders basic results Japan Cross- 2002; 2005 23 subway workers 13 non-exposed In the 2002 Exposure Performance Sarin-exposed Mean values from (Tokyo) sectional results who were exposed referent subway data, high status, age, on neuro- subway workers neurobehavioural merged to the Tokyo workers; exposure was BMI, behavioural performed less tests of with those subway sarin with the merged assumed in 5 educational tests for well in finger psychomotor of a attack (5 of these data from the workers level, psychomotor tapping tests, and function and data previous deemed to have 1998 study, 65 hospitalised smoking, and memory with the merged from stabilometry study in had high exposure, referent non- immediately drinking, function, and data, the exposed compared by 1998 and 18 low exposed after poisoning, General stabilometry group performed Student’s t-test exposure); subway whereas low Health less well in the and one-way when results workers, rescue exposure was Questionnaire backward digit ANOVA; multiple merged with 1998 staff and police assumed in the (GHQ) score, span test. regression model cross-sectional officers 18 workers who Impact of The results also applied. study of rescue attended Event Scale suggest a chronic ORs and 95% staff and police hospitals as (IES) score, decline of CIs reported for officers, there were outpatients post-exposure psychomotor and aspects of 80 exposed period (3 or 7 memory function, psychomotor subjects in all, 30 years) still evident 7 function and with high exposure years after the memory function, and 50 with low sarin exposure and also some p exposure values

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AUTHOR: Morahan et al 2007

TITLE: A gene-environment study of the paraoxonase 1 gene and pesticides in amyotrophic lateral sclerosis

HYPOTHESIS: Frequencies of some PON1 polymorphisms are greater in patients with sporadic amyotrophic lateral sclerosis (SALS) as compared to controls, and there are gene-environment interactions with pesticide/herbicide exposure

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AUTHOR: Muller-Vahl et al 1999

TITLE: Transient severe parkinsonism after acute organophosphate poisoning

HYPOTHESIS: Transient Parkinsonism is a sequela of acute organophosphate poisoning

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AUTHOR: Murata K et al 1997

TITLE: Asymptomatic sequelae to acute sarin poisoning in the central and autonomic nervous system 6 months after the Tokyo subway attack

HYPOTHESIS: Acute exposure to sarin (Tokyo subway incident) is associated with prolonged effects on Event Related Potentials (ERPs).

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure Other risk factors / Outcome Narrative description Statistical study collection of population population of bias / confounders variables of basic results methods period study exposure Japan Case- Septemb 1995. 18 subjects 18 matched No direct No differences in P300, P100 No definite Student’s t-test control er - exposed to controls for measure of age, tobacco use amplitude/latenc conclusions can be with Bonferroni Novembe sarin age, sex. exposure. and alcohol y reached from this correction. r 1995 When sarin consumption study. Analysis of cases first covariance (Incident arrived at between groups. performed on P2, took hospital The P300 data were N2, P300 place they considered consistent components March exhibited with abnormal separately taking 1995) signs/sympt performance of into account the oms of attention and/or preceding cholinergic memory function component as a poisoning. covariate. Amplitude data for P300 at the Cz and Pz was analysed using mixed model ANOVA.

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AUTHOR: Muttray et al 2005

TITLE: Acute effects of low doses of methyl parathion on human EEG

HYPOTHESIS: On a group basis, quantitative analysis of EEG may be more sensitive than serum and erythrocyte cholinesterase activity to monitor exposure to OPs

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AUTHOR: Nakajima et al 1999

TITLE: Sequelae of sarin toxicity at one and three years after exposure in Matsumoto, Japan

HYPOTHESIS: Symptoms reported one year after the Matsumoto sarin incident are likely to be sequelae of the single exposure to sarin

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AUTHOR: Nishiwaki et al 2001

TITLE: Effects of sarin on the nervous system in rescue team staff members and police officers 3 years after the Tokyo subway sarin attack

HYPOTHESIS: There are chronic effects of sarin on the nervous system

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study population Reference Measure of Other risk factors Outcome Narrative Statistical study collection of population exposure / bias / variables description of methods period study confounders basic results Japan Cross- 2 years and 2001 54 male exposed 52 non- High-exposed Age, height, Psychomotor Authors results of (Tokyo) sectional 10 months subjects, exposed persons deemed weight, alcohol function as observed neurobehavioural to 3 years consisting of referent to be those consumption, assessed by chronic decline tests report and 9 rescue team staff subjects hospitalised smoking status, finger tapping, of memory mean, SD, and p months after members of the matched for immediately after educational level; simple reaction function in values for the sarin Tokyo Fire age and poisoning, and psychometric time and choice rescue team variable of group attack in Department, and occupation low-exposed variable scores reaction time staff members in multiple March 1995 police officers in those who (IES, Impact of tests; memory and police regression the Metropolitan attended Events Scale, function officers 2 years analysis Police Department; hospitals as and GHQ, assessed by digit and 10 months subjects were also outpatients General Health span and Benton to 3 years and divided into a high- Questionnaire visual retention 9 months after exposed group of evaluating test; chronic exposure to 25 who had been general mental effects on sarin in the hospitalised health) were balance, Tokyo subway immediately after used as possible assessed by attack; the the attack, and a confounders of stabilometry; finding was low-exposed group the stabilometry, vibration independent of of 29 who attended vibration perception traumatic hospitals as perception thresholds; stress outpatients threshold, and traumatic stress symptoms neurobehavioural symptoms tests

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AUTHOR: Ohayo-Mitoko et al 2000

TITLE: Self-reported symptoms and inhibition of acetylcholinesterase activity among Kenyan agricultural workers

HYPOTHESIS: Kenyan agricultural workers suffer symptoms as a result of their exposure to pesticides; levels of inhibition of acetylcholinesterase can be related to reported symptoms, and levels of inhibition at which symptoms become increased can be evaluated

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AUTHOR: Ohtani et al 2004

TITLE: Post-traumatic stress disorder symptoms in victims of Tokyo subway attack: a 5-year follow-up study

HYPOTHESIS: Long-term somatic and mental symptoms of sarin poisoning persist 5 years after the Tokyo subway attack

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study population Reference Measure of Other risk factors Outcome Narrative Statistical study collection of population exposure / bias / variables description of basic methods period study confounders results Japan Cross- April to 2004 34 victims (20 None None; Not considered Post-Traumatic Post-traumatic Mean scores and (Tokyo) sectional October males, 14 females) victims Stress Disorder stress disorder frequency of 2000 of the Tokyo were (PTSD) (PTSD) and also symptoms on subway sarin attack treated in symptoms, and non-specific mental Clinician- who were treated at emergency other non- symptoms persisted Administered emergency wards wards for specific mental in the victims 5 Post-Traumatic for acute sarin sarin symptoms years after the Stress Disorder intoxication at St. poisoning attack; a significant Scale(CAPS); Luke’s International after the correlation between correlation Hospital in Tokyo, attack the total score of between IES-R and who agreed to IES-R and CAPS (Impact of Event undertake the was found, Scale-Revised) survey and undergo indicating that and WMS-R psychological and IES-R is a useful (Wechsler psychiatric tool for evaluating Memory Scale- investigations PTSD Revised) scores Visual memory and CAPS lower in PTSD scores, P values group reported

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AUTHOR: Okudera, 2002

TITLE: Clinical features on nerve gas terrorism in Matsumoto

HYPOTHESIS: Clinical features in patients can be described after the Matsumoto attack, and in follow-up studies

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date of Study Reference Measure of Other risk Outcome Narrative Statistical study collection study population population exposure factors / bias / variables description of methods period confounders basic results Japan Clinical 27 and 28 2002 105 poisoned N/a A presumed large N/a Clinical Miosis was the N/a (Matsumoto) study June 1994; patients; 155 amount of sarin symptoms from most common July 1994 residents gas released on examinations finding in patients examined 3 27 June, 1994 in a immediately examined shortly weeks after residential area of after the attack, after the attack; exposure the city of 3 weeks later, other complaints Matsumoto and at 1 and 3 at 3 weeks follow- years after up included exposure (these dysaethesia of are not extremities, easy described, fatigue, ocular referred to pain and eye Nakajima (1999) weakness. A few above) victims had arrhythmia and decreased cardiac contraction after the attack; abnormal EEG recorded in 2 patients

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AUTHOR: Orozco-De Los Rios et al 2005 (Abstract evaluated, article in Spanish – Paper unobtainable)

TITLE: Peripheral neuropathy and deterioration of the cognitive functions associated to chronic exposure to organophosphates

HYPOTHESIS: To evaluate the relationship between chronic exposure to organophosphorus insecticides (in the presence of neuropathy) and deterioration of cognitive functions

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study population Reference population Measure Other risk Outcome Narrative description Statistical study collection of of factors / bias / variables of basic results methods period study exposure confounders Mexico Cross- Not 2005 Workers with > 3 Workers with > 3 Not clear Alterations in Cognitive Deterioration of Not sectional reported in months of seniority months of seniority in abstract neurological function, cognitive function and reported in abstract who participated in without direct exposure function peripheral peripheral neuropathy abstract any stage of the OP to OP insecticides. NB. neuropathy greater in exposed insecticide This would need to be group cf. controls production verified

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AUTHOR: Otero et al 2000 (Abstract evaluated, article in Spanish)

TITLE: Neurobehavioural study in workers exposed to pesticides

HYPOTHESIS: To design a neuropsychological battery of tests to assess neurotoxic symptoms in workers chronically exposed to pesticides

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AUTHOR: Ozturk et al 2008

TITLE: Insecticide contamination as a cause of food related illness.

HYPOTHESIS: To describe nine OP poisoning incidents after eating bread rolls made at the same bakery from wheat flour contaminated with chlorpyrifos

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AUTHOR: Ozyurt et al 2008

TITLE: Comparison of SPECT findings and neuropsychological sequalae in carbon monoxide and organophosphate poisoning

HYPOTHESIS: To examine abnormal regional cerebral blood flow in patients with acute carbon monoxide and OP poisoning and evaluate the predictive significance of acute phase brain single photon emission computed tomography (SPECT) findings for long-term neuropsychological sequelae

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure of Other risk Outcome variables Narrative description of Statistical study collection of population population exposure factors / bias / basic results methods period study confounders Turkey Cross- Feb 1995 2008 14 patients (7 SPECT Circumstantial Previous Long term Heterogenous changes Kolmogorov- sectional to Dec acute OP image and clinical history of neuropsychological found in several lobes Simirnov Z 2003 poisoning analysis: evidence, psychological/ sequelae within first week after test; statistical taken orally – healthy plasma neurological (as revealed by poisoning (i.e. frontal, significance either in controls cholinesterase disorders SPECT image temporal and parietal); defined as suicide levels analysis performed neuropsychological p < 0.05 attempts/ within 1-3 weeks of sequelae developed in 3 accidentally) treatment) OP poisoned patients with lobe changes (i.e. disorientation). NB. Three patients with normal SPECT scans demonstrated disorientation, convulsion and tremor

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AUTHOR: Page, 2003

TITLE: Long-Term Health Effects of Exposure to Sarin and Other Anticholinesterase Chemical Warfare Agents

HYPOTHESIS: To compare the current health of military volunteers exposed to anticholinesterase agents with non-exposed volunteers

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type Data Date Study Reference Measure of Other risk Outcome Narrative description of basic Statistical of collection of population population exposure factors / bias / variables results methods study period study confounders US Cohort Not clear 2003 855 military 2 groups: (a) Experimental Age at Self reported Few statistically significant Chi-squared (Follow-up volunteers 752 military and self- testing, race, neuro- differences between general tests, hazard to previous exposed to volunteers not reported self-reported psychological long-term health effects of ratios, chi- survey AChE agents exposed to exposure. chemical impairment ANTICHOL and two control squared and t- conducted as part of an active NB. No info exposure and (incl. sleep groups; with the exception of tests, least in 1985) experimental chemicals provided re: psycho- disorders, greater no. of attention problems squares programme (NCT) and (b) levels of chemical anxiety, in OCT cf. ANTICHOL long term regression and between 871 subjects exposure exposure (i.e. depression) neurological and psychological logistic 1955-1975 exposed to ≥ 2 LSD, serynl and effects of exposure were similar regression; (ANTICHOL) other types of and cannabis neurological across groups; two statistically statistically chemical derivatives) deficits (incl. significant differences in risk significant NB. Subjects agents (i.e. peripheral estimates (for both self-reported difference were exposed anti- nerve and experimental chemical (p<0.05) cf. to to at least 1 of cholinergics, disease and exposures) between the OCT 15 AChE cholinesterase vestibular ANTICHOL and either control substances reactivators, dysfunction) group: attention problems (OCT with OP psycho- > ANTICHOL); sleep disturbance agents (sarin chemicals, (ANTICHOL > NCT). and VX) and irritants, NB. All risk estimates for non eserine the vesicants, experimental exposure larger most common drugs and than their experimental innocuous counterparts chemicals (OCT). NB. Second group added due to built in selection bias and lack of suitable control population

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AUTHOR: Palacious-Nava et al, 1999 (Abstract evaluated, article in Spanish)

TITLE: Persistent symptomatology in workers industrially exposed to organophosphate pesticides

HYPOTHESIS: To describe the patterns of persistent symptomology in workers industrially exposed to organophosphate pesticides

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure of Other risk Outcome Narrative description of basic results Statistical study collection of population population exposure factors / bias variables methods period study / confounders Not Cross- Not 1999 89 workers Managers – no Work history; Not clear Persistent Persistent symptomology found in Chi- reported sectional reported industrially further info erythrocyte from abstract symptoms 6.3 per 10 workers; highest squared in in exposed to OP provided. (This cholinesterase proportion of symptoms found in test, ORs abstract abstract pesticides (This would need to level workers aged 31-40 years with 6-13 would need to be verified as years of service from the be verified as not clear from maintenance area working as not clear from abstract) general operators or supervisors; abstract) among 13 workers with previous intoxication prevalence of persistent symptomatology was 6.9 cf. 6.1 in workers who had not been previously intoxicated

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AUTHOR: Parron et al 2011

TITLE: Association between environmental exposure to pesticides and neurodegenerative diseases

HYPOTHESIS: To understand the potential association between environmental exposure to pesticides and the development of a number of neurodegenerative diseases.

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study population Reference Measure of Other risk Outcome Narrative Statistical methods study collection of population exposure factors / bias / variables description of basic period study confounders results Spain Ecological 1998- 2011 17,429 Andalusian 8868 cases Andalusian Age, gender, Alzheimer’s Prevalence rates Prevalence rates, study 2005 residents (cases) categorised health districts, environmental disease (AD), and the risk of ORs (95% Cis), p collected from as living in Spain were pesticide Parkinson’s having AD PD, MS values reported; Chi computerised areas of categorised exposure, disease (PD), and SA were square test, Student hospital records of low into areas of interaction Multiple sclerosis significantly higher t-test; Backwards the Andalusian pesticide high and low between (MS), cerebral in districts with stepwise multiple Health Service exposure environmental pesticide use degeneration greater pesticide logistic regression (Minimum Dataset) pesticide and gender (CD), use as compared to diagnosed with any exposure polyneuropathies those with lower of the based on the (PN), affective pesticide use The neurodegenerative number of psychosis (AP), multivariate conditions of hectares and suicide (SA) analyses showed interest (see devoted to attempts that the population outcome variables). intensive living in areas with 8561 cases were agriculture and high pesticide use categorised as pesticide sales had an increased living in areas of per capita risk for Alzheimer’s high pesticide disease and suicide exposure attempts and that males living in these areas had increased risks for PN, AD and SA

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AUTHOR: Pathak et al 2011

TITLE: Nerve conduction studies in sprayers occupationally exposed to mixture of pesticides in a mango plantation at Lucknow, North India

HYPOTHESIS: To determine organochlorine pesticide residues in blood, cholinesterase activity, and nerve conduction among sprayers exposed to a mixture of pesticides in a mango plantation of Lucknow District, India

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study population Reference Measure of Other risk Outcome Narrative description Statistical study collection of population exposure factors / bias variables of basic results methods period study / confounders India Cross- Mar 2008 2011 52 male sprayers 18 administrative Questionnaire- Chronic Peripheral OC pesticide Student’s t- (Lucknow) sectional to Jun from mango office employees based interviews of disease, age, neuropathy residues (a-HCH tests, Chi- 2009 plantations who working in the personal and exposure (assessed isomer and total square regularly spray same area with occupational duration as via nerve HCH) were higher statistics, mixture of similar histories. potential conduction compared to Fisher exact pesticides like socioeconomic Blood analyses of confounders velocity controls. test, OPs, status who do not OC residues e.g. studies) Cholinesterase Spearman’s organochlorines handle pesticides hexachlorohexane levels were correlation, and carbamates. (HCH) and DDT and significantly reduced Linear their various among sprayers regression, isomers. with more than 10 p<0.05 AChE and BChE years exposure. activities Sprayers with low AChE activity had a higher risk of motor nerve conduction deficits. Negative correlation of nerve conduction deficits (motor and sensory) with duration of exposure and age were observed among sprayers

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AUTHOR: Payan-Renteria et al 2012

TITLE: Effect of Chronic Pesticide Exposure in Farm Workers of a Mexico Community

HYPOTHESIS: To evaluate the acute and chronic toxic effects in farm workers of the Nextipac population chronically exposed to pesticides

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study population Reference Measure of Other risk Outcome Narrative description of Statistical study collection of population exposure factors / bias / variables basic results methods period study confounders Mexico Transversal May to 2012 25 farm-workers 21 Nextipac Occupational Exclusions Various Acute poisoning was Cluster (Jalisco) comparative Aug 2009 and Nextipac inhabitants history. based on clinical, observed in 20% of multivariate study. Cross- inhabitants who had not Erythrocyte workers not subclinical, exposed subjects. analysis, sectional?? engaged in sprayed cholinesterase living in cytotoxic and Pesticide exposure Spearman’s pesticide spraying pesticides activity Nextipac, biomolecular was associated with correlation (mainly OPs (in during the confounding effects alterations in various coefficient, 80% of users), farming pathologies body systems including significant= p < triazines (10%) and season (May neurological symptoms 0.05; marginal organochlorine to Aug 2009) reported in 16% of significance = compounds (10%) exposed subjects and p > 0.05 and < during the farming none in unexposed 0.1 season subjects. Reported signs and symptoms included muscle cramps, dizziness, blurred vision, headaches, nausea, abdominal pain, and chronic rhinitis

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AUTHOR: Peiris-John et al 2002

TITLE: Effects of Occupational Exposure to Organophosphate Pesticides on Nerve and Neuromuscular Function

HYPOTHESIS: To investigate whether neurophysiological abnormalities occur among farmers exposed to OP pesticides and determine the relationship between these abnormalities and the extent of exposure, and also to determine the extent of exposure in persons not directly exposed

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data collection Date Study Reference Measure of Other risk factors / Outcome Narrative description of Statistical study period of population population exposure bias / confounders variables basic results methods study Sri Cross- Evaluated during 2002 30 farmers 30 Occupational Vitamin deficiency, Neuro- With respect to the T-tests Lanka sectional an who fisherman history and encephalopathy of physiological between cultivation (paired, intercultivation regularly living close details of known origin, abnormalities seasons: sensory independent season i.e. spray OP but not farming history of long term (determined via conduction velocity sample,) between pesticides involved in activities administration of various motor, significantly higher in cultivation/ pesticide obtained via psychotropic sensory and farmers cf. controls spraying spraying interviewer medication or neuromuscular (p=0.04) and motor seasons (Jun/Jul administered previous injury tests) conduction velocity 2000) and during questionnaire; resulting in significantly higher in a cultivation erythrocyte deformity and/or controls cf. farmers season AChE activity other abnormality of (p=0.04); (April/May 2000) limbs affecting neurophysiological tests peripheral conducted during sensations cultivation failed to generate any significant results; sensory conduction velocities significantly reduced during cultivation in both farmers and control groups (p<0.01 and p=0.04 respectively); farmers had higher AChE levels cf. controls although non-significant

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AUTHOR: Pilkington et al 1999a (Research Report TM/99/02b)

TITLE: Epidemiological study of the relationships between exposure to organophosphate pesticides and indices of chronic peripheral neuropathy, and neuropsychological abnormalities in sheep farmers and dippers. Phase 2. Cross-sectional exposure response study of sheep- dippers

HYPOTHESIS: To study the relationship between cumulative exposure to OPs, and clinically relevant indices of peripheral neuropathy

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure of Other risk Outcome Narrative description of Statistical methods study collection of population population exposure factors / bias variables basic results period study / confounders UK Cross- 1996- 1999 612 Two groups of low Retrospective Age, regional Clinically Higher rates of symptoms Chi-squared tests (England/ sectional 1997 farmers exposed workers: (i) exposure location, sex, relevant between OP exposed sheep of association and Scotland) with sheep 53 pig and chicken history alcohol indices of dippers as a group the kappa statistic, dipping farmers/farmworkers questionnaire consumption, peripheral compared with non-exposed logistic regression experience. with no sheep wrt. flock concentrate neuropathy workers. Sensory used to calculate dipping experience; size, handling, via symptoms symptoms were more ORs, LOWESS (ii) 107 ceramic concentrate occupational questionnaire, commonly reported than Scatterplot, workers handling and group all and motor symptoms by sheep multiple linear principal explored quantitative dippers. Markedly higher regression; p task/job; sensory tests rates of reported symptoms values reported cumulative based on (adjusted for other factors) OP exposure Mayo Clinic were reported among those based on methodology who had at some total number time been principal of dipping concentrate handlers. No days, evidence that cumulative concentrate exposure to OPs was handling associated with impairment events, of measured sensory exposure to thresholds, although the dilute dip and possibility of an associated a combined sensory neurophysiological index based component to the QST on a Phase 1 effects and concentrate model of OP exposure should not be uptake discounted

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AUTHOR: Pilkington et al 1999b (abstracted from the reference list of the following review papers: Jamal et al 2002; Lotti, 2001; Lotti & Moretto, 2005)

TITLE: Epidemiological study of the relationships between exposure to organophosphate pesticides and indices of chronic peripheral neuropathy, and neuropsychological abnormalities in sheep farmers and dippers. Phase 3. Clinical neurological, neurophysiological and neuropsychological study

HYPOTHESIS: To classify in terms of clinical disease the subjects with abnormal indices of peripheral neuropathy identified in earlier Phase 2 field studies; to describe any associations between neurological and neuropsychological abnormalities; and to examine any evidence for a relationship between neuropsychological status and estimated cumulative OP exposure

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of study Data Date Study Reference Measure of Other risk factors / Outcome variables Narrative description Statistical methods collection of population population exposure bias / confounders of basic results period study UK Nested case- Nov 1999 76 sheep 17 subjects Exposure Age, IQ, regional Neurological Neuropathy is Neuropsychological (England/ control 1995 to farmers (of without history location, previous abnormalities i.e. predominantly of a test variables were Scotland) clinical Apr 1999 which 17, neuropathy questionnaire medical history peripheral sensory type (both regressed against 36 and 23 in previous wrt. flock size, (i.e. rheumatoid neuropathy via clinically and the log transformed NB. Cross- subjects Phase 2 concentrate arthritis, family quantitative neurophysiologically) cumulative sectional comprised (neuropathy) handling and history of sensory tests, also and is characteristic exposure index, (wrt. neuro- the ‘no’, principal high arches, and nerve conduction of distal, chronic OPEXP psychological ‘possible’ task/job hypertension and neuropathy with no simultaneously outcomes) and (including a requiring electromyography. acute features; adjusting ‘probable’ recent medication); other Neuropsychological increasing severity for age and verbal and exposure neurophysiological abnormalities (i.e. of neuropathy (as IQ using multiple ‘definite’ questionnaire); abnormalities e.g. via general based on symptoms linear regression neuropathy cumulative OP carpel tunnel intelligence, and sensory tests in for the normal categories exposure syndrome and psychomotor clinic) associated responses and respectively based on radioculopathy) function, attention, with anxiety and logistic regression as derived model of OP memory, mood and depression; for the binomial from the uptake during affect tests) neuropsychological responses; field field study). sheep dipping findings were not study: session associated with reproducibility of cumulative exposure measurements via to OPs cross tabulation and kappa statistic to summarise

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AUTHOR: Pilkington et al 2001

TITLE: An epidemiological study of the relations between exposure to organophosphate pesticides and indices of chronic peripheral neuropathy and neuropsychological abnormalities in sheep farmers and dippers

HYPOTHESIS: To investigate the hypothesis that chronic low-level exposure to OPs in sheep dips is related to clinically detectable measures of polyneuropathy i.e. that repeated exposures to OPs may cause cumulative and irreversible damage to nervous tissue, which eventually becomes clinically detectable

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure of exposure Other risk Outcome variables Narrative Statistical study collection of population population factors / bias description of methods period study / basic results confounders UK Cross- 1996-97 2001 612 sheep 53 farmers Retrospective Age, alcohol Neurological/neuropathy Weak positive Linear logistic sectional (winter) dipping with no exposure info via habit, deficits (assessed via association regression farmers sheep questionnaire with country standard neuropathy between (ORs for dipping estimates of handling symptoms questionnaire cumulative reporting experience concentrate and and thermal/vibration exposure to OPs symptoms, and 107 diluted dip splashing quantitative sensory tests) and neurological LOWESS, ceramic (via empirical dermal symptoms; no multiple linear workers exposure model evidence of an regression; derived for two urinary association significance at OP metabolites); between p<0.05 cumulative exposure cumulative to OP dips calculated; exposure to OPs daily intensity of and thermal or exposures to both vibration sensory concentrate and thresholds splash estimated

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AUTHOR: Povey et al 2005

TITLE: Paraoxonase polymorphisms and self-reported chronic ill-health in farmers dipping sheep

HYPOTHESIS: OPs contribute to the reported ill-health of people who dip sheep, using a more homogenous case and referent population than in a previous (2002) study

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure of Other risk Outcome Narrative Statistical methods study collection of population population exposure factors / bias / variables description of period study confounders basic results UK case- July 1999 2005 175 cases of 234 farmers Self-reported Sex, region, Presence of The risks of Subjects were first referent to May farmers with ill nominated by the dipping activity date of first polymorphisms case status excluded on clinical study 2000 health that they cases as people in dipping, age at position 192 associated with grounds, and then attributed to who dipped sheep questionnaire and position 55 the QR or RR using discriminant sheep dip; and were not and interview; of PON1 and genotype versus analysis: a farmers blood relatives, blood sample reported ill QQ, and with stepwise method in recruited by who they thought taken for health in the LL genotype which, at each step, advertisement to be in good PON1 farmers versus LM or the variable that health, who lived genotyping MM, remained minimised the near them, were and to check elevated even unexplained within 10 years of diazoxonase after exclusion variance (Wilk’s age of them, and activity of subjects on Lambda) was with similar sheep clinical grounds entered. A dipping activity to or by minimum F to enter their own discriminant and maximum F to analysis. The remove were set. refinement of Odds Ratios the study reported for PON1- population 192 and PON1-55 made very little genotype and case difference to the status risk

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AUTHOR: Povey et al 2007a

TITLE: Final Report: Disabling Neuropsychiatric disease in farmers exposed to organophosphates: Phase 1: The Study of Health in Agricultural Work Cohort (VM02115)

HYPOTHESIS: If OP exposure were a cause of neuropsychiatric disease then any adverse ill-health would be associated with handling the sheep dip concentrate

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure of Other risk factors Outcome Narrative description Statistical study collection of population population exposure / bias / variables of basic results methods period study confounders UK Cohort (of No info 2007 1338 farmers Farmers who Self-reported Age, sex, school- Depression, Handling concentrate Cross tabulation the Study provided (from approx answered exposures from leaving age, dementia, for treating pests on and comparison of Health in 19K) from the ‘No’ to job history/ i.e. employment parkinsonism sheep was significantly of means (or Agricultural 1970s variable working in status, farm and associated with screen medians) used to Work (analysis under study specific farming affected by Foot neuropathy; identified neuropathy examine (SHAW) restricted to (i.e. for each sector, specific and Mouth ill-health and and Parkinsonism but associations study) those aged 13 screen- farming activities, Disease or seeking not screen identified between case- or over – legal identified ill sheep dip Bovine medical depression or control status age health handling Spongiform advice for dementia; risk of and demographic requirement remaining practices Encephalopathy pesticide seeking advice for and farming for agricultural/ participants (obtained via poisoning pesticide poisoning factors with horticultural who had not screening increased in farmers univariate work). NB. been questionnaire). that sheared and analysis (i.e. chi- Responses to identified as NB. Sheep dip dipped sheep and square, t-tests) to individual a case) handling handled sheep dip compare values questions practices used as concentrate; exclusion in the two used to a surrogate of of subjects who sought groups; multiple identify cumulative OP medical advice or logistic individual exposure pesticide poisoning regression used cases of (although limited resulting in non to examine the outcome by the fact that significantly but risk (odd ratio) of variables OP and non-OP elevated risks of being a case; products were neuropathy and authors report used since Parkinsonism 95% CI 1970s) associated with handling sheep dip concentrate

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AUTHOR: Povey et al 2007b

TITLE: GST, CYP and PON1 polymorphisms in farmers attributing ill health to organophosphate-containing sheep dip

HYPOTHESIS: Polymorphisms in genes other than PON1 involved in xenobiotic metabolism alter disease risk in farmers who use OP- containing sheep dip

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type Data Date Study Reference Measure of Other risk Outcome Narrative description of Statistical of collection of population population exposure factors / bias / variables basic results methods study period study confounders UK Case- July 1999 2007 175 cases of 234 farmers Self-reported Sex, region, Presence of There were elevated Frequencies for referen to May farmers with nominated by the dipping activity date of first polymorphisms but not significant risks categorical data t study 2000 ill health that cases as people in dipping, age; at position 192 associated with the and means with they who dipped questionnaire these are and position 55 CYP2D6 WT genotype SD for attributed to sheep and were and interview; reported to of PON1 and and some GST continuous data; sheep dip; not blood blood sample have had little reported ill health genotypes. There was ORs and t tests farmers relatives, who taken for PON1 effect on ORs, in farmers, and no evidence for an to detect recruited by they thought to genotyping and so unadjusted presence of association between differences in advertisemen be in good to check results are polymorphisms CYP3A4 and 3A5 categorical and t health, who lived diazoxonase presented in the genes polymorphisms and continuous data. near them, were activity, and for throughout GSTM1, GSTT1, self-reported ill health. Logistic within 10 years genotyping of GSTP1, Risk associated with regression of age of them, GSTM1, CYP2D6, PON1 genotype and analysis, and with similar GSTT1, CYP3A4 and phenotype varied with reporting ORs sheep dipping GSTP1, CYP3A5 and CYP2D6 and GSTP1 and 95% CIs, for activity to their CYP2D6, reported ill health genotype, but not risk of being a own CYP3A4 and in farmers consistently with case and PON1, CYP3A5 predictions of increased GST and CYP risk status

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AUTHOR: Povey et al 2009

TITLE: Final Report: Disabling Neuropsychiatric disease in farmers exposed to organophosphates: Phase 2: (VM02115)

HYPOTHESIS: To determine whether identified Phase 1 cases of depression, dementia, Parkinsonism or neuropathy differed in their exposure to OPs than randomly selected cohort members (to better characterise not only exposure but also health outcomes of farmers, which were previously based on crude assessments)

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study population Reference Measure of Other risk Outcome Narrative Statistical methods study collection of population exposure factors / bias variables description of basic period study / results confounders UK Case- No info 2009 234 eligible Random Lifetime estimate Lack of Depression, Crude prevalence Cross tabulation and cohort (of provided farmers from selection of pesticide clinical dementia, rate for: comparison of means the Study of phase one of other exposure (i.e. confirmation Parkinsonism depression, used for univariate Health in (screen identified farmers working life) of cases by or neuropathy dementia lower comparisons of (i) Agricultural cases of during sheep trained (via scoring or than Phase 1 rates; farmers who agreed to Work aforementioned dipping (or from expert trained nurse parkinsonism lower take part and those (SHAW) health outcomes) 1970 to present examination) or higher than who refused and (ii) study) day) using Phase 1 rates farmers who were algorithms based (depending on interviewed and those either on total definition used); who were not with number of sheep neuropathy was univariate analysis (chi- dipped or tasks higher than Phase square, t-tests) used to done. NB. 1 rates; no compare values in two These exposure association groups ; health estimates are between exposure outcomes also considered less estimates and analysed cross crude than those Phase 2 identified tabulation and used in Phase 1 depression, comparison of means dementia or (and medians) and Parkinsonism; simple univariate significant analysis; geometric/ association arithmetic mean for log between Phase 2 transformation of neuropathy and exposure estimates; p- pesticide exposure values are reported estimates

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AUTHOR: Povey, 2010

TITLE: Gene-environmental interactions and organophosphate toxicity

Date of Review 2010

Aim To critically examine some of the issues involved in studying gene-environmental interactions in OP toxicity

Topics covered Sheep farmers exposure to OP pesticides Genes involved in OP activation and detoxification Population studies examining susceptibility to OPs Health outcomes Parkinson’s disease considered Self-reported chronic ill health

Original studies Dunn, 2002. Report on an Analytical Study of OP Sheep Dip Reports. Veterinary Medicines Directorate, Surrey. http://randd.defra.gov.uk/Document.aspx?Document=VM02112_2423_FRP.doc (NB. A descriptive and exploratory study summarising exposure and not identified in symptom reports) literature search/ (not included in Povey et al 2010. Prospective cohort study of sheep dip exposure and ‘dippers flu’. HSE Res. Rep. 775, http://www.hse.gov.uk/research/rrpdf/rr775.pdf (NB. Objective was to carry out studies to support a clinical definition of dipper’s flu, to determine it’s incidence, to elucidate what causes it (in particular selected refs) whether organophosphate exposure is a factor and to characterise relevant exposure patterns if this is the case) and the extent to which sufferers go on to develop chronic disease).

NB. Other studies referenced in this review did not meet inclusion criteria (i.e. pre-dated 1999, non-OP specific or non-epi-study, mechanistic/in-vivo/in- vitro study; non-neurological health outcomes, methodological, exposure biomonitoring/biomarker studies) or are already included in the screening process

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AUTHOR: Povey et al 2010 (abstracted from the reference list of a review paper by Povey, 2010)

TITLE: Prospective cohort study of sheep dip exposure and ‘dipper’s flu’ (RR775)

HYPOTHESIS: To investigate the nature, frequency and signs of ill-health among farmers treating sheep for ectoparasites and establish whether farmers developing flu-like symptoms differed in their exposure to OPs, endotoxins and infectious agents when compared to other farmers operating at the same time who remained symptom free

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Locatio Type of Data Date Study population Reference Measure of Other risk Outcome Narrative description of Statistical n study collection of population exposure factors / bias / variables basic results methods period stud confounders y UK Phase 1: 2005 to 2010 781 sheep dip None Self reported Demographic Flu-like Increase in symptom Symptom scores; Cohort 2006 farmers who reported. pesticide use (via (e.g. sex, age, symptoms reporting immediately simple univariate planned to dip NB. work history drinking and (ascertained following treatment statistics; Phase 2: Phase 2: sheep during study Authors questionnaire e.g. smoking via symptom which was associated correlation Cross- (May period (from a note product and habits), diary, health, with the type of product analysis, p sectional 2005 to cohort of 8700 change in concentrate used); exposure and nurse and used (frequency of values less than study July sheep farmers). design of butyryl- health general symptom reporting 0.05 are 2005) NB. Farmers Phase 2 cholinesterase variables (e.g. questionnair higher in farmers using reported; follow-up times: a) from case- activity (blood); past dippers es ) OPs or pyrethroids cf. multivariate prior to sheep dip; control to pesticide urine flu) farmers used triazines. analysis of the b) during sheep cross- metabolites (for Symptom reporting in risk of reporting dipping (24-48 hrs sectional OPs or multivariate model also new symptoms after treatment due to pyrethroids) associated with health up to 48 hrs after finished); c) 2-3 difficulty measured pre- and status before treatment treatment was weeks later obtaining post- sheep dip and previous carried out using NB. All types of control treatment experience of dippers logistic treatment for sheep subjects flu, but not perceived regression with ectoparasites were risk of sheep dip. NB. and without included since pilot Holding competence adjustment for study findings certificate for handling possible indicated an pesticides and age confounders; increase in no. of associated with PCA of diary farmers using reduced risk symptom alternative complexes treatments such as pour-ons injections

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AUTHOR: Proctor et al 2006

TITLE: Effects of sarin and cyclosarin exposure during the 1991 Gulf War on neurobehavioural functioning in US army veterans

HYPOTHESIS: Low-level exposure from the 1991 Khamisiyah incident is associated with central nervous system effects 4-5 years after Gulf War deployment, specifically with poorer performances on neuropsychological tasks assessing visuospatial abilities and psychomotor functioning

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study population Reference Measure of Other risk Outcome Narrative Statistical study collection of population exposure factors / bias / variables description of methods period study confounders basic results Iraq Cross- Autumn 2006 Stratified, random Persons in Plume modelling Unit group, age, Performance on Significant Analyses of (Khamisiyah)/ sectional 1994 to subset of 1991 troop units for of estimated gender, general neuro- dose-response variance US summer Gulf War which no release and intelligence psychological relationships (ANOVAs) and 1996; veterans from the exposure level dispersion of sarin using WAIS-R tests to assess 5 between Student’s t tests exposure Devens Cohort was estimated and cyclosarin Information cognitive exposure to for continuous modelled Study; n=140; because they around the score, domains, sarin/cyclosari variables, χ² or for 4 persons in units were not in Khamisyah site; Mississippi including short- n and less Fisher’s exact days, with exposure locations persons were PTSD (Post term memory; proficient task tests for from 10th levels greater within the considered Traumatic mood states at performances categorical to 13th than 0.072 mg modelled exposed if they Stress Disorder) time of testing for psycho- variables; March min/m³ were plume areas were located in an scale scores, using the Profile motor dexterity Cohen’s effect 1991 defined as the (n=70); the area with an rank (officer vs. of Mood States and size is reported; high exposure majority were exposure estimate enlisted), (POMS) visuospatial 95% CI for each group (n=23); located in greater than the handedness, abilities were parameter persons in units Saudi Arabia General history of head present 4-5 estimate (e.g. with exposure coastal cities Population Limit of injury years following Purdue levels greater during the time 0.01296 mg exposure Pegboard, both than General period min/m³, defined by hands) reported; Population Limit the US Army and p values but no more than Centers for reported 0.072 mg min/m³ Disease Control were defined as and Prevention. the moderate Exposure exposure group estimates ranged (n=47) from 0.035 to 0.144 mg min/m³

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AUTHOR: Rainier et al 2008

TITLE: Neuropathy Target Esterase gene mutations cause motor neuron disease

HYPOTHESIS: It is possible that OP compounds contribute to motor neuron disease (MND), which occurs in OP compound-induced delayed neuropathy (OPIDN), in which neuropathy target esterase (NTE) is inhibited by organophosphrylation

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study population Reference Measure of Other risk Outcome Narrative description of Statistical study collection of population exposure factors / bias / variables basic results methods period study confounders US Genetic ?2007 2008 A consanguineous N/a Not done N/a Progressive Study shows that two N/a analysis of 2 family of Ashkenazi spastic NTE mutations are the unrelated Jewish ancestry, paraplegia and likely cause of families and a non- distal muscle autosomal-recessive consanguineous wasting in two motor neuron disease family of northern families that closely resembles European ancestry, OPIDN. These NTE in which affected mutations were subjects developed sufficient to cause the childhood onset of disorder in the absence lower extremity of apparent exposure to spastic weakness neurotoxic OPs. Study and wasting of supports the role of upper and lower NTE abnormalities in extremity muscles axonopathy produced by neuropathic OP compounds

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AUTHOR: Ray and Richards, 2001

TITLE: The potential for toxic effects of chronic, low-dose exposure to organophosphates

Date of Review 2001

Aim To review literature on chronic, low-dose exposure to OPs, including exposure of non-poisoned subjects

Topics covered Definition of low-level exposure as that which does not evoke clinically obvious poisoning; review of epidemiological studies, experimental studies, and potential mechanisms by which OPs exert their effects Health Cholinesterase inhibition, inhibition of other enzymes, neurological symptoms outcomes considered

Original studies All relevant studies identified; other studies did not meet inclusion criteria (pre-dated 1999, or were reviews), or are already covered by the COT 1999 not identified in Report on Organophosphates literature search

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AUTHOR: Rees, 2011

TITLE: Sheep Dipping Related Treatments and “Dippers’ Flu”

HYPOTHESIS: To study acute health effects in farmers following treatment of sheep for ectoparasites

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type Data Date Study Reference Measure of exposure Other risk factors Outcome Narrative description of Statistical of collection of population population / bias / variables basic results methods study period study confounders UK Cohort 2005 – 2011 8747 sheep 156 sheep A questionnaire was used Exposure to Acute health Non significant changes in Frequencies used 2006 farmers randomly farmers of to collect occupational infectious agents effects (includes butyrylcholinesterase for categorical selected who the original history data, providing and endotoxins nervous system activity in farmers data and were actively cohort detailed information on that could give rise disorders and following treatment. NB. means/SDs used treating sheep acting as treatment methods, types to flu-like dipper’s flu). Farmers pesticide for continuous during a defined their own of pesticides used, symptoms; use of Questionnaire exposures marginally data; Symptom time period (from controls handling of concentrate different types of used to collect higher than that of general scores for May 2005 until and no. of sheep dipped. treatment for sheep medical and population. Very low analysing July 2006); 781 Serum ectoparasites; co- occupational symptom prevalence responses to participated butyrylcholinesterase and use of non-OP history before before and after treatment health before treatment. urine OP and synthetic pesticides by treatment and a (commonly found in questionnaire Farmers using all pyrethroid metabolites farmers (i.e. structured general population); Paired symptom types of collected before and after pyrethroids, interview incidence of health effects scores for treatment for sheep were treated. NB. cyromazine and conducted to highest during first two individual farmers sheep Dipping remained the avermectins); collect info on days following treatment before and after ectoparasites most popular treatment previously declared symptoms but were not associated treatment were were included; (28%) with increasing use poor health status, experienced 4 with indices of OP compared using subjects were of synthetic pyrethroids, previous history of weeks before and exposure. There was little two-tailed stratified by their cyromazine and reporting dippers’ 48 hrs after relationship between urine Wilcoxon Signed exposure to avermectins. Farmers flu, perception of treatment. A levels of pesticide Ranks Test. pesticides. treated sheep for 1.5 days risk from using symptom diary metabolites and Somer’s d test Follow-up: within sheep dips; also used during symptoms as and Goodnman & 48hrs and then 2- competence treatment to demonstrated by the Kruskal’s Tau b 3 weeks after certificate; age, identify ill farmers absence of a dose test used to treatment location, female and outline response relationship analyse measures gender, smoking symptoms between body burden of of association and alcohol pesticide and symptoms between variables; consumption authors present only statistically significant d and T values (p<0.05)

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AUTHOR: Rehner et al 2000

TITLE: Depression among victims of south Mississippi’s methyl parathion disaster.

HYPOTHESIS: Depressive symptoms are experienced by victims of south Mississippi’s methyl parathion disaster

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AUTHOR: Rice et al 2009

TITLE: The paraoxonase (PON1) Q192R polymorphism is not associated with poor health status or depression in the ELSA or InCHIANTI studies

HYPOTHESIS: There are associations between the PON1 Q192R polymorphism and self-reported poor health and depression in two independent older population samples, the ELSA and InCHIANTI studies

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study population Reference Measure of Other risk Outcome variables Narrative Statistical study collection of population exposure factors / bias / description of methods period study confounders basic results UK/ Italy Cross- 2002 and 2009 3,158 men and N/a OP exposure Age, sex Self-reported The authors found Additive and per- (Tuscany) sectional 2004 in the women aged 60- is not general health and no evidence of an allele logistic ELSA 79 years from measured or depression, association regression study, not the English reported measured on the between the performed; ORs reported Longitudinal Center for PON1 Q192R and 95% CIs of for Study of Ageing Epidemiologic polymorphism and reporting fair to InCHIANTI (ELSA), and 761 Studies Depression poor general very poor health, individuals aged (CES-D) scale, or health or and of depression, 60-79 in the by diagnosis of depression in 2 and PON1 InCHIANTI study depression in ELSA independent genotype study population-based reported; studies. This is in P-values also contrast to the reported; findings of Lawlor mean and SD of et al. (2007), CES-D scores summarised reported previously

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AUTHOR: Rohlman et al 2007

TITLE: Neurobehavioural performance of adult and adolescent agricultural workers

HYPOTHESIS: Neurobehavioural performance of adolescents may be poorer than that of adults working in agriculture, since pesticides are thought to pose a considerably higher risk to children and adolescents

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure of Other risk factors/ Outcome variables Narrative Statistical study collection of population population exposure bias / confounders description of basic methods periodUS study results US Cross- Summer 2007 119 Hispanic 56 Hispanic Years spent β-coefficient is Performance on The findings Estimated slope sectional 2004 adults and adults and working in calculated for neurobehavioural suggest that, at the (β-coefficient ) is adolescents adolescents agriculture years of education test battery time of exposure to calculated currently not currently and age, as well including tests pesticides, showing the working in working in as for years in measuring adolescents are not average increase agriculture agriculture agriculture attention, more vulnerable to or decrease in response speed, the effects of each coordination and working in neurobehavioural memory agriculture measure per 5- year increase in the indicated predictor (years working in agriculture, years of education, age)

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AUTHOR: Rohlman et al 2011

TITLE: Correlating neurobehavioral performance with biomarkers of organophosphorus pesticide exposure

Date of Review 2011

Aim To review the neurotoxic effects associated with chronic or repeated exposure to OPs in humans, the reasons why so few of these studies have reported an association between these effects and current biomarkers of OP exposure and effect, and novel biomarkers that might be more effective in predicting the neurotoxicity of OPs Topics covered Neurobehavioural deficits following chronic occupational exposure Variation in neurobehavioural test outcomes Correlation between biomarkers and neurobehavioural deficits Health Neurobehavioural deficits outcomes considered

Original studies Kamel F, et al. 2003. Neurobehavioral performance and work experience in Florida farmworkers. Environ Health Perspect;111:1765–72 not identified in Eckerman DA, et al 2007. Age related effects of pesticide exposure on neurobehavioral performance of adolescent farm workers in Brazil. Neurotoxicol literature search Teratol;29:164–5.

Cole DC, et al. 2007. Reducing pesticide exposure and associated neurotoxic burden in an Ecuadorian small farm population. Int J Occup Environ Health;13:281–9.

NB. Other studies referenced in this review did not meet inclusion criteria (i.e. pre-dated 1999, mechanistic or exposure study or review paper) or are already included in the screening process

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AUTHOR: Roldan-Tapia et al 2005 (Neurotoxicol Teratol)

TITLE: Neuropsychological effects of long-term exposure to organophosphate pesticides

HYPOTHESIS: There are possible neurobehavioural deficits in agricultural workers from occupational exposure to pesticides, exposure mostly, but not exclusively, to cholinesterase inhibitors, for a varying number of years

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AUTHOR: Roldan-Tapia et al 2006

TITLE: Neuropsychological sequelae from acute poisoning and long-term exposure to carbamate and organophosphate pesticides

HYPOTHESIS: Long-term neurocognitive sequelae may be produced by acute intoxication with OP and carbamates, in comparison with non- acutely poisoned but nevertheless chronically exposed individuals

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data collection Date Study population Reference Measure of Other risk Outcome Narrative Statistical study period of population exposure factors / bias / variables description of methods study confounders basic results Spain Cross- For acutely 2006 24 male Spanish 26 controls Record of Age, Performance Both acutely SPSS (Almeria) sectional poisoned farmers who had who had not intoxication in the educational on neuro- poisoned long- software used; subjects, suffered accidental been Emergency level, butyryl- psychological term workers F, analysis of between poisoning with OP working on Medical Unit for cholinesterase test battery, and chronically variance, used January and and/or carbamates farms and acutely poisoned (BuChE) value testing high (<10 years) to compare March 1998, 3 between had no cases, attention, exposed descriptive months after a September and contact with cholinesterase memory, workers characteristics poisoning event; November 1997; OPs or levels, symptoms, reasoning, exhibited similar of subjects; in a small a second group of carbamates and substances perception, disturbances in multivariate sample of 40 non-poisoned causing language and perception and analysis for poisoned but chronically intoxication noted; visuomotor visuo-motor differences in subjects, also 1 exposed sprayers for non-poisoned domains processing, in outcomes of year later; working in different subjects, reported the absence of neuro- for non- greenhouses and years of working any related psychological poisoned spraying OPs with pesticides acute effect of tests; F value subjects, April and/or carbamates butyrylcholin- reported, and and May 1998, esterase p value for and 6 months inhibition significance later

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AUTHOR: Rothlein et al 2006

TITLE: Organophosphate Pesticide Exposure and Neurobehavioral Performance in Agricultural and Nonagricultural Hispanic Workers

HYPOTHESIS: a) Significant correlations found between OP residues in house dust and urinary OP metabolite levels of farm workers; b) Hispanic immigrant farm workers exposed to OPs have lower neurobehavioural (NB) performance than Hispanic immigrants in non-agricultural community; and c) Positive correlation between urinary OP metabolite levels and poorer NB performance (within agricultural workers)

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure of exposure Other risk Outcome Narrative description of basic Statistical methods study collection of population population factors / variables results period study bias / confounders US Cross- No info 2006 92 Hispanic 45 Hispanic Environmental house Age, sex. Neuro- Significant correlation Spearman’s sectional provided immigrant immigrant dust samples (collected education in behavioural between urinary methyl correlation to farm population from 26 farm workers the subjects deficits metabolite levels and house evaluate the workers in non- homes during same country of dust levels of total methyl association between living in an agricultural week as collection of origin OPs i.e. azinphos-methyl, OP residues in agricultural (non-AG) first urine sample): The phosmet and malathion; 23 house dust and OP (AG) community following OPs of dust samples had urinary metabolites; community (tourist confirmed by GC/mass residues that could be paired multiple linear (Hood coastal spec: AZM, diazonin, with combined molar regression used to River, town, chlorpyrifos, malathion, concentration of thiomethyl assess differences Lincoln Newport, methyl parathion, and metabolites; Hispanic on each NB test County, Lincoln phosmet; [Biomarker]: immigrant farm workers between AG and Oregon) County, Dialkyl phosphate exposed to OPs had lower non-AG groups; all Oregon) urinary metabolite neurobehavioural p-values two sided levels (collected once performance than Hispanic unless otherwise during summer and immigrants in non- indicated; one sided during Autumn). NB. agricultural community p-values used in Sample collections (performed better on 12 out cases were means coincided with the of 16 NB measurements; or correlations were middle of the growing Positive correlation between anticipated to follow seasons and time urinary OP metabolite levels a pre-chosen trend; pesticide spraying were and poorer NB performance authors report mean being applied; Work on some tests (within the score plus SE for NB practices sample of AG workers) tests

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AUTHOR: Salvi et al 2003

TITLE: Neuropsychiatric Evaluation in Subjects Chronically Exposed to Organophosphate Pesticides

HYPOTHESIS: To evaluate clinical, psychiatric and extrapyramidal symptoms and plasma acetylcholinesterase activity in a sample of workers chronically exposed to OPs

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure of Other risk factors / Outcome Narrative description Statistical methods study collection of population population exposure bias / confounders variables of basic results period study Brazil Cross- 1st 2003 1st Authors OP exposure Time and type of Psychiatric Clinically significant To make sectional evaluation: evaluation: were unable history via OP exposure, use symptoms, extrapyramidal comparisons between Dec 2001 37 workers to include a questionnaire of protective Parkinsonism, symptoms present in the two evaluations involved in healthy (chlorpyriphos clothing, , Cognitive 12 of 25 workers, the authors used 2nd family comparison and acephates activities with ability which reduced after 3 ANOVA (for evaluation: agriculture group most OPs, history of months of no OP symmetric variables) Mar 2002 of tobacco without OP predominant); acute toxicity, exposure, although 10 and Wilcoxon test (for with 3 exposure plasma AChE alcohol and subjects had asymmetric variables month OP activity levels tobacco use were significant e.g. scales scores); exposure noted as parkinsonism. ); mini- mean test scores and characteristics of mental and word-span SDs are reported for 2nd the 25 subjects scores within normal extrapyramidal evaluation: who completed range and not affected symptoms after 3 25 of above both evaluations by OP exposure; total months without workers number of affected exposure to OP (in 25 who had individuals with subjects evaluated been psychiatric diagnoses twice); statistical without dropped from 11 to 7 significance defined exposure after 3 months of no as p< 0.05 for 3 exposure months

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AUTHOR: Savy et al 2011 (Abstract evaluated, poster presented at a Conference)

TITLE: Behavioural effects of low-level exposure to organophosphate pesticides

HYPOTHESIS: To determine whether sub-chronic exposure to low-levels of OP pesticides cause neuropsychiatric and neurocognitive effects

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type Data Date Study population Reference Measure of Other risk Outcome Narrative description Statistical of collection of population exposure factors / bias / variables of basic results methods study period study confounders UK In- n/a 2011 24 Adult male Lister 12 Adult male Lister Experimental n/a Neuropsychiatric Exposure to OPs did Mean ± vivo Hood rats exposed Hood rats exposed administration and not cause SD, paired intraperitoneally to intraperitoneally to of OPs neurocognitive behavioural changes samples t- diazinon or vehicle for 5 effects associated with test, p< chlorpyrifos for 5 consecutive days depression or 0.05 consecutive days memory, although changes associated with anxiety were affected

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AUTHOR: Sedziak et al 1998 (Abstract evaluated, article in Polish – Paper unobtainable)

TITLE: Analysis of EEG frequency in workers employed in the department producing chlorfenvinphos

HYPOTHESIS: To assess the neurotoxicity of pesticides in workers employed in the production of chlorfenvinphos

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study population Reference Measure of exposure Other risk Outcome Narrative description of Statistical study collection of population factors / bias / variables basic results methods period study confounders Not Not clear Not 1998 30 males employed in Not Air concentration of Not reported Not An abnormal index was Not reported from reported in a chemical plant reported in chlorfenvinphos; red in abstract reported found in 9 (30%) persons reported in in abstract abstract department producing abstract blood cell AChE in abstract under study and in 6 abstract abstract chlorfenvinphos activity (20%) cases it was lowered mainly in the central and temporal regions and in 3 (10%) it was enhanced

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AUTHOR: Shahar et al 2005

TITLE: Extrapyramidal Parkinsonism Complicating Acute Organophosphate Insecticide Poisoning

HYPOTHESIS: To report on a child who developed extrampyramidal perturbations from acute OP insecticide poisoning and literature review on OP-induced basal ganglia impairment

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type Data Date Study population Reference Measure of exposure Other risk Outcome Narrative description of Statistical of collection of population factors / bias / variables basic results methods study period study confounders Israel Case No info 2005 14 year old child who n/a/ Case history report; n/a Parkinsonian Symptoms developed 5 n/a report provided accidentally ingested red blood cell perturbations days after ingestion raw eggplant cholinesterase and following recovery from sprayed with the OP plasma cholinesterase the acute cholinergic dimethoate levels phase. Child recovered after treatment

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AUTHOR: Solomon et al 2007 (Occup Environ Med)

TITLE: Neuropsychiatric symptoms in past users of sheep dip and other pesticides

HYPOTHESIS: To explore the prevalence and pattern of neuropsychiatric symptoms in past users of sheep dip and other pesticides

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study population Reference Measure of Other risk Outcome variables Narrative description of Statistical study collection of population exposure factors / bias / basic results methods period study confounders UK Cross- No 2007 9844 men born 6109 men Self-reported Age, area, Symptoms Neurological symptoms Modified sectional specific between 1933 born lifetime history of acute effects of associated with more common in past Cox info and 1977 between work with exposure to COPIND (chronic sheep dip users, but the regression; provided resident in 3 rural 1933 and following five pesticides in organophosphate- association is not prevalence areas of England/ 1977 categories of the year before induced specific to sheep dip or ratio (PR) Wales of whom resident in 3 pesticides completing neuropsychiatric insecticidesusers of with 95% CI 1913 had at rural areas (postal survey): questionnaire disorder), sheep dip, other some time of England/ sheep dip, other neurological insecticides and other worked with Wales who insecticides, symptoms, anxiety, pesticides reported ≥ 3 sheep dip, 832 had never herbicides, depression neurological symptoms had worked with worked with fungicides and more commonly than other insecticides any type of wood non-users; in sheep but never with pesticide preservatives dippers, higher sheep dip and prevalence of symptoms 990 had worked in men who dip more with other often but not in men pesticides but working with dip never with sheep concentrate dip or insecticides

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AUTHOR: Sosan & Akingbohungbe, 2009

TITLE: Occupational Insecticide Exposure and Perception of Safety Measures among Cacao Farmers in Southwestern Nigeria

HYPOTHESIS: To assess occupational exposure hazards among cacao farmers in Southwestern Nigeria

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study population Reference Measure of Other risk factors / Outcome Narrative description of basic Statistical study collection of population exposure bias / confounders variables results methods period study Nigeria Cross- 2001 to 2009 150 farmers who None Work history of Eating and drinking Chronic pesticide Diazonin was the second Relative sectional 2002 cultivate cacao insecticide use during spraying poisoning e.g. most common insecticide frequency as major crop and perception operations, lack of frequent fever, used (after lindane); majority (%) and applied of safety protective clothing, strained of farmers continually following insect measures; improper breathing, exposed for periods ranging pest control authors storage/disposal of sleeplessness, from 5-20 years or more; measures generate insecticides loss of memory common reported symptoms lindane, exposure experienced after spraying diazinon, measure operations included endosulfan, and based on headache, dizziness, body propoxur years of weakness or fatigue, nausea, spraying restlessness and excessive sweating which were directly proportional to years of exposure (i.e. highest % of farmers demonstrating each symptom always among group involved in insecticide application for > 20 years)

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AUTHOR: Soummer et al 2011

TITLE: Severe and prolonged neurologic toxicity following subcutaneous chlorpyrifos self-administration: A case report

HYPOTHESIS: To report a case of subcutaneous chlorpyrifos self-injection leading to severe permanent neurological injury

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type Data Date Study population Reference Measure of Other risk Outcome Narrative description of basic Statistical of collection of population exposure factors / bias / variables results methods study period study confounders France Case Not 2011 24-y old North n/a Admittance Patient also Acute and Electrophysiological testing on day n/a report specified African male who and treatment ingested intermediate 50 showed co-existence of 20Hz attempted suicide for acute OP alprazolam effects including decremental responses in proximal by self-injecting poisoning. and prolonged coma muscles and severe denervation of chlorpyrifos RBC AChE olanzapine and chronic distal muscle, consistent with subcutaneously into activity peripheral intermediate syndrome and OPIDN both arms Chlorpyrifos neuropathy respectively. residue/ Chlorpyrifos was detectable in body metabolitess in fluids up to 3 months since suicide blood and attempt. Electrophysiological testing urine on day 120 showed improvement of respectively previous responses. Signs of reinnervation in distal upper limbs only. Patient exhibited significant neuromuscular sequale (persistent severe muscle weakness) in one year follow-up

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AUTHOR: Spencer, 2001

TITLE: Epidemiological and Clinical Evidence for Residual Organophosphate Neurotoxicity

HYPOTHESIS: To seek evidence that supports or refutes the proposal that Gulf War (GW) veterans who served in the Kuwati Theater of Operations (KTO) had nervous system deficits consistent with prior exposure to organophosphorus chemicals (sarin and insecticides)

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Locatio Type of Data Date Study Reference Measure of Other risk Outcome Narrative description of basic results Statistical n study collectio of population population exposure factors / variables methods n period stud bias / y confounders Iraq/US Cross- Jan 2001 653 Desert 610 Exposure Region of OP-associated No symptom differences evident after Factor analysis sectiona 1999 to Storm Desert history taken residence, persistent CNS comparing participants in Khamisiyah of self-reported l June veterans storm from gender and damage (i.e. group with troops outside the defined health 2000 present within veterans telephone age neurobehavioural, area (although differences found symptoms; a 50 km radius with no questionnaire neuromuscular between small no. of individuals who ORs reported of Khamisiyah, known interview and witnessed detonations and other in for a study Coalition- potential neurophysiologica larger Khamisiyah group); deployed group to report Occupied Iraq exposure l deficits including troops significantly more likely to being who may have to nerve electro- report diagnosis of medical diagnosed with been exposed agents; encephalography conditions including post traumatic a particular to sarin 516 non- (EEG) analysis) stress disorder and hospitalisation for health /cyclosarin deployed depression cf. non-deployed troops; outcome; during first 2 GW-era increased burden of illness among Multivariate weeks of Mar veterans those who witnessed controlled analysis of 1991. NB. The detonation of munitions containing variance used authors do not sarin/cyclosarin; no neurological or to assess provide neurophysiological differences differences additional among three groups. among information on Insufficient information on results deployment the rationale or presented to evaluate groups wrt. method used relative activity to estimate of EEG data; 50km radius p-values are reported

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AUTHOR: Srinivasan KG et al 2010

TITLE: MRI Eye-of-the Tiger Sign in Organophosphorous Poisoning . A Case Report.

HYPOTHESIS: MRI alterations in case of acute poisoning 6 months after exposure are similar to those seen in Parkinsons Disease. .

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AUTHOR: Srivastava et al 2000

TITLE: Clinical, Biochemical and Neurobehavioural Studies of Workers Engaged in the Manufacture of Quinalphos

HYPOTHESIS: To assess the health risk associated with the manufacture of the OP pesticide quinalphos (QP)

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure of Other risk Outcome variables Narrative description of basic Statistical methods study collection of population population exposure factors / bias / results period study confounders India Cross- No info 2000 59 workers 17 Occupational Age, work Neurobehavioural No significant difference Students t-test, P< sectional provided exposed to subjects history via history, sex, deficits, memory, between AChE levels of QP- 0.05; chi-squared (conducted different employed interview; social attention and exposed subjects and test, Fishers exact over a 10 chemicals as tea blood AChE characteristics, concentration, visual controls; QP-exposed test day during the vendors, levels (done cigarette and learning and subjects had significantly period) manufacture roadside during alcohol vigilance, higher no. of complaints of of hawkers second half consumption, musculoskeletal , weakness cf. controls; QP- quinalphos of shift (after acute OP ophthalmic exposed subjects showed 5-6 hr of poisoning, outcomes (among higher prevalence of typical work past other non abnormal plantar and ankle exposure)) neurological neurological health reflex (P< 0.05); QP-exposed illness outcomes) subjects had significantly lower scores for memory, learning ability and vigilance cf. controls

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AUTHOR: Stallones & Beseler, 2002a

TITLE: Pesticide Poisoning and Depressive Symptoms among Farm Residents

HYPOTHESIS: To evaluate the association between pesticides and depressive symptoms among a population exposed to chemicals through agricultural use

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure of exposure Other risk factors Outcome Narrative Statistical study collection of population population / bias / variables description of methods period study confounders basic results US Cross- 1992-97 2002 761 No separate Pesticide exposure via Risk factors Depression, A significant Conditional sectional respondents, reference self-reported typically depressive Odds Ratio logistic who were farm population; all questionnaire; associated with symptoms was regression, residents, respondents were pesticides used on depression, such assessed through calculated for ORs operators and evaluated for farm included the OPs as age, the questionnaire depression (95%CI) their spouses, depressive terbufos, chlorpyrifos, education, marital for all participants, associated resident in an symptoms, and phosmet, dichlorvos, status, social using the Centre with eight-county selected but no analysis is support and for Epidemiologic pesticide- area of characteristics of made of association of alcohol use, were Studies- related Colorado those with high OPs as a class or of included in the Depression (CES- illness 69 respondents depressive individual chemicals logistic regression D) scale reported a symptoms were with depression: the models as pesticide- analysed for association covariates to related illness possible considered is for control for associations “pesticide-related confounding illness”

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AUTHOR: Stallones & Beseler, 2002b

TITLE: Pesticide Illness, Farm Practices, and Neurological Symptoms among Farm Residents in Colorado

HYPOTHESIS: To assess the relationship between self-reported pesticide poisoning, farming activities, and neurological symptoms in a large population based study of farm residents in North Eastern Colorado

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure of exposure Other risk Outcome Narrative description of Statistical study collection of population population factors / bias variables basic results methods period study / confounders US Cross- 1992- 2002 761 farm Pesticide exposure via Age, gender, Neurological Odds of reporting having an OR(95% CI); sectional 1997 residents, Respondents questionnaire existing symptoms acute pesticide related stepwise/ operators and who answered interview based on health illness increased in those multivariate spouses. A “No” to whether working hours, using crop OP (but not logistic total of 69 they reported pesticide use and livestock OP or herbicides); regression; experiencing a respondents application, and significant increased ORs multivariate reported having pesticide related illness (692 previous pesticide for reporting reoccurring conditional experienced a poisoning i.e. having neurological symptoms in regression physician respondents) diagnosed were used as had an acute pesticide those with pesticide related pesticide-related comparison related illness; illness experience i.e. illness groups pesticides used on problems with memory , farm included the OPs concentration, terbufos, chlorpyrifos, comprehension, phosmet, dichlorvos depression, hypersomnia (and other classes of and headaches (among pesticides) other symptoms)

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AUTHOR: Starks et al 2012a

TITLE: Neurobehavioural function and organophosphate insecticide use among pesticide applicators in the Agricultural Health Study.

HYPOTHESIS: Long term low-level OP exposure of pesticide applicators and spouses is associated with impaired performance of neuropsychological tests.

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type Data Date Study Reference Measure of Other risk factors / bias / Outcome Narrative Statistical of collection of population population exposure confounders variables description of basic methods study period study results US Cohort Participants 2012. Agricultural None Take home Common covariates of Tests used; Overall no Linear (Iowa, study enrolled Health questionnaire filled neurobehavioural test Continuous consistent evidence regression North between Study in within 1 month of outcomes (age, height, Performance, for an association analyses. Carolina) 1993-1997. cohort enrolment.(Phase education, state, Digit-Symbol, between OP use Sensitivity and tested 1). A five and 10 smoking status, alcohol Finger tapping, and adverse analyses between year follow-up consumption, exposure Grooved neurobehavioural also 2006-2008. telephone interview to potentially neurotoxic pegboard test performance.. undertaken. (Phases 2 and 3) substances. Head (dominant and injury, current non-dominant), antidepressant use, Auditory verbal caffeine consumption. learning (total Additionally recall, delayed administered tests of recall, learning reading ability, affect recognition), and visual acuity. Sequences A and B.

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AUTHOR: Starks et al 2012b

TITLE: Peripheral Nervous System Function and Organophosphate Pesticide Use among Licensed Pesticide Applicators in the Agricultural Health Study

HYPOTHESIS: Long term OP pesticide use is associated with adverse peripheral neurological outcomes

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type Data Date Study population Reference Measure of Other risk factors / Outcome variables Narrative description of Statistical of collection of population exposure bias / confounders basic results methods study period study US Cohort 1993- 2012 678 male None Self-reported Exclusions based Neurological Significantly increased Linear and 1997 pesticide information on on subjects having dysfunction odd ratios observed for logistic applicators of the “ever use” and medical conditions (assessed via associations between regression, Agricultural “lifetime days of and treatments neurological clinical ever-use of 10 of 16 OP ORs and Health Study use” of 16 OP known to examination, pesticides and one or 95% CIs, (AHS) who pesticides (via confound tests, electrophysiological more the six neurological Chi-squared completed all interview and drinking ≥ 42 testing of the physical examinations. test for AHS questionnaire) alcoholic peroneal motor Abnormal toe trend questionnaires were used to beverages per nerve, hand proprioception was and had higher create “ever-use” week and strength, sway significantly associated lifetime use of 10 and “lifetime days physician speed, vibrotactile with ever-use of six OP OP pesticides of use” exposure diagnosed threshold pesticides. Monotonic variables. NB. pesticide increases in strength of Similar variables poisoning. association with were also created Potential increasing use was for four carbamate confounders observed for three of the pesticides explored include six pesticides. Mostly null age, height, state, associations were smoking status, observed between OP education, alcohol pesticide use and use, ear infection/ electrophysiological tests, surgery, hand strength, sway neurotoxic speed, and vibrotactile substance threshold exposures and BMI

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AUTHOR: Steenland et al 2000

TITLE: Neurologic function among termiticide applicators exposed to chlorpyrifos

HYPOTHESIS: Neurological function was affected among current and former termiticide applicators who had used or were using chlorpyrifos

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure of exposure Other risk Outcome Narrative Statistical study collection of population population factors / bias / variables description of methods period study confounders basic results US Cross- 1998 2000 191 current 106 non- “Ever worked as a Age, race, Performance Lack of Mean and (North sectional and former exposed termiticide applicator” education, on exposure effects median years of Carolina) termiticide controls who and reported exposure current neurological on clinical application of applicators were friends of as applicator: smoking, BMI tests of examination, chlorpyrifos, using the study group; years of application of for tests of central and and few chlordane and chlorpyrifos in also 83 non- chlorpyrifos, chlordane, peripheral peripheral significant other pesticides, a 12-county exposed blue and other pesticides; neuropathy function differences and mean and area of North collar North applicators had an found in the median levels of Carolina Carolina State average of 2.4 years tests conducted; TCP in urine; employees applying chlorpyrifos the findings for p values (maintenance and 2.5 years applying self-reported reported for workers and other pesticides; symptoms raise tests in which corrections levels of chlorpyrifos some concern, the exposure officers) metabolite TCP (3,5,6- as does the effect had a p trichloro-2-pyridinol) in finding of low value of ≤0.10 urine performance in those reporting prior poisoning

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AUTHOR: Stephens and Sreenivasan, 2004

TITLE: Neuropsychological effects of long-term low-level organophosphate exposure in orchard sprayers in England

HYPOTHESIS: Exposed individuals would show neuropsychological decrements when compared with unexposed individuals, and cumulative OP exposure would be correlated with neuropsychological performance

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study population Reference Measure of exposure Other risk Outcome Narrative Statistical study collection of population factors / bias / variables description of methods period study confounders basic results UK Cross- Not 2004 37 male orchard 26 pig farm Self-reported exposure Age, weekly Performance Relative to Neuro- (England sectional specified sprayers from 53 workers from to pesticides; orchard alcohol on 7 construction psychological ) orchard same sprayers had taken consumption computerised workers, test scores businesses in geographical part in an occupational and neuro- orchard compared Hereford, areas as the hygiene survey the educational psychological sprayers were using ANOVA; Worcester, East participating previous year, in which level recorded tests significantly p values Anglia, Kent and orchards; they were found to slower on reported Sussex 31 construction have used chlorpyrifos negative workers from on average for 5 days statements of employees of a per year for 14 years; the syntactic South Yorkshire OP metabolites DEP reasoning test; construction and DETP were no relationship company measured in urine the was found morning after spraying between in this previous survey, cumulative and compared to a exposure and sample taken in the test response present study at time of neuropsychological testing

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AUTHOR: Tahmaz et al 2003

TITLE: Chronic fatigue and organophosphate pesticides in sheep farming: a retrospective study amongst people reporting to a UK pharmacovigilance scheme

HYPOTHESIS: Repeated exposure to OP pesticides in sheep dip may increase the probability of developing chronic fatigue

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of study Data Date Study Reference Measure of Other risk Outcome Narrative Statistical collection of population population exposure factors / bias / variables description of methods period study confounders basic results UK Cross- Survey 2003 26 ‘cases’ from 37 ‘controls’ Self-reported Not analysed; Chronic Authors found SPSS version 9 sectional conducted in farmers who from farmers exposure; job response rate Fatigue as limited used; geometric 2001; had reported to who had title for estimate of only 40% assessed by evidence for mean estimated farmers the VMD reported to the of long-term the CIS an association exposure for reported to Suspected VMD average Questionnaire between CF high and low the VMD Adverse Suspected exposure; an and exposure Chronic Fatigue (Veterinary Reaction Adverse exposure metric to OP sheep (CF) categories, Medicines Surveillance Reaction was developed dip, with a P values Directorate) Scheme; ‘cases’ Surveillance to estimate the tendency for a reported; between had more than 3 Scheme; subjects’ dermal few subjects Pearson 1985 and symptoms of ‘controls’ had exposure to OPs with highest correlation 2001 chronic fatigue one symptom estimated coefficient as measured on or less on the exposure to between CF the Checklist CIS have higher score and Individual Questionnaire CF scores cumulative Strength (CIS) exposure, P Questionnaire values reported for measuring chronic fatigue. NB. Case- control design was abandoned

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AUTHOR: Teixera et al 2003

TITLE: Hearing health of workers exposed to noise and insecticides

HYPOTHESIS: Peripheral auditory disorders develop in a group of workers exposed to OP and pyrethroid insecticides

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AUTHOR: Tochigi et al 2002

TITLE: Serum cholesterol, uric acid and cholinesterase in victims of the Tokyo subway sarin poisoning: a relation with post-traumatic stress disorder

HYPOTHESIS: Serum levels of cholesterol, uric acid and cholinesterase are altered in post-traumatic stress disorder (PTSD) in victims of the Tokyo sarin attack on 20 March, 1995

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure of Other risk factors / Outcome Narrative Statistical study collection of population population exposure bias / confounders variables description of methods period study basic results Japan Cohort Within 1-3 2002 34 victims of 34 age-matched Victims had Current and PTSD; 8 of the victims One-way analysis (Tokyo) study days after Tokyo and mostly sex- been treated in previous status of serum levels developed PTSD, of variance the sarin subway sarin matched Emergency for other mental of cholesterol, and only 2 (ANOVA), attack, and poisoning volunteers sarin poisoning disorders uric acid and currently had Student’s t-test 5 years enrolled as at the general evaluated using cholinesterase PTSD; and Wilcoxon test later controls, mainly hospital in Mini-International cholinesterase to compare recruited from Tokyo after the Neuropsychiatric was significantly among or staff of the Tokyo sarin subway Interview; all lower in victims between subject University attack; serum subjects and who developed groups; P values Hospital cholinesterase controls PTSD than in reported level within 1-3 completed the matched controls, days of the State-Trait Anxiety 5 years after the attack available Inventory attack for 25 of the victims

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AUTHOR: Tochigi et al 2005

TITLE: Support for relationship between serum cholinesterase and post-traumatic stress disorder; 5-year follow-ups of victims of the Tokyo subway sarin poisoning

HYPOTHESIS: There may be a correlation between serum levels of cholinesterase and severity of post-traumatic stress disorder (PTSD) symptoms in the total number of victims

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure of Other risk factors / Outcome Narrative description Statistical study collection of population population exposure bias / confounders variables of basic results methods period study Japan Cohort Within 1-3 2002 34 victims of 34 age- Victims were Current and Current and The authors confirm Pearson’s (Tokyo) study days after Tokyo matched and involved in previous status of lifetime scores of the association correlation the sarin subway sarin mostly sex- the Tokyo other mental PTSD; serum between PTSD coefficients attack, and 5 poisoning matched subway sarin disorders evaluated cholinesterase symptoms and serum calculated years later volunteers poisoning using Mini- level 1-3 days cholinesterase levels between PTSD enrolled as International after the attack, in the victims of the scores and controls Neuropsychiatric and 5 years later sarin attack; current serological Interview; all and lifetime scores of studies in the subjects and re-experiencing, victims; p controls completed lifetime score of values the State-Trait avoidance, and reported Anxiety Inventory overall PTSD score were correlated with cholinesterase level immediately after the attack

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AUTHOR: Van der Mark et al 2012

TITLE: Is pesticide use related to Parkinson Disease? Some clues to heterogeneity in study results

Date of Review 2012

Aim To update the literature published on PD and exposure to pesticides by performing a systematic review and meta-analysis

Topics covered Summary risk ratios were calculated for pesticide exposure, and the subcategories of herbicides, insecticides and fungicides, using random effects meta- analyses and investigating sources of heterogeneity between studies by meta-regression and stratified analyses Health The risk of PD and exposure to herbicides, insecticides and fungicides outcomes considered

Original studies Elbaz et al. 2009, Professional exposure to pesticides and Parkinsons’s disease, Ann Neurol 66:494-504; Engel et al. 2001, Parkinsonism and occupational exposure to pesticides, Occup Environ Med 58: 582-589; Kamel et al. 2007, Pesticide exposure and self-reported Parkinson’s disease in the not identified in Agricultural Health Study, Am J Epidemiol 165: 364-374 literature search

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AUTHOR: Wang et al 1999

TITLE: Positron Emission Tomography (PET) scan in cortical visual loss in patients with OP intoxication

HYPOTHESIS: Visual loss is a rare outcome of OP poisoning, and can be better detected by PET scanning than by conventional neuroimaging techniques

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of study Data Date of Study Reference Measure of exposure Other risk Outcome Narrative Statistical collection study population population factors / bias / variables description of methods period confounders basic results Taiwan 2 observational Case 1, 1999 2 cases of N/a Case 1, injection of N/a Blurred vision as Uptake of N/a case studies July 1995 acute 15ml of O-ethyl-O-p- sequela of OP glucose in the to January poisoning nitrophenyl poisoning visual cortex was 1996; phenylphosphonate; diminished in 2 Case 2, Case 2 had drunk a patients who had December bottle of Mevinphos been poisoned 1996 with OPs compared with normal subjects

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AUTHOR: Wesseling et al 2002

TITLE: Long-term neurobehavioural effects of mild poisonings with organophosphate and n-methyl carbamate pesticides among banana workers

HYPOTHESIS: Poisoning with an organophosphate or a carbamate compound is associated with long-term effects on the central nervous system

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type of Data Date Study Reference Measure of Other risk Outcome Narrative Statistical study collection of population population exposure factors / bias / variables description of methods period stud confounders basic results y Costa Cross- May to 200 81 workers 130 non-poisoned Poisoning was Age, education, Performance on The poisoned BMDP Rica sectional September 2 from banana workers, who verified from long-term neuro- group as a whole software (Atlantic 1994 plantations who included field worker’s medical exposure to behavioural test performed less used; multiple Region) had had mild workers and file, report of the cholinesterase battery, well than the linear poisoning employees in National inhibitors, including non-poisoned regression caused by packing plants who Insurance alcohol intake, memory, group on 13 of analyses, cholinesterase- had never had any Institute, solvents, loss of attention, the 14 Regression inhibiting contact with ChE- information consciousness, psychomotor neurobehavioural Coefficient pesticides and inhibiting provided by the examiner, time and visuomotor tests, but and 95% CI who were pesticides, as well company about of day of abilities and differences on reported, and treated at a as field workers nematocide testing, plasma language most tests were p values health centre, who worked with used, and cholinesterase small. Deficits but were not ChE-inhibiting worker’s report levels occurred more hospitalised pesticides in clearly among varying degrees the OP-poisoned subjects, with significantly more neuropsychiatric symptoms

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AUTHOR: Wesseling et al 2010

TITLE: Symptoms of psychological distress and suicidal ideation among banana workers with a history of poisoning by organophosphate or n- methyl carbamate pesticides

HYPOTHESIS: Episodes of acute poisoning with cholinesterase inhibiting pesticides, either OPs or carbamates, are associated with symptoms of psychological distress and suicidal ideation; this study re-visits the data collected in 1994 and described in the previous Wesseling et al. 2002 study

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AUTHOR: Wills et al 2008

TITLE: Paraoxonase 1 (PON1) organophosphate hydrolysis is not reduced in ALS

HYPOTHESIS: PON1 genetic variants correlate with reduced rates of PON1 organophosphate hydrolysis in ALS (amyotrophic lateral sclerosis)

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AUTHOR: Yamasue et al 2003

TITLE: Voxel-based analysis of MRI reveals anterior cingulated gray matter volume reduction in posttraumatic stress disorder due to terrorism

HYPOTHESIS: To explore structural brain differences in the gray matter and white matter between victims of the Tokyo subway sarin attack with and without posttraumatic stress disorder (PSTD)

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type Data Date Study population Reference Measure of Other risk factors / Outcome Narrative description of Statistical of collection of population exposure bias / confounders variables basic results methods study period study Japan Case- 2000 - 2003 9 victims of the 16 matched Serum Age, gender, history Structural Significant gray matter ANOVA, t- control 2001 Tokyo subway victims of the cholinesterase of alcohol and brain volume reduction in left statistic sarin attack with same event level (as a substance abuse, changes anterior cingulated cortex (P<0.001); PTSD (never without measure of acute neuropsychiatric (via MRI (ACC) in trauma survivors correlational received PTSD intoxication) disorders analysis) with PTSD cf. those analysis, psychiatric without PTSD; severity of P<0.05 treatment for PTSD negatively PTSD) correlated with gray matter volume of the left ACC in PTSD subjects

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AUTHOR: Yamasue et al 2007

TITLE: Human Brain Structural Change Related to Acute Single Exposure to Sarin

HYPOTHESIS: To identify persistent morphological changes subsequent to an acute single-time exposure to sarin and the neurobiological basis of long-lasting somatic and cognitive symptoms in victims exposed to sarin

STUDY DESCRIPTION EXPOSURE & HEALTH OUTCOME RESULTS Location Type Data Date Study Reference Measure of Other risk factors / Outcome variables Narrative description Statistical of collection of population population exposure bias / confounders of basic results methods study period study Japan Case- 2000 - 2007 38 right- 76 healthy Serum Age, sex, Chronic somatic Reduced regional ANOVA, control 2001 handed matched cholinesterase handedness, complaints related white matter volume multiple victims of subjects from levels measured socioeconomic to interoceptive correlated with linear 1995 Tokyo hospital staff immediately and status, presence or awareness; human decreased serum regression , subway and longitudinally history of neurological brain structural cholinesterase levels t-statistic sarin attack acquaintances after exposure illness, traumatic changes (via T1 and with severity of p<0.001, brain injury, weighted and chronic somatic correlation substance abuse, diffusion tensor complaints related to analysis p< addiction history, magnetic interoceptive 0.05 history of psychiatric resonance awareness disease imaging)

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AUTHOR: Yan et al 2011 (Abstract evaluated, Article in Chinese)

TITLE: Progress in cognitive impairment induced by low-dose exposure to organophosphate pesticides

Date of Review 2011

Aim To review the syndromes and recent research progress in cognitive impairment induced by low-dose OP exposure

Topics covered Mechanism of chronic low-level OP-induced memory impairment

Health Memory/cognitive impairment outcomes considered

Original studies N/a (abstract used only) not identified in literature search

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AUTHOR: Yanagisawa et al 2006

TITLE: Sarin experiences in Japan: Acute toxicity and long-term effects

Date of Review 2006

Aim To describe various aspects of human toxicity caused by nerve agent Sarin including physical and psychological sequelae with a 10 year follow up

Topics covered The Masumoto incident (background, clinical observations, treatment and follow-up) Tokyo subway incident (background, clinical observations, treatment and follow-up)

Health outcomes Electroencephalography abnormalities, post traumatic stress disorder, asthenopia (eye strain), psychic symptoms i.e. flashbacks, nervousness and loss of considered concentration, lowering of backward digit span, blurred vision, easy fatigability and difficulty in concentration and near vision, headaches

Original studies Studies referenced in this review did not meet inclusion criteria (i.e. pre-dated 1999, unobtainable documents, or non-epi-study) or are already included in not identified in the screening process literature search/ (not included in selected refs)

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AUTHOR: Yao & Zhou, 2008 (Abstract evaluated, article in Chinese – Paper unobtainable)

TITLE: Progress of Studies on Human Health Impacts of Long-term Exposure to Organophosphorus Pesticides

Date of Review 2008

Aim Not clear from abstract

Topics covered Adverse health effects associated with long term exposure to low doses of pesticides (OPs)

Health outcomes Neural/ neurobehavioral (among others) considered

Original studies Paper unobtainable not identified in literature search/ (not included in selected refs)

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AUTHOR: Yokoyama, 2007

TITLE: Our recent experiences with sarin poisoning cases in Japan and pesticide users with references to some selected chemicals

Date of Review 2007

Aim To summarise recent observations of health effects in sarin poisoning cases of Tokyo subway attack and pesticide users (tobacco farmers) in Malaysia in relation to Green Tobacco Sickness

Topics covered Stipulated in the above (Aims) Non-neurological effects of pesticides and other chemicals in relation to genetic polymorphism and oxidative stress Health outcomes Neurobehavioural and neuropsychological effects considered

Original studies Kimura et al 2005. Effects of pesticides on the peripheral and central nervous system in tobacco farmers in Malaysia: studies on peripheral nerve conduction, brain evoked potentials and computerised posturography. Ind Health ; 43: 285-94 not identified in literature search/ NB. Other studies referenced in this review did not meet inclusion criteria (i.e. pre-dated 1999, non-OP specific or non-epi-study, mechanistic/in-vivo/in- (not included in vitro study; non-neurological health outcomes, methodological, exposure biomonitoring/biomarker therapy studies) or are already included in the selected refs) screening process

181 TOX/2012/26 Annex 3

COMMITTEE ON TOXICITY OF CHEMICALS IN FOOD, CONSUMER PRODUCTS AND THE ENVIRONMENT

DECISIONS ON PUBLICATIONS SCREENED IN FULL (TABLE 4) AND SUBDIVISION OF SELECTED PAPERS ACCORDING TO STUDY TYPE AND HEALTH OUTCOME (TABLE 5)

HPA COT Secretariat

August 2012

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TOX/2012/26 Annex 3

COMMITTEE ON TOXICITY OF CHEMICALS IN FOOD, CONSUMER PRODUCTS AND THE ENVIRONMENT

Table 4 DECISIONS ON PAPERS SCREENED IN FULL

Count Author and Date Accept Rationale For Rejection Yes No 1. Abdel Rasoul 2008 X 2. Alarcon 2011 X Abstract only available; not OP specific 3. Albers 2004a X 4. Albers 2004b X 5. Albers 2004c X 6. Albers 2007 X 7. Al-Shehab 2000 X Methodology study on NCS (nerve conduction studies) as a screening test for changes induced by chronic low-level exposure to OPs; abstract evaluated as journal issue not available through British Library 8. Androutsopoulos 2011 X Chosen as a “relevant review” 9. Araoud 2011 X Butyrylcholinesterase activity only 10. Araki 2005 X 11. Arima 2003 X Case report of transient Parkinsonism as result of OP poisoning; Parkinsonism is a known rare outcome of OP poisoning 12. Aubeneau 2008 X Article in French – case report of massive exposure over 10 years, effectively a poisoning 13. Baldi 2001 X Not OP specific – authors unable to get accurate information on names of pesticides used 14. Bayrami 2012 X 15. Bazylewicz-Walczak 1999 X 16. Beard 2011 X 17. Beckmann 2009 X Commentary on Mackenzie Ross et al 2009 study 18. Beseler 2006 X Not OP specific – risk of depression presented in relation to lifetime pesticide use and history of pesticide poisoning 19. Beseler & Stallones 2008 X Not OP specific 20. Beseler 2008 X 21. Bhatt 1999 X Reports an acute and reversible health outcome of OP poisoning (acute and reversible parkinsonism) 22. Browne 2006 X 23. Buchanan 2002 X Methodology paper, investigating reproducibility of measured indices of chronic peripheral neuropathy in sheep dippers and comparing field and clinical measures 24. Burstyn 2009 X Study concerns methodology, comparison of a “correct” model with a deliberately mis-specified simulated model 25. Camarinha 2011 X Article in Portugese 26. Carod-Artal & Speck-Martins X Article in Spanish; case report of one worker 1999 without detailed exposure information

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Count Author and Date Accept Rationale For Rejection Yes No 27. Catano 2008 X AChE activity only 28. Chao 2010 X 29. Chatterjee & Sarma 2003 X Case report of poisoning and combined features of intermediate syndrome and delayed neuropathy, known outcomes of poisoning 30. Cherry 2002 X 31. Cherry 2010 X 32. Chuang 2002 X Case report of OP induced delayed neuropathy after poisoning 33. Colosio 2009 X Chosen as a “relevant review” 34. Cox 2005 X 35. Crawford 2008 X 36. Dahlgren 2004 X 37. Das 2011 X 38. Dassanayake 2007 X Acute OP poisoning only 39. Dassanayake 2008 X 40. Dassanayake 2009 X 41. Davies 1999 X Paper evaluated in COT 1999 report 42. de Araujo 2007 X Abstract evaluated because article in Portugese; exposure is to pesticides, not specifically OPs 43. Delgado 2004 X 44. Dick 2001 X Measures acute effects of recent exposure to chlorpyrifos 45. Dunn 2002 X Report was considered by COT in 2007 (TOX/2007/21/annex a) 46. Elbaz 2009 X 47. Farahat 2003 X 48. Finkelstein 2010 X Chosen as a “relevant review” 49. Firestone 2005 X 50. Fletcher 2005 X 'Report was considered by COT in 2007 (TOX/2007/21/annex a), forms DEFRA Project no. VM0299, SHAPE: the telephone survey 51. Fonseka 2003 X Relates only to poisoning, no chronic effects; patient made complete recovery 52. Friedman 2003 X Exposure to OPs only in 1 of the 2 cases, and OP exposure not separated from exposure to other anti-cholinesterases 53. Friedman 2007 X Letter responding to study by Heaton et al, 2007, not peer-reviewed article 54. Garcia-Martin 2010 X No reference to OP exposure 55. Gatto 2009 X 56. Gauthier 2001 X Exposure considered is to “pesticides”, OP exposure not identified separately 57. Goel 2006 X Case report of acute poisoning 58. Gomez 2010 X Article in Spanish 59. Hancock 2008 X 60. Hanna 1999 X Exposure to a few specific OPs is not described separately from other chemicals 61. Hashim 2011 X Case report of transient Parkinsonism as result of OP poisoning 62. Hayden 2010 X 63. Heaton 2007 X

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Count Author and Date Accept Rationale For Rejection Yes No 64. Hong 2009 X Not OP specific 65. Horowitz 1999 X 66. Hoshino 2008 X 67. Hsieh 2001 X Evaluates subacute effects of OP poisoning- transient extrapyramidal syndrome, similar to Intermediate Syndrome 68. Jalali 2011 X 69. Jamal 2001 X 70. Jamal 2002a X 71. Jamal 2002b X Chosen as a “relevant review” 72. Jayasinghe & Pathirana 2011 X Acute effects 73. Jin 2008 X Evaluates subacute effects of OP poisoning , indicative of Intermediate Syndrome 74. Julu 2007 X 'Report was considered by COT in 2009 (TOX/2009/26) 75. Kamel 2000 X 76. Kamel 2003 X Exposure evaluated is to performing “farm work”, OPs not specified 77. Kamel 2005 X 78. Kamel 2007a X 79. Kamel 2007b X 80. Kara-Peketi 2009 X Not OP specific 81. Kawada 2005 X 82. Kawana 2001 X 83. Keifer 2000 X 84. Kesavachandran 2009 X Multiple pesticide exposure, OPs not considered separately 85. Kesavachandran & Mudiam X Correspondence, not peer-reviewed article 2010 86. Kilburn 1999 X 87. Konieczny 1999 X 88. Lawlor 2007 X Study considers association of PON1 variant with depression, but with no reference to OP exposure 89. Lee 2003 X 90. Little 2010 X Sensory ataxia is an expected outcome of acute effects of OPs 91. Loh 2010 X Although it reports on neuropsychological/ cognitive sequelae arising from acute exposure which are well documented, the study also reports on effects on memory 92. London 2004 X Reports on Guillain-Barre syndrome - a reversible de-myelinating disease 93. London 2005 X Chosen as a “relevant review” 94. Lotti 2002 X Chosen as a “relevant review” 95. Lotti & Moretto 2005 X Chosen as a “relevant review” 96. Lubis 2008 X Paper unobtainable 97. Mackenzie Ross 2009 VM02302 X Report considered by COT in 2009 (TOX/2009/26). Findings subsequently published in a peer-reviewed journal (See Mackenzie Ross 2010) 98. Mackenzie Ross 2010 X 99. Mackness 2003 X

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Count Author and Date Accept Rationale For Rejection Yes No 100. Manthripragada 2010 X 101. Matmurodov 2011 X Abstract of conference paper, not peer-reviewed article 102. McCauley 2001 X 103. Miranda 2002a X 104. Miranda 2002b X 105. Miranda 2004 X 106. Mittal 2011 X 107. Miyaki 2005 X 108. Morahan 2007 X Exposure considered is to pesticides, not specifically OPs 109. Muller-Vahl 1999 X Letter, not peer-reviewed article 110. Muttray 2005 X Analysis of EEG readings used only as an alternative means of exposure monitoring instead of AChE 111. Nakajima 1999 X 112. Nishiwaki 2001 X 113. Ohayo-Mitoko 2000 X Not OP specific 114. Ohtani 2004 X 115. Okudera 2002 X Paper is concerned with acute clinical features of exposure; refers to Nakajima above regarding longer-term sequelae 116. Orozco-De Los Rios 2005 X Article in Spanish 117. Otero 2000 X Article in Spanish 118. Ozturk 2008 X Letter, not peer-reviewed article 119. Ozyurt 2008 X Report on expected outcome of acute OP poisoning 120. Page 2003 X Not OP specific 121. Palacios-Nava 1999 X Article in Spanish 122. Parron 2011 X Exposure considered is to pesticides, no specific study of OPs 123. Pathak 2011 X Not OP specific 124. Payan-Renteria 2012 X AChE activity only 125. Peiris-John 2002 X 126. Pilkington 1999a X Report was considered by COT (phase 2 study, TM/99/02b) 127. Pilkington 1999b X Report was considered by COT (phase 3 study, TM/99/02c) 128. Pilkington 2001 X 129. Povey 2005 X 130. Povey 2007b X 131. Povey 2007a Phase 1 VM02115 X Report was considered by COT in 2007 (TOX/2007/21) 132. Povey 2009 Phase 2 VM02115 X Report was considered by COT in 2009 (TOX2009/26) 133. Povey 2010 X Chosen as a “relevant review” 134. Povey 2010 RR775 X HSE report on research project VM02115 135. Proctor 2006 X 136. Rainier 2008 X Aim of study is genetic analysis relating NTE (Neuropathy Target Esterase) abnormalities in motor neuron disease; no exposure to OPs is considered

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Count Author and Date Accept Rationale For Rejection Yes No 137. Ray & Richards 2001 X Chosen as a “relevant review” 138. Rees 2011 X Study considers symptoms associated with 'dipper's flu' and does not fit into any of the health outcome categories analysed in this review 139. Rehner 2000 X 140. Rice 2009 X Study is response to Lawlor et al. (2007) above. No OP exposure 141. Rohlman 2007 X Exposure is years spent working in agriculture, not OP specific 142. Rohlman 2011 X Chosen as a “relevant review” 143. Roldan-Tapia 2005 X 144. Roldan-Tapia 2006 X 145. Rothlein 2006 X 146. Salvi 2003 X 147. Savy 2011 X Not human data 148. Sedziak 1998 X Article in Polish 149. Shahar 2001 X Reports on acute (reversible) Parkinsonian symptoms in a child following accidental OP poisoning 150. Solomon 2007 X 151. Sosan & Akingbohungbe 2009 X Not OP specific 152. Soummer 2011 X 153. Spencer 2001 X 154. Srinivasan 2010 X 155. Srivastava 2000 X 156. Stallones & Beseler 2002a X Not OP specific 157. Stallones & Beseler, 2002b X Accept, although study Indirectly associates health outcome with OP exposure 158. Starks 2012a X 159. Starks 2012b X 160. Steenland 2000 X 161. Stephens & Sreenivasan 2004 X 162. Tahmaz 2003 X 163. Teixeira 2003 X Exposure considered is to OP and pyrethroid insecticides combined 164. Tochigi 2002 X 165. Tochigi 2005 X Although a letter, not an article, it reports correlation coefficients as supporting evidence for the data in Tochigi 2002 166. Van der Mark 2012 X Chosen as a “relevant review” 167. Wang 1999 X Report of 2 cases with ophthalmic sequelae of OP poisoning 168. Wesseling 2002 X 169. Wesseling 2010 X 170. Wills 2008 X Study of genetic association; no pesticide exposure information 171. Yamasue 2003 X 172. Yamasue 2007 X 173. Yan 2011 X Paper in Chinese 174. Yanagisawa 2006 X Chosen as a “relevant review”

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Count Author and Date Accept Rationale For Rejection Yes No 175. Yao & Zhou 2008 X Paper unobtainable 176. Yokoyama 2007 X Chosen as a “relevant review”

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Table 5 SUBDIVISION OF SELECTED PAPERS ACCORDING TO STUDY TYPE AND HEALTH OUTCOME

STUDY TYPE HEALTH OUTCOME Peripheral Autonomic Parkinsonism/ neuropathy, nervous Parkinson’s Neurophysiological Neuropsychological Psychiatric Other neuromuscular system Disease dysfunction effects COHORT Albers 2004a X chronic Albers 2004b X X X X neurological Albers 2007 X Beard 2011 X Delgado 2004 X X Engel 2001 X dementia and Hayden 2010 Alzheimer’s Disease Kamel 2007a X Kawana 2001 X X X neurological Miranda 2002a X Miranda 2002b X Miranda 2004 X Nakajima 1999 X X X neurological Starks 2012a X Starks 2012b X Tochigi 2002 X Tochigi 2005 X CASE-CONTROL Cherry 2002 polymorphisms Cherry 2010 polymorphisms Crawford 2008 X Das 2011 X Dassanayake 2008 X Elbaz 2009 X Firestone 2005 X

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STUDY TYPE HEALTH OUTCOME Peripheral Autonomic Parkinsonism/ neuropathy, nervous Parkinson’s Neurophysiological Neuropsychological Psychiatric Other neuromuscular system Disease dysfunction effects Gatto 2009 X Hancock 2008 X Jamal 2001 X Jamal 2002a X X X X Mackness 2003 polymorphisms Manthripragada 2010 X polymorphisms Murata 1997 X Povey 2007 polymorphisms Povey 2005 polymorphisms Yamasue 2007 MRI scan CROSS-SECTIONAL Abdel Rasoul 2008 X X X Albers 2004c X Araki 2005 X MRI scan Bayrami 2012 X X neurological Bazylewicz-Walczak 1999 X X X X symptoms – central Beseler 2008 X Browne 2006 X X polymorphisms Chao 2010 X MRI scan Cox 2005 X X neurological Dassanayake 2009 X X Farahat 2003 X X Heaton 2007 MRI scan Horowitz 1999 X Hoshino 2008 X Jalali 2011 X retinal Kamel 2000 degeneration Kamel 2005 X X X neurological

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STUDY TYPE HEALTH OUTCOME Peripheral Autonomic Parkinsonism/ neuropathy, nervous Parkinson’s Neurophysiological Neuropsychological Psychiatric Other neuromuscular system Disease dysfunction effects Kamel 2007b X X Kawada 2005 X Keifer 2000 X X X Kilburn 1999 X X X neurological Kimura 2005 X X Konieczny 1999 X X neurological, Lee 2003 polymorphisms Mackenzie Ross 2010 X X chronic McCauley 2001 X X X physical/ neurological McCauley 2002 X X X neurological Misra 1994 X SPECT brain Mittal 2011 X scan Miyaki 2005 X X Nishiwaki 2001 X X X Ohtani 2004 X X neurological Peiris-John 2002 X X Pilkington 2001 X Proctor 2006 X X Rehner 2000 X Roldan-Tapia 2005 X Roldan-Tapia 2006 X Rothlein 2006 X Salvi 2003 X X X Solomon 2007 X neurological Spencer 2001 X X X X Srivastava 2000 X X X Stallones 2002b X X X neurological Steenland 2000 X X X Stephens 2004 X X Tahmaz 2003 chronic fatigue

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STUDY TYPE HEALTH OUTCOME Peripheral Autonomic Parkinsonism/ neuropathy, nervous Parkinson’s Neurophysiological Neuropsychological Psychiatric Other neuromuscular system Disease dysfunction effects Wesseling 2002 X X Wesseling 2010 X Yamasue 2003 MRI scan CASE SERIES Dahlgren 2004 X X CASE REPORT Loh 2009 X Soummer 2011 X Srinivasan 2010 MRI scan

10 TOX/2012/26 Annex 4

COMMITTEE ON TOXICITY OF CHEMICALS IN FOOD, CONSUMER PRODUCTS AND THE ENVIRONMENT

EVALUATION OF NEUROPSYCHOLOGICAL ABNORMALITIES

ROHLMAN et al 2011 A free copy of the article can be found at; http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3057226/?tool=pubmed

HPA COT Secretariat

August 2012

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TOX/2012/26 Annex 4

COMMITTEE ON TOXICITY OF CHEMICALS IN FOOD, CONSUMER PRODUCTS AND THE ENVIRONMENT

EVALUATION OF NEUROPSYCHOLOGICAL ABNORMALITIES

OVERVIEW OF COT 1999 REPORT

1. The COT evaluation published in 1999 can be found in Chapter 7 of the report paragraphs 7.12-7.7.29.

Studies in Individuals with a History of Acute Poisoning

2. The COT concluded; ‘Despite their methodological limitations the findings in studies of poisoned subjects are unlikely to be wholly attributable to confounding effects or to chance. The patterns of abnormality reported are not entirely consistent, but this may in part reflect differences in the severity of the poisoning which subjects had suffered. On balance, the Working Group interpreted the studies as providing reasonable, although not conclusive, evidence that OP poisoning of sufficient severity to require hospital admission can lead to persistent cognitive impairment. This effect is most evident in neuropsychological tests involving sustained attention and speeded, flexible cognitive processing, for example, the digit symbol substitution test. The studies reviewed provide no evidence that long-term memory is affected by acute OP poisoning apart from impaired visual memory in one investigation. Thus, if low-level exposure to OPs causes neuropsychological abnormalities these are most likely to be shown on tests of cognitive function other than memory.’

3. The overall conclusion reached (paragraph 1.13) was ‘The balance of evidence supports the view that neuropsychological abnormalities can occur as a long-term complication of acute OP poisoning, particularly if the poisoning is severe. Such abnormalities have been most evident in neuropsychological tests involving sustained attention and speeded flexible cognitive processing ("mental agility"). In contrast, current evidence suggests that long-term memory is not affected after acute poisoning’.

Studies in Individuals with No Past History of Acute OP Poisoning

4. The COT concluded ‘When account is taken of these limitations* and of the inconsistencies between studies, the research reviewed provides little support for the hypothesis that prolonged low-level exposure to OPs gives rise to long-term changes in the cognitive functions that would be expected to show impairment in the postulated syndrome of COPIND. The most consistent findings are with respect to simple reaction time and a test (digit-symbol substitution) that depends on multiple

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cognitive functions, places individuals under time pressure, and is known to be sensitive to cognitive impairment following neurological insult such as traumatic brain injury. No study, including those with positive results on other measures, has indicated effects of OP exposure on long-term memory function. It is noteworthy that the finding of positive effects on the digit-symbol substitution task, but without a decrement in long-term memory, is similar to that in people who have previously been acutely poisoned by OPs.

Possible differences between exposed and controls other than OP exposure, not adequately taken into account in the statistical analyses

[*Small study size so that effects that are large enough to be medically important may not have been distinguishable from random variation

Possible biases due to an association between a subjects’ willingness to participate in the research and their state of health.

The inclusion of some subjects with an unrecognised past history of acute poisoning

Restriction to workers currently or recently exposed to OPs. This means individuals too ill to remain in employment will have been excluded.]

5. The overall conclusion reached (paragraph 1.18) was ‘Although some studies suggest impairment in the same tests that are affected after acute poisoning, others do not. The balance of evidence does not support the existence of clinically significant effects on performance in neuropsychological tests from low-level exposures to OPs. If such effects do occur, they must either be relatively uncommon or so small that they are not consistently detectable by standard methods of testing’.

OVERVIEW OF LITERATURE PUBLISHED AFTER COT 1999 REPORT

6. Short summaries of the key studies are given below. Detailed information can be found in Annex 4 Table 6 (methods) and Table 7 (results). Assessment of neuropsychology test data has been grouped into functional domains, although individual tests cited may provide data on several or many of the domains. A summary of neuropsychological tests outcomes grouped into functional domains is appended as Table 8. Inclusion of tests in a particular domain is based on the domains suggested by the majority of investigators, although there were a few differences between the studies reviewed. An overview of the neuropsychological tests considered in the draft COT discussion paper is provided (table 9) to aid members understanding and consideration of the tests. The influence of confounding factors, which included age and education, has been considered in the tables.

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ACUTE EXPOSURE WITH CHRONIC NEUROPSYCHOLOGICAL ABNORMALITIES

Cohort Study

7. The literature review identified one prospective cohort study of subjects from Nicaragua who were poisoned (hospitalised) with OPs, and who were followed for a period of up to 2 years (data for 53 poisoned subjects at all time points up to and including 2 years, compared to data from 28 controls from fish/cattle cooperatives) (Delgado et al 2004) (Annex 4, Table 6.A.1). A limited range of neuropsychological tests were administered. A persistent reduction in Digit symbol (a test of psychomotor performance) was reported over the 2 year follow up period which was significant after adjustment for age, education and alcohol consumption (decrement 2y compared to discharge was -7.69 (-17.6-2.24) (Annex 4, Table 7.A.1). This finding is consistent with the conclusions reached by the COT Working Group in 1999. This was a good study of poisoned subjects with 85% of the cohort tested at the 2-year follow-up. The authors considered a range of potential confounding factors.

Cross-Sectional Studies

8. Cross-sectional investigations of five different exposure scenarios were retrieved. These were Banana workers with acute cholinergic poisoning, subjects with acute organophosphorous poisoning from India, subjects with acute OP (and carbamate) poisoning from Spain, follow-up studies of Gulf War Veterans exposed acutely to OPs arising from the Khamisiyah incident and individuals exposed to sarin following the Tokyo subway incident. These very different exposure situations are considered separately.

Banana workers

9. Wesseling et al 2002, undertook neuropsychological testing of 81 Costa Rican banana workers identified from reports to the National Insurance Institute regarding cholinergic poisoning. Pesticides responsible for poisoning were reported for 78 subjects and included OPs for 54 cases and carbmates for 24 cases. It was reported that all poisoned subjects needed medical attention but poisoning was not sufficiently severe to require hospitalisation. A control group of 130 non-poisoned banana workers identified from pay rolls was used (Annex 4, Table 6.A.3). A comprehensive set of neuropsychological tests was undertaken at least one year after the poisoning incident. Poisoned subjects performed less well than controls in 13 out of the 14 tests administered, but differences were small. The only statistically significant finding was a decrease in WAIS Digit symbol performance (regression coefficient -2.7 (P<0.05)), but other tests of psychomotor performance were unaffected. The difference between poisoned/non-poisoned was evident in both subjects with and without recent handling of pesticides (3 months) but were more evident in workers with recent contact with cholinesterase inhibitors. A range of factors was included in the analysis including age, education cumulative life-time exposure to cholinesterase inhibitors, alcohol use, solvent exposure, loss of consciousness, examiner, time of testing and plasma AChE. There were no

3 THIS IS A DRAFT PAPER FOR DISCUSSION. IT SHOULD NOT BE QUOTED, CITED OR REPRODUCED statistically significant effects of attention, visuo-spatial function, memory or vocabulary. The authors reported that deficits (across all neuropsychological tests) were more clearly seen in data for OP exposed subjects than carbamate exposed subjects (Data presented graphically) (Wesseling et al 2002) (Annex 4, Table 7.A.3).

Subjects with acute organophosphate poisoning- India

10. Mittal T et al 2011, undertook neuropsychological testing of 28 patients with acute OP poisoning. Testing was undertaken just prior to discharge and at 3 months after discharge. A control group of hospital employees or attendants of patients matched for age and gender was used (Annex 4, Table 6.A.3). At discharge and at 3 months after discharge significantly impaired performance in verbal fluency, visual recognition, and verbal retention (subtests of the PGI memory scale, which is a modification of the Weschler memory scale) were reported in OP poisoned subjects. In addition poorer performance of the Bender-Visual-Motor-Gestalt test (a test of visual-motor coordination) was reported in OP poisoned subjects. The authors did not report information on any confounding variables included in the analyses. However, patients with any abnormal neurocognitive dysfunction to any cause prior to OP poisoning were excluded by Mittal et al 2011.(Annex 4, Table 7.A.3)

Subjects with acute organophosphate/carbamate poisoning-Spain

11. Roldan-Tapia et al 2006, undertook comprehensive neuropsychological testing of 24 green house workers (gender not stated) who had been poisoned with OPs and carbamates at 3 months and 1 year after hospital discharge. The investigators compared the data for these subjects to unexposed controls (26 males) and 40 male subjects with prolonged exposure to OP/carbamate pesticides (20 high exposed (>10years), 20 low exposed (<10 years)). The authors undertook analyses by grouping tests into domains (Annex 4, Table 6.A.3). Results showed significant differences in some tests for assessment 3 months after poisoning related to memory (Rey Auditory learning test, Benton Visual Retention Test and recall of Rey Osterrieth Figure Complex) but overall this domain was not significantly affected (F(24,207=1.11, p0.326). Significant changes in perceptive and visuomotor domains were reported. Perceptive domain (F(9,222)=2.74, p=0.005); Benton Visual Recognition Form Test, Picture completion Visuomotor domain (F (9,222)=2.31, p=0.003) Block design and quality and time of copy of Rey Osterrieth Complex Figure. For acutely poisoned subjects, 1 year after discharge there was reduced performance in a test of perception (Picture completion) , reduced performance in tests of memory (Rey-Auditory Verbal learning, Logical memory and Rey-Osterrieth Figure Test, and visuomotor components of tests (Rey-Osterrieth Figure Test and Benton Visual Form Test). At the 1 year evaluation, the previously increased anxiety score (at 3 months) was no longer evident. The authors controlled for possible confounding by age, education and BuChE level. This study was limited in that the selection process for exposed and control subjects was not reported in detail, an assessment of exposure (in poisoned subjects) was not undertaken, and the loss of subjects to 1 year follow-up was not reported. (Roldan-Tapia et al 2006) (Annex 4, Table 7.A.3).

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Gulf War veterans

12. Gulf War veterans were exposed to sarin/cyclosarin for a two week period in early March 1991 following a munitions explosion at Khamisiyah. Follow up studies of 3.5-5 years and 10 years after the incident were published (Proctor et al 2006, Chao et al 2010). A separate follow-up study was published by Spencer et al 2001, but there are too few details in the available report to draw any conclusions (Spencer et al 2001). Proctor et al 2006, undertook neuropsychological assessment of 70 Gulf War veterans (3.5-5 years post incident) with reported moderate/high exposure to OPs (as defined by the authors) compared to a group of 70 veterans with low or no exposure to OPs (Annex 4, Table 6.A.3). It is notable that Gulf war veterans did not report acute cholinergic symptoms after the incident. The authors reported a dose- dependent reduction in performance of Purdue pegboard (timed, fine manual dexterity) (decrement in high exposed ; dominant -0.93 (-16 to -0.28) P=0.005) and non-dominant (-0.48 (-0.92 to -0.04) P=0.03) and Block Design (visuo-spatial construction with a motor component) (decrement in high exposed -4.0 (-5.8 to -2.2) P<0.0001). However, an improvement in Finger Tapping was reported. Performance of Purdue pegboard was significantly reduced after adjusting for Finger Tapping performance. Covariates included age, gender, officer status during Gulf War, WAIS-R test (intelligence), head injury and PTSD symptomatology. There were no effects on tests of attention, executive function. Memory tests were not administered in the 3.5-5 year follow up investigation (Proctor et al 2006) (Annex 4, Table 7.A.3).

13. Chao et al 2010, published a 10 year follow-up and undertook neuropsychology tests in 40 Khamisiyah exposed veterans compared to 40 veterans with no exposure to OPs (Annex 4, Table 6.A.3). (There were no differences between the groups with regard to gender, age, education, handedness, PTSD, major depression or chronic multisymptom illness.) The study did not identify any effects on groove pegboard or digit symbol tests of psychomotor performance, or the Block Design test or tests of memory (Chao et al 2010) (Annex 4, Table 7.A.3).

14. These studies are difficult to interpret in terms of potential effects of OP exposure as it is known that Gulf war veterans who report symptoms associated with the conflict perform more poorly on neurobehavioural measures (of memory, attention and response speed) when compared to veterans who did not report symptoms (Storzbach D et al, 2000). Self-reported exposure to chemical warfare agents among Gulf war-deployed veterans is associated with poorer performance of cognitive tests of memory and attention (White RF et al 2001). Psychological stress, including perception of a chemical warfare agent has been reported to be associated with chronic multi-symptom illness in Gulf War veterans (Riddle JR et al 2003).

Tokyo subway sarin incident

15. Fire crew and police officers who attended the Tokyo sarin incident were acutely exposed to sarin. Obu and colleagues reported that over 5,500 were injured in the attack. Of these, 641 were seen at St Lukes International Hospital on the day of the attack, five were in a critical condition, 106 were hospitalised with moderate severity, and 531 were categorised as mild and treated as outpatients (Ohbu S et al

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1997). Follow up neuropsychological testing was undertaken at three periods after the attack. These were 2 years 9 months-3years 10 months, 5years, and at 7 years.

16. Nishiwaki et al 2001, evaluated neuropsychological test performance in 27 male Fire Department rescue staff and 30 police officers at 2 years 9 month-3 years 10 months after the Tokyo subway incident. Referents were fire staff and police officers with no exposure to sarin (Annex 4, Table 6.A.3). Some evidence for decreased psychomotor function was reported in finger tapping (dominant) performance (132.7 (SD 1.2) in high exposed compared to 120.7 (SD1.2) in controls, P<0.05 in multiple regression model). The authors also reported an OR of 3.19 (95% CI 1.06-10.38) for decreased performance of digit span (Backward) in the high exposed which was interpreted as an effect on memory. There were no differences between these two groups in performance of digit span (forward), simple and choice reaction times, finger tapping non-dominant and the Benton visual retention test. Adjustment for age, height, weight, alcohol, smoking, education and measures for current PTSD and mental health was included in the analysis. (Nishiwaki et al 2001) (Annex 4, Table 7.A.3).

17 A more limited neuropsychological investigation (visual memory) was undertaken at 5 years after the incident in a small (self-selected) group of Tokyo subway incident victims who had been treated at one emergency department (11 subjects with PTSD and 23 referents) (Ohtani et al 2004) (Annex 4, Table 6 A.3). Decreased visual memory (97.6 ±13.1, compared to 108 ±10.4, P<0.05) was reported in exposed subjects who also had symptoms of PTSD. Potential confounding factors were not reported (Annex 4, Table 7.A.3). Only limited weight of evidence can be attached to this result.

18 Miyaki et al 2005, undertook a more comprehensive neuropsychological investigation of Tokyo subway workers 7 years after the incident (Miyaki et al 2005). Data were also presented for a combined group with data for 3 year and 7 year follow-up. There were 23 exposed subway workers included in the 7 year follow up (13 subway workers in referent group). The combined 3 year and 7 year group (which comprised subway workers, rescue workers and police officers) had 80 subjects (combined referent group contained 65 subjects) (Annex 4, Table 6.A.3). At 7 years there was a reduction in performance of Finger tapping (dominant and non-dominant) but no effects were reported in tests for attention (Digit span forward and backward), psychomotor function (simple and choice reaction times) and visual memory (Benton). Combined data for 3 year and 7 year follow-up reported reduced performance in finger tapping (dominant (OR for high exposure 3.44 (95% CI 1.18- 10.1)), and non-dominant (OR for high exposure 2.77 (95% CI 1.0-7.70)), and a nearly significant effect on digit span (backward) (P=0.055), but no effect on visual memory. The authors reported that symptoms of PTSD were higher in sarin exposed individuals. Potential confounding factors considered included age, BMI, education, smoking, alcohol and measures of PTSD and current mental health (Annex 4, Table 7.A.3).

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Case-Series Investigation

19. Dahlgren et al 2004, published a case-series investigation of a family who were acutely exposed to diazinon when their house was inadvertently excessively sprayed (Annex 4, Table 6.A.4). The follow-up investigations reported effects on memory and psychomotor functions in a number of these patients 3 years after exposure (Dahlgren et al 2004) (Annex 4, Table 7.A.4).

Case-Report

20. Loh et al 2010, reported effects on information processing and reduced attention to task in a senior explosive disposal officer acutely exposed to sarin (Loh 2010) (Annex 4, Table 6.A.5 and Table 7.A.5).

Conclusion on Acute Exposure with Chronic Neuropsychological Abnormalities

21. The most consistent information for the assessment of acute OP exposure (leading to overt cholinergic poisoning) resulting in chronic neuropsychological effects comes from the cohort study by Delgado et al 2004 and the cross-sectional study of banana workers (Wesseling 2002), The results of both of these studies support the conclusion reached by the COT working group in 1999 that acute intoxication can lead to persistent deficits in psychomotor performance (particularly with respect to reduced performance in digit symbol test). The study of acute OP/carbamate poisoning in Spain reported evidence for persistent effects 1 year after poisoning on a range of tests measuring perception (Picture completion), memory (Logical memory and Rey-Osterrieth Figure test) and also on visuomotor skills (quality of copy of Rey-Osterrieth Figure and time of copy of Benton Visual Form test) (Roldan-Tapia 2006). These particular tests have not been used in other studies and additionally the functions assessed have not been investigated in detail in other studies. It is difficult to draw any definite conclusions based on this study. The study of Mittal et al 2011 was undertaken at only a comparatively short 3-month period after OP poisoning. It is difficult to draw any conclusions as to whether OP exposure induced neuropsychological deficit in Gulf War veterans exposed to sarin/cyclosarin at the Khamisiyah incident, particularly as neuropsychological deficits have been found in Gulf war veterans irrespective of exposure to sarin/cyclosarin. There is some limited evidence for a deficit in psychomotor function and in the digit span (backward) test (which was interpreted as an effect on short term memory) in individuals exposed to sarin from the Tokyo incident, but results between studies which covered different periods of follow-up are inconsistent (Nishiwaki et al2001, Ohtani et al 2004, Miyaki et al 2005).

CHRONIC LOW-LEVEL EXPOSURE

Cohort Studies

22. Three cohort studies reporting neuropsychological testing of OP exposed subjects was retrieved.

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Study of Dow employees manufacturing chlorpyrifos-USA

23. Albers and colleagues administered the Mini Mental State Examination (MMSE) and a qualitative questionnaire (of reading, memory, concentration and problem solving) to Dow employees engaged in the manufacture of Chlorpyrifos (Albers et al 2004b). A total of 53 OP exposed individuals were examined at the initial and at the one year follow-up. A control group of 60 employees engaged in the manufacture of Saran plastic film wrap was used (58 at the second examination) (Annex 4, Table 6.B.1). Exposure to cholinesterase inhibitors was confirmed by biological monitoring (urinary excretion of Chlorpyrifos metabolites and decreased plasma butylcholinesterase activity). There were no differences between exposed and controls (engaged in manufacture of Saran plastic film) with regard to qualitative assessment of neuropsychological function (reading memory, concentration and problem solving) or from the Mini mental State Examination (MMSE). Exposed and referents were matched for age, height, weight, BMI, reading scale, smoking and anxiety (Annex 4, Table 7.B.1).

24. This study provides evidence to support the view that chronic OP exposure is not associated with neuropsychological effects. There was 80% participation of eligible subjects but the extent of neuropsychological testing was limited and the duration of follow up was only 1 year.

Study of pesticide applicators Iowa and North Carolina

25. Starks et al 2012a, undertook neuropsychological tests of 701 male participants selected from the Agricultural Health Study (AHS) (Starks et al 2012a). The AHS is a large prospective cohort study of private pesticide applicators, their spouses and commercial pesticide applicators. Enrolment was between 1993-1997 at the time of pesticide licensing and recertification. The authors administered tests from the Neurobehavioural Evaluation System version 3 (which included Continuous Performance, Digit Symbol, Fingertapping (dominant), Auditory Verbal learning Test (AVLT-three subtests), Sequences A and B) and the Groove pegboard (dominant) test. Neuropsychology tests were administered by trained technicians unaware of participants exposure status. The mean age of participants was 61 years (SD 12 years). Data on ever-use (assumed to be one season) and life-time days of use of 16 OP pesticides were obtained from AHS interviews undertaken between 1993- 2007 and at the Neurobehavioural (NB) test appointment (Annex 4, Table 6.B.1).

26. There was no association between total OP dose and any NB test. There were some associations between exposures to specific OP pesticides and poorer performance in NB tests (e.g. ever use of ethoprop and life-time days malathion use and reduced performance in the Digit Symbol test. In contrast there several findings of improved performance in NB tests (e.g. exposure to chlorpyrifos, coumaphos, parathion, phorate and tetrachlorvinphos and improved performance AVLT subtests). The authors note these results could have occurred by chance. Overall, it was concluded that there was no consistent evidence for an association between OP pesticide exposure and adverse performance of neuropsychological tests. It was noted that this was an older sample of pesticide workers than previous studies and possible selection bias could have occurred. However, major advantages of this study was the large sample tested and the reliability and accuracy of the estimation

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of pesticide use. There was possible selection bias in that only 40% of potential participants provided information on potential exposure and neuropsychological testing was undertaken in 701/1807 of these subjects. The authors reported that they had oversampled at the high end of lifetime OP use (Starks et al 2012a) (Annex 4, Table 7.B.1).

Study of Israeli subjects exposed to OPs

27. One publication reporting a retrospective study of Israeli subjects exposed to OPs was retrieved (Annex 4, Table 6.B.1). Although effects on Trails B and Digit symbol were reported, there are insufficient details were available to make any assessment. (Finkelstein et al 2010 ) (Annex 4, Table 7.B.1). (A literature search for Finkelstein revealed publications on post-mortem AChE levels in OP poisoned subjects and a publication on antidotal therapy for acute OP poisoning but no further studies on neuropsychology assessment.)

Case-Control Study

28. One study was identified. (Jamal et al 2002) (Annex 4, Table 6.B.2). However too few details of results were available to make any assessment of this study (Annex 4, Table 7.B.2).

Cross-Sectional Studies

29. Fourteen cross-sectional studies were retrieved. These have been grouped according to the country where the study was undertaken.

Studies undertaken in England

Study of Orchard Sprayers

30. Stephens et al 2004, undertook neuropsychological testing of 37 male orchard sprayers who used chlorpyrifos from different regions of England and compared the test results to data from neuropsychological testing of pig farmers (26 males) and construction workers (41 males) (Stephens et al 2004). The response rates in the exposed group was 68%, but details of the selection procedure for the initial cohort of 60 orchard sprayers was not reported (e.g. how many farms were approached and how many agreed to participate). For pig farmers, the site response rate was 9%. For construction workers 100 potential subjects were approached and 41 agreed to participate. A period of at least 2 months between last application of OP and neuropsychological testing was applied to ensure the absence of acute effects (Annex 4, Table 6.B.3). Biological monitoring at this time suggested that levels of OP metabolites in urine samples were similar in all three groups. Orchard sprayers had significantly reduced performance in the Automated Cognitive Test System (ACTS) Syntactic reasoning response to negative statements compared to construction workers (P=0.012 corrected). The investigators considered this result indicated a slowing of processing speed. Performance of orchard sprayers and pig farmers was similar for many of the other neuropsychological tests used. The study

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investigators reported no reduced performance in orchard sprayers for other tests of attention/psychomotor functions (e.g. simple reaction time, digit span (backward), processing speed (digit symbol), and tests of memory (e.g. digit span forward, location recognition, category search, subjective memory questionnaire). There was no relationship between cumulative OP exposure and neurobehavioural test performance. Weekly alcohol consumption was substantially higher in construction workers. There were no statistically significant differences between the groups with respect to age and education, although a higher percentage of orchard sprayers (16%) and pig farm workers (12%) were educated to degree level compared to construction workers where none were educated to degree level (Annex 4, Table 7.B.3).

Study of Sheep Dippers

31. Mackenzie-Ross et al 2010, undertook neuropsychological testing of 127 sheep farmers with at least 5 years exposure to OPs (67 working, 60 retired due to ill health), compared to 78 rural policemen (38 working, 40 retired on ill health grounds) (Mackenzie-Ross et al 2010). Recruitment of sheep farmers involved writing to farm owners listed on the relevant databases (UK national Business Directory, National Farmers Union membership lists) and telephoning every 5th person on list held by Wool Marketing Board). 393 sheep farmers were contacted; 59% response. Additional farmers recruited through advertising or reply to articles in media. Initially a total of 434 farmers came forward; exclusion of 67% using inclusion/exclusion criteria. Inclusion included age 18-70 y, living in South West or North England, retired subjects on basis of ill-health and exposure to OPs for minimum of 5 years prior to 1991. Exclusion criteria included on history of psychiatric, neurological or serious medical problems, substance abuse (including alcohol) or acute OP intoxication. Recruitment of controls was undertaken by enlisting the help of local constabularies and the National Association of Retired Police Officers who contacted members by email or newsletter. The study was also advertised in the police press. Initially 252 police officers came forward; exclusion of 63% (inclusion/exclusion parameters included having worked in rural setting in South West or North England retired on ill health grounds and with no known exposure to OPs). A semi-structured interview was used to assess exposure which was highly variable ranging from 8-49 years for the working group and 5-66 years for the retired group. The number of years since last dipping varied from 0-37 years for the working group and 0-42 years for the retired group. The number of days spent dipping/year also varied from 0.5-30 days/year for the working group and 1-21 days/year for the retired group. A comprehensive set of neuropsychological tests was undertaken (Annex 4, Table 6.B.3).

32. Farmers (both working and retired) were significantly impaired (P<0.05) on measures of memory (working- Digit span forwards/backwards, letter number, arithmetic), response speed (Digit symbol, Trails A), fine motor control (Groove pegboard), mental flexibility (Trails B, Stroop, CALCAP) and strategy (verbal fluency) (full details are provided in Table 10). There were no impairments on verbal abilities, visuo-spatial abilities and visual and verbal reasoning. A significant effect of exposure was reported for Full Scale WAIS but was due to patchy under- functioning on certain WAIS subtests. General intellectual ability was reported to be well preserved. This pattern of findings was confirmed if the data were compared to

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normative comparison standards. Farmers and controls were matched for gender, education and premorbid IQ. Age corrected psychometric test data was used. Analyses were run controlling for anxiety and depression. Significant negative correlations between poorer performance and exposure duration were reported in auditory and visual memory (WMS III visual/auditory tests), verbal ability (WAIS III vocabulary), strategy making (verbal fluency) and fine motor control (Groove pegboard). It is possible that the selection procedure may have preferentially included sheep farmers with chronic illhealth (Mackenzie-Ross et al 2010) (Annex 4, Table 7.B.3).

Studies undertaken in USA

Study of Apple Orchard Thinners

33. Keifer et al 2000, investigated neuropsychological function (using WHO Core Test battery) in orchard thinners exposed to azinphos-methyl following treatment of apple trees to control codling moth (Keifer et al 2000). Neuropsychology testing was undertaken prior to the 1994 spray season (to investigate the effects of past chronic low-level exposure) and after the 1994 season (to investigate seasonal change). There were 137 subjects included in the first examination and 90 in the second examination (data for 87 available). The authors did not report the participation response rate for this study. Each exposed farm worker was matched on age, gender and education with a non-agricultural referent (employed in garment manufacturing, hotels and restaurants) (Annex 4, Table 6.B.3). Pre-1994 tests revealed poorer performance (P<0.05) in tests of attention (Digit span (backwards), Trailmaking A) and in a test of psychomotor function (Santa Ana dominant) (see Table 10 for full details). The authors noted that other tests of attention and psychomotor function were unaffected. Additionally there was no seasonal effect in any test in the WHO Core Test battery. The authors measured the Peabody Picture Vocabulary (which correlates with education) at the first examination (pre-1994 season) and included gender, age and haemoglobin level in the analysis. The authors considered that there was no consistent effect of a season of thinning on neuropsychological test performance (Annex 4, Table 7.B.3).

Study of Tobacco Workers

34. Salvi et al 2003, administered the MMSE and word span tests to tobacco workers after 3 months of exposure to OPs (n=37), in particular to chlorpyrifos, and again 3 months after the cessation of OP use (n=25) (Salvi et al 2003) (Annex 4, Table 6.B.3). There was no effect on plasma cholinesterase levels in this study suggesting exposures were low. Performance in MMSE and word span was within expected range for the population. There were no differences between the two time points assessed. There was no description of the selection procedure for the 37 exposed subjects or the response rate. There was no consideration of confounding factors (Annex 4, Table 7.B.3).

Study of Oregon Farmworkers

35. Rothlein et al 2006, undertook neuropsychological testing of 92 Hood river Oregon Hispanic immigrant farmworkers who lived in close proximity to orchards

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sprayed with OPs (Rothlein et al 2006). Control subjects were taken from Hispanic immigrant workers from Newport, Oregon (a tourist costal town with little agriculture). The selection procedure for exposed and controls was reported but the response rate was not provided. Neuropsychology test data were available from 45 control subjects. Exposure to OPs was confirmed in dust samples from farm workers’ homes and in biomonitoring investigations (analysis of urine samples for thiomethyl phosphate metabolites). A comprehensive set of psychomotor and cognitive function tests was undertaken (Annex 4, Table 6.B.3). After adjusting for age, sex and years of education poorer performance (P<0.05) in 5/16 test attention/psychomotor indices was associated with higher levels of average combined thiomethyl- metabolites (selective attention latency, symbol digit latency, preferred hand finger tapping, alternate hand finger tapping, and continuous performance hit latency). (Negative findings for Digit span (forward/backward), Progressive ratio, Reaction time, Selective attention trials, selective attention inter stimulus interval, serial digit learning, finger tapping non-preferred hand, Continuous performance; %hits, % correct rejects, and false alarm latency.) These data suggest a deficit on attention and psychomotor functions (Annex 4, Table 7.B.3).

Study of Termiticide Workers Applying Chlorpyrifos

36. Steenland et al 2000, undertook neuropsychological testing of termiticide applicators from a 12 county area of North Carolina who had applied chlorpyrifos from 1987-1997 (Steenland et al 2000). The Neurobehavioural Evaluation System (NES) was administered consisting of vocabulary test, mood scales, digit span, continuous performance, simple reactions time, digit symbol test, pattern memory. In addition, the investigators also administered Trails A and B tests. The selection procedure and response rates for exposed and controls were reported. A total of 193 applicators were tested. Controls were either friends of exposed subjects who attended the test centre (106) or North Carolina state employees (83) with no exposure to pesticides. Information on pesticide use was gathered by telephone interview and current chlorpyrifos exposure was measured by analysis of 3,5,6- trichloro-2-pyridinal (TCP) excretion in urine (Annex 4, Table 6.B.3). Approximately 34% of applicators had used chlordane (median 4.5 years (range 0.5-28years)) prior to 1988 when chlorpyrifos was introduced. The period of chlorpyrifos use was relatively short (median 1.8 years (range 0.1-10.3 years)). Creatinine corrected values for TCP in urine from applicators exposed in last week, not exposed in last week and non-exposed were 331, 55 and 3 ug/g creatinine respectively. Apart from poorer performance in the Pegboard task, there were no significant differences between Termiticide applicators and controls for any other neuropsychological test. The level of TCP did not significantly predict performance in any test except for Vocabulary, for which subjects with more TCP did significantly worse (p=0.02). There were no associations for current v former exposure, duration of use of chlorpyrifos, chlordane or other pesticides. Self-reported poisoning by chlorpyrifos (eight subjects) was associated with decrease in Continuous performance test (p=0.0001) and on Simple reaction time (p=0.06). Overall, there was no convincing evidence for poorer neuropsychological performance in this group of termiticide applicators with current exposure to chlorpyrifos. The authors reported possible selection bias in that 38% of termiticide applicators could not be traced (Annex 4, Table 7.B.3).

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Study of Subjects Exposed to Chlorpyrifos

37. Kilburn and colleagues undertook comprehensive neuropsychological testing of 22 patients (10 self-referred, 12 attorney referred) with exposure to chlorpyrifos, predominantly arising from treatment of homes or offices of the occupants (Kilburn et al 1999). These patients were selected from 384 patients evaluated for possible neurobehavioural effects of chemicals in a neurotoxicology clinic (6% response rate) (Annex 4, Table 6.B.3). The authors report limited information on possible exposures with a mixture of acute and repeated exposures documented. Neuropsychological tests of the 22 patients revealed a wide range of deficits following analysis of variance. Testing revealed a perceptual motor function impairment (peg board, Trails A and B were all decreased). There were finger writing errors in the left (but not right) hand. Story recall and long term memory functions of information, picture completion diminished (but similarities was not). Profile of Mood States (POMS)/depression score was elevated in the patients. This study was limited by the selection process which resulted in self/attorney referrals which may have selected patients with pre-existing neuropsychological deficits (Annex 4, Table 7.B.3).

Studies undertaken in Egypt

Studies of Cotton Field Sprayers

38. Farahat et al 2003, undertook neuropsychological testing of 53 cotton workers exposed to a range of OPs and other pesticides (none had been hospitalised for acute poisoning) and 50 male clerks who lived and worked near to cotton fields as a control group The authors reported a response rate of 81% for exposed participants (Farahat et al 2003). A description of potential routes of exposure of sprayers and agricultural field workers was provided (Annex 4, Table 6.B.3). Serum cholinesterase was significantly reduced in the exposed group. A comprehensive set of neuropsychological tests was undertaken. Statistically poorer performance (P<0.05) of six tests was reported which included tests of verbal abstraction (Similarities), attention/memory (Digit span (forward and backward) and Benton Visual Retention test), visuomotor speed (Digit symbol, Trails A and B), and attention (Letter cancel). No effects of exposure were reported for Block Design (visuospatial), the Paced Auditory Serial Attention test (PASAT, attention/working memory) and Story recall A and B (memory). The authors concluded that moderate chronic OP exposure may not only affect visuomotor speed as reported previously, but also verbal abstraction, attention and memory. Analysis included adjustment for age and education. The possibility that some of the exposed group had suffered acute intoxication with OPs cannot be excluded (Annex 4, Table 7B.3).

39. Abdel-Rasoul et al 2008, investigated the effects of occupational exposure to OPs resulting from spraying cotton fields on neurobehavioural performance in children (Abdel-Rasoul et al 2008). Male children from 5/50 villages (randomly chosen) were approached. 56 were identified. 50 participated (response rate 89.3%). Two age groups were studied, 9-15 years and 16-19 years. Data for the 16-19 year group (n=20) have been summarised. For each sprayer, a control subject who had never worked in the cotton fields was selected from friends/relatives living in the same community and attending the same schools. Data on spray application history

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was available but no direct estimate of OP exposure was available. A comprehensive set of neuropsychological tests was used (Annex4, Table 6.B.3). A significant lower measure of intelligence (WAIS Information) was reported in sprayers. Reduced performances (P<0.05) were observed in tests of attention/working memory (WAIS Arithmetic, Digit span forward/backward, and Trails A), executive function/mental flexibility (Trails B), psychomotor function (Digit symbol), visuo-spatial (WAIS Block Design) and memory function (Benton Visual Retention Test) (full details in table 10). Analysis included age and education. Little weight can be attached to the results of this study with regard to potential neuropsychological effects in adults as the study focused on neuropsychological testing of children and adolescents (Annex 4, Table 7.B.3).

Study undertaken in Spain

Study of Greenhouse Workers

40. Roldán-Tapia et al 2005, undertook a comprehensive neuropsychological testing of 40 male Green house sprayers from Southeastern Spain (Roldán-Tapia et al 2005). These subjects had used a mixture of pesticides (predominantly OPs/carbamates) for between 6 months to 30 years (mean pesticide use 10.86 years (SD 7.49 years). A control group of 26 male workers (drawn from a variety of professions) who had never worked on farms or had contact with toxic substances were tested. Full details of the selection procedure for exposed and controls was not provided. Neuropsychology tests of attention, memory, perception, praxis (apraxia defined below), expressive language, motor performance and assessment of emotional condition were used (Annex 4, Table 6.B.3). The majority of tests yielded negative results when exposed and controls were compared. Recent exposure was a significant predictor of quality of copy of Rey-Osterreich figure (p=0.019), but there were no significant differences between exposed and control groups with regard to BuChE levels. Cumulative exposure was a significant predictor of recall after delay in the Rey-auditory Verbal Learning test (a test of memory), quality and time of copy of Rey-Osterreich Figure (a test of praxis), Benton Visual Form Discrimination (a test of perception) and Taylor Anxiety Scale. The authors calculated Odds ratios (ORs) for cumulative exposure (years working with pesticides) and recent exposure (BuChE levels) for tests which had yielded statistically significant differences between exposed and control. There was a significantly raised OR for poor performance (below cut off point) for the longest duration working with pesticides (11-30 years) for the Rey-Osterreich Figure copy quality (OR 5.00 (95%CI 1.22- 20.40)) and time (OR 4.12 ((5%CI 1.18-14.39)), a test for visuo-constructional praxis and for the Benton visual form discrimination (OR 6.93 (1.52-31.51)), a test for integrative perception. This study was limited in the small study size and in that testers were not blind to the exposure status of the subjects. In addition, the authors did not report details of subject selection for this study (Annex 4, Table 7.B.3). (Apraxia defined as total or partial loss of the ability to perform coordinated movements or manipulate objects in the absence of motor or sensory impairment.)

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Study undertaken in Poland

Study of Green House Workers

41. Bazylewicz-Walczak et al 1999, undertook neuropsychological testing of 26 women exposed to OP while performing gardening/green house jobs (Bazylewcz- Walczak et al 1999). A control group of 25 women matched with exposed for age, education, place of habitation, smoking, alcohol and drug use, who worked in canteens, kitchens and administrative jobs at garden centres, was studied. The authors did not describe how the exposed or control groups were selected. The psychological tests administered were the Polish adaptation of the WHO Core Test battery and the Finnish Subject Symptom Questionnaire. Psychology tests were undertaken in January-February (preceeding intensive OP use) and in June (following pesticide applications). Air sampling and dermal exposure to OPs (predominant OPs used were dichlorvos, methamidophos, methidathion, and pirimiphos-methyl) was undertaken (Annex 4, Table 6.B.3). It was noted workers were also exposed to carbamates, synthetic pyrethroids and dithiocarbamates. Exposure was seasonal for approximately 7-46 days with cycles of 4-7 days of spraying with an interval of approximately 3 days between spray applications. The daily cumulative exposure (combined inhalation/dermal) on 6 consecutive days after the restriction period was between 0.001-0.009 % of the toxic dose (based on dermal LD50s). The duration of spraying varied between 1-24 years (mean 11.9y SD 6.8y). The OP exposed group (assessed prior to spray season, i.e. measuring cumulative exposure) when compared with controls showed a significant (P<0.04) slowing down of perceptual motor function functions (Simple reaction time) and lower hand movement efficiency (Aiming) (see table 10 for full details). Exposed women also reported a higher degree of anxiety, anger, depression and fatigue-inertia. Apart from errors in the Aiming test, there was no deterioration in cognitive and psychomotor function or in emotional states or subjective symptoms over one season. There was a significant improvement in some neuropsychological tests (e.g. digit symbol, digit span and Santa Ana Dexterity) and in mood scales over the season, which was most likely a seasonal effect (Annex 4, Table 7.B.3).

Study undertaken in Israel

Study of Agricultural Community

42. Browne et al 2006, report neuropsychological test data for 23 exposed individuals (a mixture of residents living near to sprayed fields and agricultural workers) (Browne et al 2006). These participants were selected from a group of 291 residents living 25m-150m near to sprayed fields. Control test data were obtained for 23 controls (living in urban environments) taken from a group of 91 control subjects who were matched for age, sex and education (Annex 4, Table 6.B.3). Exposure to cholinesterase inhibitors was confirmed by static monitoring and reduced serum AChE in exposed residents/agricultural workers. Neuropsychological tests of attention, reaction time and memory were undertaken. A significant reduction in the performance (P<0.05) of the delayed memory task (Weschler visual reproduction) was reported. There were no effects on Continuous performance, Digit span (backward) or the Hebrew version of the Rey auditory learning scale. This

15 THIS IS A DRAFT PAPER FOR DISCUSSION. IT SHOULD NOT BE QUOTED, CITED OR REPRODUCED study was limited by the small group size of investigated participants and possible selection bias (Annex 4, Table 7.B.3).

Study undertaken in Iran

Study of Horticulture Farmers

43. Bayrami et al 2012 applied the Mini mental State Examination (MMSE) to a group of 40 horticulture workers from Iran who were exposed to OPs. (Bayrami et al 2012) A control group of villagers, not exposed to OPs was used (Annex 4, Table 6.B.3). No differences in performance of MMSE and its subscales (orientation, registration, attention/calculation, recall, and language) were reported. Significantly lower plasma AChE was reported in exposed farmers. The study was limited by its small size and lack of assessment of OP exposure and limited assessment of neuropsychological functions (Annex 4, Table 7.B.3).

Study undertaken in India

Study of Manufacture of Quinalphos

44. Srivastava et al 2000, undertook neuropsychological testing of all 59 workers engaged in the manufacture of Quinalphos (Srivastava et al 2000). These subjects would possibly have been exposed to a range of chemical intermediates as well as quinalphos. Control subjects (17) were engaged as tea vendors or roadside hawkers and were not exposed to OPs. The selection procedure and response rate for the controls were not reported (Annex 4, Table 6.B.3). Whole blood AChE was not statistically different between exposed and controls. Four exposed subjects had whole blood AChE lower than the control range and one subject with a low blood AChE was shifted to a job with no OP exposure. Subjects were tested in a limited number of psychological tests (digit span, digit symbol and Bourdon Weirsma vigilance test). Statistically significant poorer performance (P<0.05) was reported in all three tests in the exposed group. It is noted that the study did not control for the effects of education (a higher proportion of controls were graduates (47.1%) compared to 25.5% in exposed) (Annex 4, Table 7.B.3).

Discussion on Chronic Exposure with Chronic Neuropsychological Abnormalities

45. It is extremely difficult to draw conclusions as to whether chronic low-level exposure to OPs can result in chronic neuropsychological effects. The studies identified have used a wide range of neuropsychological tests (data from over 100 different tests were retrieved) examining a full range of potential abnormalities. The data from separate tests have been collated into functional domains (Attention, Executive functions/mental flexibility, Psycho-visuomotor, Visuo-spatial, Memory and Language and Verbal/visual reasoning). Functional domains have been reviewed in the Handbook of Psychological Assessment, 5th edition, Groth-Marnat G,published 2009 John Wiley and Sons Inc. The grouping of tests into functional domains in this discussion paper has been based on the grouping(s) suggested by the authors of the

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studies considered which occasionally leads to some differences between studies regarding the allocation of a test to a particular domain.

46. Additionally a wide range of exposure scenarios have been included (e.g. sheep dippers, orchard sprayers/thinners, cotton field sprayers, agricultural workers, termiticide applicators and tobacco workers) where exposure to a range of OPs and other pesticides would have occurred. There is no evidence to suggest that these studies investigated subjects who were acutely intoxicated by OPs, although there is evidence that current exposures in some of these studies were sufficient to reduce AChE levels (predominantly serum AChE measured) (Farahat et al 2003, Abdel Rasoul et al 2008, Browne et al 2006, Keifer et al 2000). Many of these studies also report more subjective symptoms in OP exposed subjects including difficulty in concentration, feeling depressed/irritable (Abdel Rasoul et al 2008), anxiety/depression (Bazylewicz-Walczak et al 1999), dizziness (Farahat et al 2003) and weakness (Srivastava et al 2000), but overall there is no evidence of overt acute intoxication to OPs in the subjects investigated (with the possible exception of Farahat et al 2003. Thus, the magnitude of OP exposure in these studies is likely to be similar to the studies reviewed by COT in 1999.

47. No formal scoring assessment of study quality has been undertaken in this review. There is no guidance available on the selection, undertaking and assessment of the neuropsychology tests cited in this draft discussion paper. However, overall, the cohort study by Stark et al 2012 was the largest study and had good assessment of exposure, and was considered the best study in this review. These authors also considered a range of potential confounding factors. The findings of this study were largely negative which included the following neuropsychological tests (see table below). (Less weight of evidence has been attached to the other cohort study by Albers 2004b in view of the limited nature of neuropsychological testing undertaken by this group).

Summary of Negative Findings Reported by Starks et al 2012a.

Neuropsychology test Functional domain in Functional domain in this (Neurobehavioural published report review. Evaluation System version 3) Continuous Performance Sustained attention Attention Digit-symbol Visual scanning and Psycho-visuo motor processing Finger Tapping, Motor speed Psycho-visuo motor Groove pegboard Fine motor coordination Psycho-visuo motor Auditory verbal (total recall) Verbal learning and memory Memory Auditory verbal learning Memory Memory (delayed recall and recognition) Sequences A latency Motor speed and scanning Attention Sequences B latency Motor speed and scanning Executive function/mental flexibility

48. The results of the study by Starks et al 2012 have to be weighed against the fourteen cross-sectional studies which used a large number of tests, but when taken together reported both positive and negative results for all of the functional domains reviewed in this discussion paper (see below).

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49. The advantages and disadvantages of cohort design compared to cross- sectional design have been briefly summarised below (taken from Mann, 2003).

Study Advantages Disadvantages Cohort Describes incidence, analyses risk Confounding factors are a factors. Studies measure events in major problem in analysing temporal sequence. Retrospective cohort studies cohorts are available which are cheaper Subject selection and loss to and quicker follow up is a major potential cause of bias Cross-sectional Best way to determine prevalence, Do not differentiate between relatively quick cause and effect Can study multiple outcomes.

50. Subject selection was identified by Starks et al 2012a as a major cause of bias in this cohort study. There was, however, evidence that study groups in the cross-sectional studies were also highly selected. Assessment of these neuropsychological data would require the evaluation by a neuropsychologist. An attempt to draw all the data together under the main functional neuropsychological areas investigated is provided below.

Attention/working memory

Study Exposure Positive results (Effect Negative results size where available) Abdel Rasoul Cotton field WAIS Arithmetic (0.2) None reported 2008 sprayers, Egypt Digit span (forward (1.0) Digit span (backward( (1.0) Trails A (0.3) Bazykiwiz- Green house None reported Digit span (forward and Walczak 1999 workers Poland backward) Farahat 2003 Cotton field Digit span (forward) (0.53) Paced Auditory Serial sprayers, Egypt Digit span (backward) (0.8) Attention. Letter cancel (errors) (0.53) Trails A (0.56) Keifer 2000 Apple orchard Digit span (backward) Digit span (forward) thinners, USA Trails A Kilburn 1999 Patients exposed Trails A (0.85) None reported to chlorpyrifos USA Mackenzie Ross Sheep farmers Digit span (forward) (0.74) WAIS Arithmetic 2010 Digit span backward (0.59) Letter number (0.87) Trails A (0.61) Roldán- Greenhouse None reported Digit span Tapia2005 sprayers, Spain. Stroop A’ cancellation Trails A Rothlein 2006 Farm workers USA Continuous performance Digit span (forward and Selective attention backward) (deficits associated with elevated thiomethyl OP metabolite excretion) Srivastava 2000 Workers engaged Digit span (direction not None in quinalphos stated) (0.21) manufacture India

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Starks 2012a Agricultural Health None reported Continuous Study cohort USA Performance, Sequences A (Trails A equivalent) Steenland 2000 Termiticide None reported Continuous applicators USA Performance, Digit span (forward and backward) Stephens 2004 Orchard sprayers None reported Digit span (forward and UK backward)

Comment: Attention/Working Memory

51. Neuropsychological tests of attention/working memory have been undertaken for a variety of occupational exposure situations where exposure varied and included situations where exposure was predominantly to OPs (e.g. termiticide applicators), to mixtures of pesticides including OPs and in one study where exposure was to quinalphos and its manufacturing intermediates. Measurement of absorbed OP dose was reported in one study (Rothlein et al 2006). The studies all controlled for the effects of age and education on neuropsychological tests, but results were inconsistent between studies. Thus, there were results for digit span tests in ten publications, of which four reported positive results (cohen’s d effect size 0.2-0.8), one study a mixture of positive and negative results and five studies which reported negative results. Six cross-sectional studies reported results of Trails A test. Five documented reduced performance in OP exposed groups (cohen’s d effect size 0.3- 0.85) and one cross-sectional study was negative. However, a negative result for Trails A was also reported by Starks et al 2012 a, in the large Agricultural Health cohort study which had good measures of OP exposure. Trails A is a test frequently used to assess impairment in attention (Gorth-Marnet, 2009). Little weight is placed on the results reported by Abdel-Rasoul (tests undertaken in adolescents) and Kilburn (self- or attorney selected subjects). Overall, though, the balance of evidence does not allow a clear conclusion to be reached. Members may consider that the results of the neurophysiology testing, particularly prolongation of the P300 wave of the Auditory Evoked Potential may support a more definite conclusion regarding attention/working memory. (see Annex 5 and section on neurophysiology testing)

Executive function/Mental flexibility

Study Exposure Positive results (Effect Negative results size where available) Abdel Rasoul Cotton field sprayers, Egypt Trails B (0.1) None 2008 Farahat 2003 Cotton field sprayers, Egypt Trails B (0.61) None reported Kilburn 1999 Patients exposed to Trails B (0.73) None reported chlorpyrifos USA Mackenzie Sheep farmers UK Trails B (0.58) CALCAP choice Ross 2010 Stroop Roldán- Greenhouse sprayers, Spain. None reported Trails B Tapia2005 Starks 2012a Agricultural Health Study Non reported Trails B cohort USA

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Comment: Executive Function/Mental Flexibility

52. There are relatively few studies which have included investigations of executive function/mental flexibility. Executive functions involve a person’s ability to effectively regulate and direct self behaviour. Positive results were reported for Trails B which is a test of attention and mental flexibility in 4/6 studies. Caution should be placed on interpreting the results reported by Abdel Rasoul since the subjects tested were adolescent. A positive result was reported by Kilburn who tested 22 self- or attorney-referred patients. Little weight is attached to this study since there was a high level of selection of subjects who may have had pre-existing neuropsychological impairments. The two remaining cross-sectional studies which reported positive results In Trails B investigated Sheep dippers in England (Mackenzie Ross 2010) and cotton field sprayers in Egypt (Farahat 2003). However, the possibility of selection bias cannot be excluded from these studies. Negative results were reported by Starks et al 2012a in the large Agricultural Health cohort study which also had good measures of OP exposure. Overall, though, there is no convincing evidence for an effect of chronic low-level exposure to OPs and an effect on executive function/mental flexibility, but the available data are limited.

Psycho-visuo motor

Study Exposure Positive results (Effect Negative results size where available) Abdel Rasoul Cotton field sprayers, Digit symbol (0.4) None 2008 Egypt Bazylewicz 1999 Green house workers Aiming errors (0.67) Digit symbol Poland Simple reaction time Santa ana dexterity (fastest) (0.44) (dominant and non dominant) Browne Subjects living near to None reported Tower of Hanoi treated field, Israel Farahat 2003 Cotton field sprayers, Digit symbol (0.77) None reported. Egypt Keifer 2000 Apple orchard thinners, Santa ana dexterity (non- Pursuit aiming USA dominant) Santa ana dexterity (dominant) Simple reaction time Kilburn 1999 Patients exposed to Culture Fair A (0.76) None reported chlorpyrifos USA Choice reaction time (0.72) Digit symbol (1.06) Finger writing errors (0.54) Mackenzie Ross Sheep farmers UK Digit symbol (0.86) CALCAP simple 2010 Groove pegboard (dominant) (0.88) Groove pegboard (non dominant) (1.0) Roldán-Tapia Greenhouse sprayers, None reported Hands coordination 2005 Spain. Rhythm reproduction Rothlein 2006 Farm workers USA Digit symbol Progressive ratio Finger tapping Simple reaction time (dominant/non dominant) (deficits associated with elevated thiomethyl OP

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Study Exposure Positive results (Effect Negative results size where available) metabolite excretion) Srivastava 2000 Workers engaged in Digit symbol (1.02) None reported. quinalphos manufacture Starks 2012a Agricultural Health None reported Digit symbol Study cohort USA Finger tapping Groove pegboard (dominant and non dominant) Steenland 2000 Termiticide applicators None reported Digit symbol USA Groove pegboard (dominant and non dominant) Stephens 2004 Orchard sprayers UK ACTS Syntatic reasoning ACTS Syntatic reasoning accuracy (0.41) latency

Comment: Psycho- Visuo-Motor

53. Neuropsychological tests of psycho- visuo-motor functions have been undertaken for a variety of occupational exposure situations where exposure varied and included situations where exposure was predominantly to OPs (e.g. termiticide applicators), to mixtures of pesticides including OPs and in one study where exposure was to quinalphos and its manufacturing intermediates. Measurement of absorbed OP dose was reported in one study.(Rothlein et al 2006) Positive results have been reported in 5/8 studies where the digit symbol test was applied. Little weight can be placed on the results reported by Abdel-Rasoul (tests undertaken in adolescents) and Kilburn (self- or attorney selected subjects). It is also possible that some subjects in the Farahat study experienced acute OP intoxication. The three remaining positive results taken together suggest an effect of low-level exposure to OPs. (Rothlein et al 2006, Srivastava 2000, Mackenzie Ross 2010) These studies have to be weighed against the negative result for Digit symbol from the large Agricultural Health Study cohort which studied more than double the number of subjects than all three cross-sectional studies added together. The Digit symbol test was described in the 1999 COT report as a test that depends on multiple cognitive functions, places individuals under time pressure, and is known to be sensitive to cognitive impairment following neurological insult such as traumatic brain injury. Gorth-Marnet G (Handbook of Psychological Assessment, Wiley, Fifth edition 2009, Chapter 5 Wechsler Intelligence Scales pp 119-181) lists a variety of functions investigated using this test of which the most important are psychomotor speed, ability to follow directions, clerical speed and accuracy, visual short-term memory and paper-pencil skills. There is no consistent evidence for a psycho-visuo motor effect from any of the other tests which have been used in subjects exposed to OPs (e.g. Santa ana dexterity). Thus although there are some data to support an effect of OP exposure on digit symbol test performance and this would be consistent with the evidence reviewed by COT in 1999, the balance of evidence does not allow a clear conclusion to be reached.

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Visuo-spatial

Study Exposure Positive results (Effect Negative results size where available) Abdel Rasoul 2008 Cotton field sprayers, WAIS Block Design (0.1) None Egypt Farahat 2003 Cotton field sprayers, None reported WAIS Block Design Egypt Keifer 2000 Apple orchard None reported WAIS Block Design thinners, USA Mackenzie Ross Sheep farmers UK Non reported WAIS Block Design 2010 WAIS Spatial span

Comment Visuo-Spatial Tests

54. There are very limited neuropsychological studies of visuo-spatial effects in subjects chronically exposed to low-levels of OPs. Little weight can be placed on the results reported by Abdel-Rasoul etal 2008, (tests undertaken in adolescents) and Kilburn et al 1999 (self- or attorney selected subjects). The available very limited data do not allow a clear conclusion to be reached regarding an association between OP exposure and visuo-spatial effects.

Memory

Study Exposure Positive results Negative results (Effect size where available) Abdel Rasoul Cotton field sprayers, Egypt Benton visual None 2008 retention test (0.2)

Browne Subjects living near to WMS Visual delayed Serial word learning treated field, Israel memory (0.67) WMS Visual immediate Farahat 2003 Cotton field sprayers, Egypt Benton visual Story recall A and B retention test (0.76)

Kilburn 1999 Patients exposed to Picture Completion Serial word learning chlorpyrifos USA (0.62) Story recall (immediate (0.86)/delated (0.77)) Mackenzie Ross Sheep farmers UK WMS Auditory Non reported 2010 (immediate (0.68), delayed (0.53)) WMS auditory, recognition delayed (0.33) WMS Visual (immediate (0.7), delayed (0.48)) Roldán-Tapia Greenhouse sprayers, None reported Benton visual retention 2005 Spain. Rey auditory verbal Logical memory Rey-Osterreich figure Starks 2012a Agricultural Health Study None reported Auditory verbal learning cohort USA

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Study Exposure Positive results Negative results (Effect size where available) Steenalnd 2000 Termiticide applicators USA None reported Pattern memory Stephens 2004 Orchard sprayers UK None reported ACTS Location recognition latency/accuracy ACTS Category search latency/accuracy (performed better than controls.

Comment: Memory Tests

55. Several cross-sectional studies (5/7) found evidence for impaired visual memory. However most auditory memory tests or tests of language were negative. Little weight has been placed on the study by Abdel Rasoul et al 2008, which reported tests using adolescents, and Kilburn which reported tests in a self-selected or attorney referred subject. The clearest evidence for an effect on memory comes from the study of sheep farmers by Mackenzie Ross and colleagues. A correlation between poorer performance of auditory and visual memory tests and duration of sheep dipping was reported. However the large cohort study of subjects in the Agricultural Health Study found no evidence for an effect of OP exposure on auditory learning. (Starks et al 2012a). Overall there is no consistent evidence for an effect of long term low-level exposure to OPs and effects on memory functions, but the data do not allow a clear conclusion to be reached.

Language/verbal, visual reasoning

Study Exposure Positive results (Effect Negative results size where available) Farahat 2003 Cotton field sprayers, Similarities (0.74) None reported Egypt Kilburn 1999 Patients exposed to WAIS Vocabulary (0.4) None reported chlorpyrifos USA Mackenzie Ross Sheep farmers UK Verbal fluency (1.02) None-reported 2010 Graded naming (0.35) Picture arrangement (0.4)

Steenland 2000 Termiticide applicators None reported Vocabulary USA

Comment: Language, Verbal-Visual-reasoning

56. There are only a few studies which report investigations of language, verbal- and visual reasoning in subjects chronically exposed to low-levels of OPs. It is possible that some subjects in the study by Farahat et al 2003, experienced acute OP intoxication. Limited weight is placed on the results from Kilburn where patients testes were self- or attorney referred. The clearest evidence for an effect comes from the study by Mackenzie Ross et al 2010, where the effect on verbal ability showed an exposure duration response (unclear from paper which tests this result refers to). A negative result was reported by Steenland et al 2000, for a test of

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vocabulary in Termiticide applicators. Overall, the data do not permit a definite conclusion being reached.

Overall comment chronic exposure to OPs and chronic neuropsychological effects

57. It is difficult to interpret studies where isolated changes in one or a few neuropsychological tests have been reported. Thus, Stephens et al 2004, reported reduced performance in the Automated Cognitive Test System (SCTS) Syntactic reasoning to negative statements but no effects were found in a wide range of other neuropsychological tests performed (Stephens et al 2004). The approach taken has been to evaluate the results of neuropsychological tests in functional domains. It is proposed for this draft discussion paper that it is necessary to have consistency in the results for tests in each domain in order to reach a conclusion. An alternative approach to weighing the evidence from multiple tests has been suggested by Rohlman et al 2011 (see discussion of this review paper below in paragraphs 60,61). However, the neuropsychological test data for all the domains considered are inconsistent.

58. An alternative is to weigh the evidence according to study quality. For this review, the recent Agricultural Health Study was the largest study with good assessment of OP exposure and was attributed considerable weight in deriving conclusions, although further assessment of the quality of neuropsychological testing undertaken for this study is required. It is noted that the study authors deliberately oversampled high exposed subjects for the study. As a general observation, the 14 cross-sectional studies used report a mixture of positive and negative results for neuropsychological tests but are much smaller studies than the AHS study, and could have also potentially suffered from selection bias. On this basis, no clear conclusions have been reached in this draft discussion paper.

Other Functional Domains

59. One study reported there was evidence for poor performance (below cut off point) for the longest duration working with pesticides (11-30 years) for the Rey- Osterreich Figure copy quality and time, a test for visuo-constructional praxis and for the Benton visual form discrimination (OR 6.93 (1.52-31.51)), a test for integrative perception (Roldán-Tapia et al 2005). There are no other studies available to confirm these results.

Consideration of review by Rohlman et al 2011 (appended at end of Annex 4)

60. Rohlman and colleagues review published a review of neurobehavioural studies of OP exposure citing literature up to 2008 (Rohlman et al 2011). Apart from the more recent studies considered in this draft discussion paper, the literature considered by Rohlman in her review is different to that used in this discussion paper. A number of studies used by Rohlman were excluded from this review as definite exposure to OPs was not stated in the paper (e.g. Kamel et al 2003, Eckerman et al 2007, Cole et al 2007 ). A number of other papers were identified for

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the COT review which were not considered by Rohlman et al (e.g. Keifer et al 2000, Salvi et al 2003, and Kilburn et al1999,) in addition to papers post dating 2008 (e.g Mackenzie Ross et al 2010, Starks et al 2012a).

61. Rohlman considered the results of neuropsychological tests under functional domains, which are generally equivalent to those used in this draft discussion paper, but did not tabulate or list negative results. A review using study quality was not included in the Rohlman et al publication. Rohlman argues that inconsistent test results between publications could have resulted from a number of factors including competence of subjects to undertake the tests, cross cultural effects, differences in the application of tests between studies, and lack of effects due to small sample sizes. Rohlman suggested that variations in method, procedure and population could explain the outcome of OP studies and concluded that a systematic review of the specific factors contributing to different outcomes is problematic because the impact of the variables can only be suspected, not documented. Overall, Rohlman comes to a conclusion that the findings of studies are consistent and compelling

CONCLUSIONS ON NEUROPSYCHOLOGY

Acute Exposure with Chronic Neuropsychological Effects

62. The most consistent information for the assessment of acute OP exposure (leading to overt cholinergic poisoning) resulting in chronic neuropsychological effects comes from the cohort study by Delgado et al 2004 and the cross-sectional study of banana workers (Wesseling et al 2002). The results of both of these studies support the conclusion reached by the COT working group in 1999 that acute intoxication can lead to persistent deficits in psychomotor performance (particularly with respect to reduced performance in digit symbol test). The study of acute OP/carbamate poisoning in Spain reported evidence for persistent effects 1 year after poisoning on a range of tests measuring perception (Picture completion), memory (Logical memory and Rey-Osterrieth Figure test) and also on visuomotor skills (quality of copy of Rey-Osterrieth Figure and time of copy of Benton Visual Form test) (Roldan-Tapia et al 2006). These particular tests have not been used in other studies and additionally the functions assessed have not been investigated in detail in other studies. It is difficult to draw any definite conclusions based on this study. The study of Mittal et al 2011 was undertaken at only a comparatively short 3- month period after OP poisoning. It is difficult to draw any conclusions as to whether OP exposure induced neuropsychological deficit in Gulf War veterans exposed to sarin/cyclosarin at the Khamisiyah incident, particularly as neuropsychological deficits have been found in Gulf war veterans irrespective of exposure to sarin/cyclosarin. There is some limited evidence for a deficit in psychomotor function and in the digit span (backward) test (which was interpreted as an effect on short term memory) in individuals exposed to sarin from the Tokyo incident, but results between studies which covered different periods of follow-up are inconsistent (Nishiwaki et al 2001, Ohtani et al 2004, Miyaki et al 2005).

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Chronic Low-Level Exposure with Chronic Neuropsychological Effects

63. The approach used in this draft discussion document involved grouping the results of neuropsychological tests conducted with subjects with low-level chronic exposure to OPs into functional domains. It was considered necessary to have consistency of results within a domain in order to reach a definite conclusion. The available data were inconsistent for tests of attention/working memory, executive functioning/mental flexibility, Psycho-visuomotor, visuo-spatial, memory and language/verbal, visual reasoning tests. Both positive and negative findings were reported. Assessment using study quality suggested that the best study was a recent publication from the US Agricultural Health Study which provided largely negative results. The remaining 14 cross-sectional studies yielded inconsistent results for each functional domain assessed. On this basis, it is suggested that no clear conclusion regarding evidence for an association between long-term low-level OP exposure and chronic neuropsychological deficit can be reached. Members may wish to consider the evidence for prolongation of P300 latency in the Auditory Event Potential test may provide supporting evidence for an effect on attention/working memory (see neurophysiology section (Annex 5) of this draft discussion paper).

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Table 6 NEUROPSYCHOLOGY STUDY DESIGN DETAILS

First Date Country Study Reference Health assessment Health Measure of Risk factors/ Statistical Author population population method outcome Exposure bias/ analysis variables confounders A. Acute Exposure with Chronic Effects 6.A.1. Cohort studies Delgado 2004 Nicaragua All persons 74 from fishing, Neuropsychological testing Rey auditory Not quantified. Age, education, Two-way hospitalised at two cattle cooperatives at Examinations I, II and II. verbal learning Assessment based lifestyle, general ANOVA (time/ centres (Leon, around Leon. 35 Neuropsychiatric symptoms test. Digit symbol on severity of health, alcohol exposure). Chinandega) from only participated in assessed. test. Modified Q- symptoms consumption, Adjustment for 1 July 1992 -15 examination I. 16 previous age, education December 1996 Thus there were neuropsychiatric exposure to and alcohol for acute OP data for 39 for symptom neurotoxic consumption. intoxication were examinations I and assessment. substances or Undertaken for 3 eligible. 77 II and data for 28 pesticides (10 in levels of enrolled and data at examination III. OP- poisoned exposure for 62 obtained at group reported Low (all examinations I and previous moderate II (time of poisoning by occupational discharge and pesticides. n=31). Moderate ≈7weeks after Previous (all severe discharge) and 53 exposure to OPs occupation, at examination III quantified. No n=15) and (≈2 years after other potential Severe (all non discharge). Of the confounder was occupational, 53 (median age reported by n=7) 25y(14-64y), participants, Linear median education including regression 4y (0-11y)),there exposure to analysis of were 31 with solvents, means (7weeks moderate arsenic, lead, v discharge, 2y v occupational mercury, regular discharge, 2y v 7 exposure, 15 with drug intake, loss weeks), adjusted severe of consciousness for age, occupational for over 30 mins, education, exposure and 7 exposure to alcohol with non vibrating consumption. occupational (oral) machinery, exposure to OPs history of chronic (all severe) illness (diabetes, thyroid, arthritis, kidney or other neurological

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6.A.3. Cross-sectional studies Chao 2010 Iraq 40 Gulf War 40 veterans Neuropsychological Fourteen tests CIA modelled No significant Demographic/ veterans taken selected from investigation (expanded investigating exposure in 1996 differences descriptive from group of 230 remaining 190 number of tests compared intelligence and in 2000 between characteristics who participated veterans of similar to Proctor 2006),Clinical (WAIS-III, WRAT- exposed/ (Kruskal-Wallis in a previous study age, sex, diagnosis of current major III reading) unexposed in for continuous of Gulf War Iillness handedness, depression (MDD) and attention, gender, age, variables, chi- between 2002- educational level current PTSD determined (Continuous education, square for 2007. These 40 and similar on Structured Clinical performance, Trail handedness, categorical veterans were Clinician Interview for DSM-IV and making A, WAIS- PTSD, MDD, or variables). exposed to Administered Clinician Administered III digit span, chronic Neuropsycholog sarin/cyclosarin as PTSD Scale PTSD Scale. MRI executive function multisymptom y data- Kruskal- a result of the scores including estimates of Gray Trail B, Short illness. No Wallis, munitions matter (GM), White matter category test, difference in Spearman’s explosion at (WM) and hippocampal controlled oral factor analysis- correlation Khamisiyah volume word association derived between between 10-13 test psychomotor syndromes individual unit- March 1991 function, Groove (impaired level dose pegboard, WAIS- cognition, estimates and III Digit symbol confusion-ataxia, test matching arthro-myo- performance, visuospatial neuropathy, and linear trend abilities, WAIS-III phobia-apraxia, models. Block design fever- Spearman’s short term adenopathy, and correlation used memory California weakness- to assess verbal learning incontinence relationship test II , WMS-III between Logical memory, neuropsychology Brief visual and total GM, memory test-R WM and and genuine effort hippocampal (malingering) Test volumes of memory Gray matter, white matter and cerebral spinal fluid and intracranial volumes

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First Date Country Study Reference Health assessment Health Measure of Risk factors/ Statistical Author population population method outcome Exposure bias/ analysis variables confounders determined. Mittal T 2011 India 28 patients (14 20 adults matched Neuropsychological testing Trailmaking A and In 19 patients, the Not reported Data were men, 14 women) for age, sex from undertaken just prior to B. OP compound was expressed as with acute OP previous study. discharge and after 3 PGI memory know, chlorpyrifos mean (±SD). poisoning (suicidal They were either months. scale (5), dichlorvos (7), Statistical 17, accidental 11) hospital MRI and single photon (modification of phorate (7) analysis for mean age 26.4 employees or emission computed Weschler memory Nature of categorical years (14-48y)(No healthy attendants tomography (SPECT) were scale) compound couldnt variables using difference in age of the patients. undertaken in patients Verbal fluency be assessed for 9 chi-square test between sexes). during the acute phase of test (test of patients. and Students t- Mental status OP toxicity. mental flexibility) test for assessed by Bender-Visual parametric questionnaire Motor Gestalt test variable. P<0.05 GHQ-12)) (BVMG) (a test of considered Admission visual-motor significant. between July 2009 coordination. and December 2010. (patients PGI had subtests, with any abnormal visual retention, neurocognitive visual recognition, dysfunction to any verbal retention cause prior to OP poisoning were excluded) Miyaki 2005 Japan 55 sarin exposed 13 referent subway Neurobehavioural tests for Finger tapping Exposure not Multiple After subjects and workers gave psychomotor function, (dominant, non- assessed. High regression transformation, referent subway informed consent. memory and stabilometry dominant hands). exposure assigned including age, comparison of workers attended a Data combined Simple and choice to subjects who BMI, educational data by meeting on 7 year with previous study reaction times were hospitalised level, smoking, Student’s t-test, follow-up. 23 giving total of 65 (psychomotor following attack and drinking, General one way ANOVA exposed included referents function). low exposure Health for high, low and in study. Subjects Digit span treated as Questionnaire referent groups. stratified into (forward and outpatients score (GHQ) Non-parametric high/low exposure backward) and mental health Wilcoxon rank based on severity Benton visual assessment, sum test for of symptoms. ( memory function Impact of Event memory function high n=5, low (5/10 latter Scale (IES, n=18) geometric current PTSD Data also patterns for symptoms), combined with memory). exposure level, previous study of Body sway (strain post exposure rescue workers gauge type force period (3 or 7 y) and police officers. platform) Total exposed 80 (high 30, low

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First Date Country Study Reference Health assessment Health Measure of Risk factors/ Statistical Author population population method outcome Exposure bias/ analysis variables confounders exposure 50) Nishiwaki 2001 Japan Study of 27 male Referents, fire staff Stabilometry and vibration Psychomotor Exposure not Confounding for Transformation rescue team staff and police officers. perception threshold function: assessed. High Stabilometry to normal (Tokyo Fire Matching measured(2 subjects with Finger tapping, exposure assigned included age, distribution. Department) and undertaken in each low back pain and previous simple and choice to subjects who height, weight, Mean values 30 police officers department fracture of auditory ossicles reaction times were hospitalised alcohol, compared using exposed during (roughly for age). excluded from Memoryfunction: following attack and smoking, IES, Student’s t-test. Tokyo subway 29 male rescue stabilometry). Digit span low exposure GHQ and also Welch’s method incident. I subject staff and 23 police (forward and treated as for for dose- excluded for officers (52) Neurobehavioural tests backward) outpatients neurobehavioura response amnesia. Self undertaken at between 2y and Benton visual l tests: assessment. report of 10months and 3y 9months retention test educational Wilcoxon rank hospitalisation after the sarin incident. level. used for memory used to group 25 data (discrete) to high exposure Impact of Event Scale (for Re-analysis Multiple (hospitalised) and PTSD symptoms) and undertaken regression 29 low exposure General health excluding 15 analysis. Logistic (outpatient Questionnaire for Police staff regression for treatment) evaluating general mental members who discrete health routinely were variables exposed to solvents and reagents. In addition where appropriate comparisons were made between hypoxia positive and hypoxia negative subjects Ohtani 2004 Japan 565 victims of No referent group Wechsler Memory Scale- Visual memory No meaure of None reported None reported. Tokyo subway Study investigated Revised (WMS-R) exposure. Pearson attack (treated at long-term somatic administered. (Authors report that correlation of one emergency and mental PTSD diagnosed using self immediately after Impact of Scale- centre) were sent symptoms 5 years rating questionnaire, Impact attack acute Revised (PTSD a letter inviting after sarin attack of Event Scale-Revised, symptoms included current them to participate. and Clinician Administered miosis, headache, symptoms) with 170 responders of PTSD scale. Concurrent dyspnea, nausea, WMS-R whom 64 gave mental disorder diagnosed ocular pain, blurred Correlation of consent to using Mini International vision, vomiting, psychiatric involvement. Data Neuropsychatirc Interview coughing, muscle indeceswith for 34 subjects (20 weakness and WMS-R male, 14 female, agitation) (Pearson prduct) 21-69y, mean age reported.

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First Date Country Study Reference Health assessment Health Measure of Risk factors/ Statistical Author population population method outcome Exposure bias/ analysis variables confounders male 50.2±11.9 y, female 39.6 ±10.4). Subjects divide into PTSD (n=11)and non- PTSD groups (n=23) Proctor 2006 Iraq A stratified random Low or no Subjects evaluated Neuropsychologic CIA modelled Co variates age, Values > 3SD subset of the exposure group between autumn 1994 to al tasks: exposure in 1996 gender, officer were truncated Devens cohort of (n=70). Rate of summer 1996 (3.5-5 y after Attention and in 2000 status during at 3SD (2%). 1991 US Gulf War current major deployment). Medical, Continous GW, WAIS-R ANOVA and Veterans (3000 depressive occupational history performance test test score, head Students’ t-test individuals). (In disorder was assessed by questionnaire, (sustained injury, PTSD for continuous early March 1991 higher in the low to semi structured attention), Trail symptomatology variables and US troops no exposure group environmental interview. making A (spatial chi-squared or detonated a compared to Neuropsychological test attention, Fisher’s exact for munitions store at high/moderate battery administered. visuospatial categorical Khamisiyah which sarin exposure Scales assessing tracking), variables was later found to groups psychological symptoms WAIS-R Digit (P<0.05 contain sarin and (Brief Symptom Interview, span foraward significance level cyclosarin. 145 BSI), Mississippi Scale for (spatial attention). used). Dose- participants, of Post Traumatice Stress Executive function response using which data from Disorder (PTSD), Trail making B linear trend 140 participants psychological diagnostic (spatial attention), models using deployed was interviews, Clinician Wisconsin card unit level of provided. Three Administered Scale for sorting (inferential exposure. exposure groups PTSD (CAPS) and reasoning, Magnitude of defined high strucutred Clinical Interview visuospatial effect sizes (n=23), moderate for DSM IIIR Axis 1 tracking). WAIS (Cohen’s) using (n=47). Higher Disorders. General Digit span adjusted combat experience Intelligence assessed by backward difference in was reported in WAIS-R Information subset (tracking and scores (from moderate and high attention) analysis of exposure Psychomotor covariance) function divided by SD. Finger tapping The effect size (motor speed), for age Purude Pegboard determined using (motor dexterity) separate linear Visuospatial regression abilities models WAIS-R block regressing designs (spatial neuropsycho- abilities) logical test score

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First Date Country Study Reference Health assessment Health Measure of Risk factors/ Statistical Author population population method outcome Exposure bias/ analysis variables confounders Short term on age memory Californian verbal learning (verbal memory), WMS-R verbal period (retention of verbal information), WMS visual reproductions (learning retention of visual designs) Roldan- 2006 Spain 24 poisoned Two reference For poisoned subjects, data A wide range of Pesticides To control for F, analysis of Tapia farmers who populations were on new possible poisoning neuropsychologic responsible for possible variance to received treatment used. incidents, health complaints al tests were used acute posioning confounding compare at the Internal and cholinesterase levels Attention episodes were including age, descriptive medicine Non-poisoned but recorded at both 3 month Digit span metamidophos, education and characteristics of department at the chronically and 1 year evalautions.. (backwards) fenamiphos (Ops), BuChE value. subjects. Hospital de exposed Stroop Test methomyl Multivariate Poniente (Almeria, population. There In case of non-poisoned ‘A’ cancellation (carbamates), and analysis of Spain) and who were 20 subjects high/low chronic exposures, Trail making A in some cases of neuropsychologi had suffered in high exposure, physical and Trail making B mixture of these cal and accidental and 20 subjects in neuropsychological Digit symbol with pyrethroids emotional tests poisoning with OP low exposure examination were recorded Concept (permethrin) or for control, and/or carbamates at time of maximal formation/reasoni organochlorines acutely posioned within the past 3 A non-exposed exposure to pesticides ng.Similarities (endosulfan). and chronically months (Sept-Nov, control group (26 (from 2-7 days after the last WAIS exposed. 1997) were subjects) was fumigation and in the period Memory Chronic exposure Ananlysis was recruited by recruited from of lowest exposure (6 Digit span subjects were performed by phone. The same demographic months later) (forward) subdivided into grouping tests in farmers worked in area, although Rey-Auditory those with less than cognitive greenhouses, were they didn’t work on Neuropsychological Verbal learning 10 years exposure domains. The all male, Spanish farms and had no evaluation and blood test. (low) and those with authors used aged 16-66 years contact with samples of control subjexts (sum trial 1-5, and longer than 10 Pillais’s criterion at the time of OPs/carbamates. were undertaken at their after delay) years (high for significance testing with a workplaces during the Logical memory a exposure) testing in score of at least 28 Individuals with period corresponding to (immediate recall) Products used MANOVA. Two on MMSE. previous history of high fumigation of exposed Logical memory during last year and ananlyses were Participants had brain damage, subjects (delayed recall in last fumigation undertaken First no history of any psychiatric Rey-Osterreich were mthomyl, acute posioning disease or disorders or in Figure Complex mancozeb, oxamyl 3 months after condition that receipt of medical (short term recall (carbamates), intoxication with could induce treatment that and long-term dimethoate, non-poisoned nervous system could affect recall) methamidophos, chronic exposure

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First Date Country Study Reference Health assessment Health Measure of Risk factors/ Statistical Author population population method outcome Exposure bias/ analysis variables confounders damage and could cognitive or motor Benton Visual fosetyl and and controls. A affect testing. abilities were Retention Test malathion (OPs) trend ananlysis Subjects who had excluded from Perception and sometimes a was used to intentional participation Picture mixture with determine poisoning were Completion WAIS cypermethrin, relationships excluded. (Most Benton Visual endosulfan and between degree frequent symptoms Form abamectin. of exposure and included nausea, Discrimination test neuropsychologi abdominal pain, Poppelreuter Test cal performance excessive Stereognosis (Assuming aucte sweating, general Language posioning>chhro weakness, Boston Naming nic high>chronic salivation, Test low>control. headache, Visuomotor Linear and vomiting, blurred Rey-Osterreich quadratic tresnd vision, muscle Figure Complex were tested for cramps and (time and copy each variable. breathing quality) Post hoc difficulties. There Block Design comparisons was no loss of WAIS between group consciousness. Coordination averages using movements least significance Full details of the Rythm difference selection reproduction statistic. procedure were Altern Movements not given. In the second Mood sates analysis scores Neuropsychology examined using of acutely was undertaken 3 Beck Depresion posioned months after Inventory subjects 1 year poisoning and in a Taylor Anxiety after intoxication smaller group at 1 Scale. and the sample year after of chronically poisoning. exposed and controls. The authors noted possible test learning (retest) effects but considered this would allow a test for long-term squelae of acute poisoning. Spencer 2001 USA A pool of 3219 GW Number of Level 1 neurobehavioural Neurobehavioural Not reported Not reported Not reported

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First Date Country Study Reference Health assessment Health Measure of Risk factors/ Statistical Author population population method outcome Exposure bias/ analysis variables confounders veterans veterans was veterans outside tests administered on 624 test results, deployed identified (923 the Khamisiyah GW veterans (but exposure psychological to Khamisiyah, 927 region (610) or not status not given). tests Khamisiya non-Khamisiyah, deployed (516) Details of level 1 tests not h 1369 non- provided deployed). 2918 contacted by phone (530 not eligible, 555 refused to take part). 1833 interviews undertaken. Data for 1779 reported. 653 were deployed in Khamisiyah Wesseling 2002 Costa Rica Costa Rican Control group non- RBC and plasma WHO Indices of exposure Data on a range Multiple Linear banana workers poisoned from cholinesterase measured. Neurobehavioral generated (number of confounders regression using (for at least one payrolls of Neurobehavioural testing Core Test Battery of days/year, reported, age, education, year) with no participating undertaken between May- (NCTB), but number of years including alcohol cumulative life- history of any banana September 1994 instead of Profile and fraction of day consumption, time exposure to disease or plantations. of Moods, the exposed to smoking status, cholinesterase condition which Subjects with authors used cholinesterase work with inhibitors, might affect history of pesticide Swedish inhibitors) solvents alcohol, solvent performance (eg poisoning Questionnaire – (>3months daily exposure, loss of severe head excluded. Of 144 16 (validated in and continuous), consciousness, trauma, severe eligible, 10 refused Nicaragua) and loss of examiner, time of alcohol/drug and 4 were Brief Symptom consciousness day of testing abuse, hearing arbitrarily Inventory (BSI) for > 1h and poor and plasma impairment, proposed by near visual AChE. Groups inability to read plantation Memory Benton acuity. Other were also numbers, history of managers. Final Visual Retention factors included stratified into epilepsy or serious unexposed group test, Rey verbal in assessment those with or illness such as was 130 field learning. were other without recent (3 cancer). Subjects workers or packers neurologic/ months) identified from with no exposure. Attention Digit psychiatric exposure to reports to National Some control field vigilance, Digit disorders, cholinesterase Insurance Institute workers had span. malaria, chronic inhibitors. Seven regarding exposure to metabolic/ subjects with cholinergic cholinesterase Psychomotor infectious poor near visual poisoning inhibiting Santana Dexterity disorders, acuity were between May- pesticides. A (coordination), current use of eliminated from June, August subgroup of this Pursuit aiming II medication, Benton, Pursuit 1994. Of 162 group of field (steadiness), examiner, hours aiming, digit identified, 94 workers reported Finger tapping sleep night prior vigilance, digit-

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First Date Country Study Reference Health assessment Health Measure of Risk factors/ Statistical Author population population method outcome Exposure bias/ analysis variables confounders located, 82 mild symptoms (speed), Simple to assessment, symbol and eligible. and some results Reaction Time sense of well Trails A. Information for 81 were reported (SRT). being, liquor and Unstandardised included separately for this caffeine intake and standardised group. Visuomotor Digit- on day of testing. coefficients were Testing symbol (coding), Study estimated for all undertaken at least Trails A undertaken poisoned one year after (planning), Block during spray workers and for poisoning. design (problem season, and subgroups with solving) 54.3% of OP or poisoned and carbamatepoison Language 27.7% of non ing.. In addition Weschler poisoned had analysis was Vocabulary contact with undertaken with cholinesterase subset of inhibitors 3 controls who had months before never testing experienced any symptom attributable to pesticide

6.A.4. Case series studies Dahlgren 2004 USA 7 subjects acutely None Detailed clinical Static Body Wipe samples None None reported exposed to examination at ER. Family Balance, Simple taken on June 22 diazinon (through advised not to return to and choice visual 1999, June 29, mistaken house (eventually returned reaction times, July10, and month application of 11 months post diazinon peg placement 8 (29 February excessive amount application). (Lafayette slotted 2000) to their home) Neuropsychological testing pegboard), color Air samples taken undertaken in August 2002, discrimination on July 9 and on Patient 1 mother 3 years post exposure. (Lanthony July 10, 1999 by a (37y) Subject 7 (exposed in utero desaturated 15 separate laboratory. Patient 2 Father and aged 2y at assessment hue test), Trail Bulk samples were (39y) ) did not undergo making A and B, taken on July 10; Patient 3 daughter neuropsychology testsing visual fields, and carpet. Bulk (11y) until 36 months of age grip strength samples taken at Patient 4 daughter 6.5 months (1 (8y) December 1999) Patient 5 son (6y) including sofa Patient 6 son (1y) material near Patient 7 mother kitchen, carpet and was pregnant 5 pad from living months gestation room, toy from

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First Date Country Study Reference Health assessment Health Measure of Risk factors/ Statistical Author population population method outcome Exposure bias/ analysis variables confounders children’s room near garage and children’s clothing from top of dresser in child’s bedroom near garage 6.A.5. Case reports Loh 2010 USA A senior explosive None Clinical evaluation Intelligence 3-5 ml of sarin was None Tests compared (exposed disposal (EOD) (physical, biochemistry, WAIS-III Full identified in the IED. to laboratory in Iraq) sergeant was haematology, toxicology, scale IQ, Verbal normal exposed to sarin in MRI of brain/spine, IQ, Performance May 2004. He (and electromyography/nerve IQ, Processing assistant) loaded conduction, PET) and speed index. IED (improvised neuropsychological testing Wide Range explosive device) 8 months post exposure Achievement into vehicle. test (WRAT)-III Several minutes reading. Word later patient and memory assistant had Psychomotor; acute cholinergic Finger tapping, symptoms grooved pegboard. Language; Boston naming, Thurstone verbal fluency, Visuoconceptual Rey complex figure copy, Hooper visual organisation. Attention/ executive function Auditory consonant trigrams 9", 18", 36". WAIS-III subtest Digit span Seashore rhythm Trail making A,B Wisconsin card sort categories,

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First Date Country Study Reference Health assessment Health Measure of Risk factors/ Statistical Author population population method outcome Exposure bias/ analysis variables confounders FTMS(failure to maintain sets), CVLT trial 1 (Californian Verbal Learning test). Memory Wechsler memory scale-III (logical memory, visual reproduction score, Rey complex figure recall). CVLT Trail 2 B. Chronic Low-Level Exposure 6.B.1. Cohort studies Albers 2004b USA All Dow employees Dow employees Interview including queries Five level ‘Likert’ Cumulative Chlorpyrifos t-test for engaged in engaged in on cognition (e.g. memory scale for memory, exposure estimated exposed and difference of manufacture of manufacture of complaints at baseline and reading skills, from air monitoring referents were means. Fisher chlorpyrifos (aged Saran (plastic film) also recall for comparison ability to data from initial matched for age, exact test or chi- 18-65y) employed with no known with 10 years previously). concentrate, and employment up to height, weight, squared for on 1 Sept 1999. Of exposure to Questionnaire devised by problem solving. baseline,and from BMI, reading associations. No 66 potentially neurotoxicants. Of authors using 5-level Likert The Mini-Mental baseline to 1 year scale, smoking adjustment for eligible, 53 took 74 workers asked, scale questions. The State Examination follow-up. pack year and multiple part (80%). All 60 (81%) second assessment (MMSE) was Exposure also anxiety. There comparisons. these subjects participated, with updated information after 1 applied which measured between was a slightly P<0.05 took part in 1 year 58 also year of follow-up. included baseline and 1-year higher education considered follow up participating at 1 The Mini-Mental State information on follow-up using level for significant year follow-up Examination (MMSE) was orientation(positiv urinary excretions chlorpyrifos applied e finding >2 of 3,5,6-trichloro-2- exposed errors/10 items), pyridinol (TCP) (mean14.3 attention/calculati (corrected for (years, SD 2.1) on (positive urinary creatine. compared to finding >2 errors Average of 4 nightly 13.6 years, SD on 5 items), recall collections), plasma 1.5, in referents (positive finding butyrylcholinesteras (P=0.06) >2 errors on 6 e (BuChE) and red items), language blood cell (positive finding cholinesterase >2 errors on 4 (AChE) items) Finkelstein 2010 Israel. Israeli cohorts Not stated Neuropsychological tests, Neuropsychologic Not stated Not stated Not stated

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First Date Country Study Reference Health assessment Health Measure of Risk factors/ Statistical Author population population method outcome Exposure bias/ analysis variables confounders examined in the details not specified al test data, 1980s details not specified Starks 2012a USA Enrolment No reference NB tests were administered Neurobehavioural Information on Age, height, Linear questionnaire in population by trained technicians test pesticide exposure education, state, regression Agricultural Health unaware of participants history was smoking status, Unadjusted study in 1993-1997 exposure status. Eight Tests obtained from the alcohol association of subjects at time computerised tests from the administered were questionnaire used consumption, between each of pesticide English language version of Continuous during all three AHS head injury, covariate and licensing and the Neurobehavioural performance, Digit phases as well as current each outcome. recertification 40% Evaluation System, version symbol, finger the NB antidepressant Covariates with a of participants also 3. tapping (dominant questionnaire. use, caffeine p<0.20 were completed take hand), Auditory Exposure data were consumption and selected for home . verbal obtained in slightly exposure to multiple linear questionnaire (with learning(AVLT) different ways at other potentially regression. All questions on (total recall, each phase. In neurotoxic final multivariate pesticide delayed recall, phase 1 50 specific substances models included exposure). (Phase recognition) pesticides were (such as age and ART. 1). A five and ten sequences A included (data on solvents, For Continuous year follow up latency ever use, frequency soldering/weldin performance telephone sequences B and years of use g fumes). Tests Positive Affect interview (phases latency and obtained). For the of reading ability, (PA) score and 2 and 3). Male manual Grooved take home affect, visual caffeine. residents in AHS pegboard test questionnaire data acuity. NES3 Digit Symbol PA cohort residing in on ever use of includes an Adult score, education, Iowa and North specific chemicals Reading Test state, visual Carolina (NC) (150 obtained. For (ART) to acuity score. miles from test Phases 2 and 3, estimate Finger tapping facility) were participants intellectual PA score and invited to provided open function and the state. participate. ended responses Positive and Groove Exclusion included regarding pesticide Negative Affect pegboard medical conditions use since last Schedule. caffeine (amyotrophic interview.. The NB consumption, lateral sclerosis, questionnaire state visual multiple sclerosis, gathered data on acuity. Parkinson’s pesticide use in AVLT (delayed disease, past 12 months recall) negative retinal/macular (ever mix or apply affect score (NA) degeneration, and duration of use PA score , stroke, (days)). Data for 16 education, state. hypothyroidism, OP pesticides used AVLT recognition diabetes), drinking by at least 50 PA score, ≥42 alcoholic participants education state. beverages/week, reported. Ever-use Sequences A

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First Date Country Study Reference Health assessment Health Measure of Risk factors/ Statistical Author population population method outcome Exposure bias/ analysis variables confounders reported history of based on any and B, PA score, pesticide poisoning positive report, and state. at most recent lifetime days of use, Confounding be interview. 1807 based on lifetime related pesticide were eligible. The days of use exposures authors reported at each Spearman oversampled interview. With correlations were applicators with regard to the ‘take calculated for high lifetime use of home’ pesticides OPs (based on questionnaire, data associated with lifetime days of from phase 1 was NB outcomes use of 10 OPs used to generate with a p-value assessed in phase lifetime days of use. <0.10. 1) Among An overall summary Moderately participants, a of all OP pesticide correlated stratified sample use was also pesticide pairs was selected derived. An (r≥0.30) were based on equal assessment of 4 added sampling from the carbamates was simultaneously upper and lower derived and an to final base portion of the OP overall assessment models and the lifetime day’s of 50 pesticides pesticide distribution. In assessed in phase variable Iowa a cutpoint of 1 included. OPs parameter 75% was used. In included were nine estimates were NC a cutpoint of from phase 1; compared to 66 % was used. chlorpyrifos, models with only 701 male coumaphos, one pesticide. participants were diazinon, Sensitivity included in the dichlorvos, fonfos, analysis study and a further malathion, Analyses questionnaire (NB parathion, phorate conducted questionnaire) and terbufos; six excluding administered at the further OPs were /including appointment. included in the ‘take individuals with home’, medical questionnaire; conditions or use acephate, of medication, dimethoate, (Use of disufoton, ethoprop, benzodiazepines phorate and 18, opiates 12, terbufos. A further anticonvulsants chemical was 3, barbiturates 2, introduced in antipsychotics 3, 1995;tebupirimfos. donepezil 1.

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First Date Country Study Reference Health assessment Health Measure of Risk factors/ Statistical Author population population method outcome Exposure bias/ analysis variables confounders Medical conditions identified at NB test appointment; history of alcholoism, brain tumour 5, alchol use on day of test 3, struck by lightening 1, renal failure 1, macular degeneration 1, severe dementia 1.

Analyses also excluding individuals with a history of physician diagnosed pesticide poisoning (8). 6.B.2. Case-control study Jamal 2002a U.K. 79 sheep farmers None Clinical, neurological and Cambridge Questionnaire on Not reported for Not reported for from a study of Neuropsychological neuropsychologic recent exposure neurpsychologic neuropsycho- 685 subjects assessment. Mood and al test battery administered. al assessment logical underwent affect assessed by General (including assessment neuropsychologica Health Questionnaire and assessment of l assessment. Hospital memory, Data analysed for Anxiety/Depression scale attention, higher 72 sheep farmers. brain function). 23 of these had Tests for attention probable/definite (motor screening, neuriopathy, 34 reaction time, and possible matching sample neuropathy and 15 to visual search). no neuropathy. Tests for memory included pattern recognition, spatial recognition,

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First Date Country Study Reference Health assessment Health Measure of Risk factors/ Statistical Author population population method outcome Exposure bias/ analysis variables confounders paired associate learning and spatial span. Rey audiroty verbal learning test. 6.B.3. Cross-sectional studies Abdel 2008 Egypt Cotton field Control who had Children with assistance of Tests for No direct measure Age, education t-test, chi- Rasoul sprayers (aged 9- never worked in parents completed Information of exposure. Spray squared, 15y (n=30) and cotton fields medical/work history, blood (intelligence), application history Pearson’s 16-19y (n=20))’ selected for each taken for serum AChE. Similarities assessed. Serum correlation. Data for older sprayer from Appropriate versions of (concentration/ AChE measured Holms’ group summarised friends/relatives WAIS and abstract thinking), correction of p in this table living in same neurobehavioural tests Arithmetic values. community and administered. Investigators (attention Multiple linear Male children from attending same blind to exposure status. /concentration), regression 5/50 villages schools. (Control Eysenck Personality Block Design adjusting for (randomly chosen) groups of Questionnaire administered (spatial relations), effects of age, were approached. equivalent sizes (appropriate age version) Digit Span education 56 were identified. compared to (Forward, reverse, (adjusted for a 50 participated applicators) total-short term 17 year old with (response rate auditory memory), 9 years 89.3%) Digit symbol education and (perceptual BMI 25.10). memory speed), Second multiple Benton Visual linear regression Retention test model to BVRT, short term correlate visual memory performance with Trail making A & days worked in B (attention visual season and conception) years worked and AChE controlling for age Bayrami M 2012 Iran 40 horticultural 40 workers not Mini mental State Cognitive function Plasma AChE Not stated. Two-sample t workers (age engaged in any Examination (MMSE) assessed through activity measured. test was used for range 15-80 years) agricultural work questionnaire administered. assessment of statistical who lived around a with no history of orientation, comparisons. village, Hafte in the job-related OP All subjects subject to registration, Pearson Southwest of Arak, exposure. comprehensive clinical attention, correlation Iran. examination to identify any calculation, recall coefficient signs or symptoms of long- and language. wasused to Subjects with lasting illnesses such as study the

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First Date Country Study Reference Health assessment Health Measure of Risk factors/ Statistical Author population population method outcome Exposure bias/ analysis variables confounders chronic disease, arterial hypertension, heart Blood samples association alcohol failure, cancer, thyroid collected between consumption, disturbance, asthma, throughout the variables. antioxidant diabetes and anaemia. course of the consumption, spray season and/or under drug between 7-8am usage or contact to before arriving at poisonous the workplace on materials, radiation Saturday as the therapy or beginning of substance abuse weekly work. were excluded from the study. Bazylewicz- 1999 Poland 26 women 25 women Polish adaptation of WHO Simple Reaction Exposure assessed No information Two-way Walczak (35.4±7.9y) (36.0±8.6y) recommended time, Digit during spray provided on ANOVA. performing employed in Neurobehavioural Core Symbol, Digit season (March- consideration of Analysis for standard canteens, kitchens Test battery (NCTB). Span, Benton May). Air sampling risk factors. seasonal gardening and administrative Assessment was Visual undertaken at 5 Exposed- changes in jobs/green house jobs at the three undertaken in Jan/Feb Recognition, sites in green house reference groups performance in workers. Duration large gardening before spraying and in June Santa Ana during 4 randomly matched for age, exposed and of OP exposure 1- enterprises in this after the end of spraying Aiming, Profile of selected periods of education (years controls and 24years, mean study season Mood States, the working day. schooling), effect of 11.9±6.8y. Acute Finnish Subjective Concentrations of smoking, alcohol exposure (group poisonings in past Symptoms pesticides consumption and effect or chronic not recorded Questionnaire determined on use of drugs exposure) cellulose pads Participant placed on individual selection was not parts of garments. described. Browne 2006 Israel Neurospychologica Control test data Nueropsychological testing Neuropsychologic Exposure Age, sex, Students’ t-test, l test data for 23 control (23 subjects) al tests included ascertained using education (but ANOVA available from 23 subjects (living in Whole blood and plasma Tower of Hanoi Agri-Screen Tickets data not reported exposed urban stored at -70oC for (serial reaction (which screen for for group individuals from a environment) who measurement of time), cholinesterase subjected to group of 60 were matched to Paraoxonase, arylesterase Continuous inhibitors) placed in neuro- individuals who exposed on age and serum Performance Test field and at 20 m psychological gave written (±5y), sex and acetylcholinesterase and (attention and intervals (5 testing) consent. These 60 education. These butylcholinesterase. response to distances) from individuals were were taken from a Genotyping for PON1 specified digit field. Discs taken from a group group of 91 control Q192R and PON1 l55M. sequence), collected after 12h. of 291 resident subjects Digit span (from Control included living 25m-150m WAIS), placement of Agri near to sprayed Visual Screen ticket in an fields (age 4-90, reproduction automobile mean 36.5 subtest of (negative control)

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First Date Country Study Reference Health assessment Health Measure of Risk factors/ Statistical Author population population method outcome Exposure bias/ analysis variables confounders y±21.7y, Wechsler 149males, 142 Memory Scale, females). 65 of Long term these individuals vocabulary were also (Hebrew version agricultural of Rey Auditory workers exposed Learning Test) to pesticides. Biochemcial investigations undertaken on 30 exposed individuals (10 of whom were also agricultural workers) Farahat 2003 Egypt 52 male 50 male Personal, occupational and Similarities (test of Exposure not Analyses Multiple Linear agricultural clerks/administrato medical questionnaire verbal directly measured. adjusted for Regression for (cotton) workers rs working for administered. Clinical abstraction), Spray history effect of age and neurobehavioura from Berket-El Ministry of examination of chest, heart, Digit symbol and recorded. Serum education l performance Sabe district, Agriculture, never and abdomen, and Trail making A AChE measured data, with Holm’s Menoufiya exposed to neurological tests for and B (visuomotor modification of Governate, Egypt pesticides, from sensory and motor speed), Block Bonferroni from a total of 64 same functions,including cranial design (problem correction for eligible workers socioeconomic nerves, the motor system, solving), Paced multiple (from June-Sept grouping as involuntary movements, Auditory Serial comparisons 2000). Among exposed, lived in muscle tone and power, Addition Test eligible group 12 same district, coordination, reflexes and (PASAT) were excluded or worked in buildings the sensory system. andLetter declined near to cotton A series of Cancellation participation. fields. neurobehavioural tests (attention), Digit Response rate Mean age 42.48y were administered. span, Benton 81%. (SD 5.54), duration Visual Retention Mean age 43.63 of work 17.08y (SD test (BVRT), Story (SD 5.51). Mean 4.37) recall parts A and duration of work B (memory) and 18.04y (SD Subjects exposed Eysenck 8.29)Job and/ or controls Personality categories placed were excluded if Questionnaire them in fields they were (EPQ, during spraying. seasonal workers, personality). The exposed had <12y Venous blood group consisted of: education, or had from 45 exposed, agricultural medical diagnoses 37 unexposed engineers (37%), including diabetes, subjects used to

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First Date Country Study Reference Health assessment Health Measure of Risk factors/ Statistical Author population population method outcome Exposure bias/ analysis variables confounders assistants (38%), liver/kidney determine serum mixers (10%), disease, peripheral acetyl- mechanics (15%). neuropathy, cholinesterase Most (88%) did not vitamin deficiency, and liver and use personal anaemia, kidney function protective addiction, or long equipment (PPE), term use of 3 (6%) used it psychotropic occasionally, and 3 drugs, previous (6%) frequently head injury or used cloth masks. recent exposure to None had acute other neurotoxic exposures agents requiring hospitalisation Keifer 2000 USA 137 apple orchard Non-agricultural WHO Neurobehavioral Performance on No direct measure The Peabody Multiple Linear thinners workers (garment CoreTest battery, block Vibration of exposure Picture Regression (Wentachee, manufacturers, design from Weschler Adult hand/foot, Santa undertaken. Hours Vocabulary including gender, Washington) hotel and Intelligence Revised test, Ana (dominant of thinning used to (correlates with haemoglobin, (mean age 28, restaurant paired associates memory and non assess exposure. education and age and in some 45% female) workers) matched tests, Peabody Picture dominant), trails Acetylcholinesteras was applied in analyses assessed during on age, education Vocabulary test, and A, Symbol digit, e levels measured; first season) Peabody Picture the thinning (within 3y) and depression scale from Brief Reaction time, AChE was inversely consistently Vocabulary season April- gender. Symptom Inventory, Q-16 Pursuit aiming, related to hours predicted score. P<0.05 August 1994. . 90 Authors report that neurological symptom paired associates thinning. performance in two tailed testing apple thinners most blue collar questionnaire (Spanish). test (easy and neurobehavioura used for (mean age 28, workers in the area Additional tests included R- tough), Digit span l tests. Gender, significance. 42% female) also participate in R interval testing and Brief (forward, age and Logistic tested 6-9 months cherry harvesting, Symptom Inventory backward) Block haemoglobin regression, chi- later, prior to new but no OPs used depression scale. Design, Benton included in square and season. Apple on cherries near to Structured interview for visual retention analyses. Fischer exact thinning involves harvest. Number demographics, alcohol, test test applied to hand picking to of referents tested home pesticide use, work some variables reduce number of not reported history, health and general apples on trees to social history. enhance the Venous blood from willing growth of the subjects (most) for acetyl- remaining apples. cholinesterase, This is undertaken paraoxonase, chlorpyrifos at the same time oxonase and diazinon that the trees are oxonase. sprayed with Blood analyses were azinphos-methyl to undertaken at the end of control coddling the exposure season and at moth the beginning of the next

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First Date Country Study Reference Health assessment Health Measure of Risk factors/ Statistical Author population population method outcome Exposure bias/ analysis variables confounders

The authors did not report the response rate for participation of exposed subjects in this study. Kilburn 1999 USA 22 patients seen Neurobehavioural Subjects completed Simple and There were no Predicted linear Comparisons between 1991- testing undertaken questionnaire (rating 35 Choice reaction direct measures of regression between 1997 who were in 264 men and common health complaints) time exposure. Detailed adjusted for age, exposed and evaluated using women (age 18- and a standard respiratory Cognitive Culture schedules for education, unexposed made neurobehavioural 83y, mean 45y, questionnaire, and fair A, Digit pesticide height, and other as % of tests and who had education 3-20y, questions for occupational symbol, applications for factors when predicted using identified mean 12.9y, 54% and other exposures to Vocabulary offices of patients 9, they had a step wise linear chlorpyrifos as women). No hazardous chemicals, Perceptual motor 14, 17-20. Four significant regression their major history of exposure tobacco use, alcohol (also speed Pegboard, patients had coefficient. chemical to neurotoxic measured in expiratory air), Trail making A clothing or rugs Factors including exposure. This chemicals drug use, unconsciousness, and B. analysed. Patient 2 family income, represented 6% of anaesthesia, head trauma, Recall Story was present when hours of general the possible 384 medical histories. immediate, Story chlorpyrifos was anaesthesia, exposed Neruophysiological and delayed sprayed in an weight and participants. (age neuropsychological testing Finger writing entryway to a motel POMS (Profile of 34-77y, mean undertaken. errors Right and (occupied room for Mood States) 44.7, 59% women, left. 3 days). Patients 3 had no education 6-20y). Long term and 4 had their significant 19 were exposed memory manufactured home coefficient for in homes/offices (8 Information, sprayed, became ill any test. of these had single picture and eventually left exposure, whilst 9 completion, the home. Patients were exposed similarities 6,7,8 had their repeatedly for Profile of Mood home sprayed for periods up to States Mean termites, (patient 7 months/years). score, Depression returned home, One was exposed mean score. whilst patients 6 through aerial and 8 stayed away spraying of a field, for several months. 2 had worked as Patients 10 and 11 pesticide moved to a log applicators/mixers cabin after it was and one was sprayed, and exposed in a motel moved out after 3 room. weeks. Neurobehavioural testing was undertaken 9-108

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First Date Country Study Reference Health assessment Health Measure of Risk factors/ Statistical Author population population method outcome Exposure bias/ analysis variables confounders months post exposure. Mackenzie 2010 England 127 Sheep 78 controls (rural An extensive psychometric Working memory: Self-reported - a Farmers and Two factor Ross Farmers with at policemen; 38 test battery was WAIS –III semi-structured controls matched ANOVA. Age least 5 y exposure working, 40 retired administered including parameters digit interview was for gender, added as to OPs prior to on ill health Wechsler Adult Intelligence span (forwards, administered education and covariate when 1991 (67 working, grounds). Scale-III, 11 subtests:. backwards), premorbid IQ but variables were 60 retired on ill Recruitment by Wechsler Memory Scale-III arithmetic, LNS not age. not aged-scaled. health). enlisting the help (verbal, visual memory), (letter number) Age corrected Multivariate tests Recruitment of local Trailmaking A and B (motor Visual memory: psychometric were used for involved writing to constabularies and speed, mental flexibility),. visual (immediate, test data used. assessment of farm owners listed the national Stroop test of mental delayed) Analyses for domains. on the relevant Association of flexibility, Auditory memory cognitive effects Chi square was databases (UK Retired Police Graded Naming Test ( WMS-III auditory re-run factoring used for national Business Officers who verbal fluency), (immediate, for anxiety and CALCAP and Directory, national contacted Grooved Pegboard test delayed, depression Stroop where Farmers Union members by email (fine motor control), recognition numbers with membership lists) or newsletter. The California Computerised delayed) normal/abnormal and telephoning study was also Assessment Package Response speed: test data are every 5th person advertised in the (CALCAP) to assess simple WAIS –III digit reported on list held by police press. and choice reaction time, symbol, Trails A, Wool Marketing Initially 252 came Medical Symptom Validity CALCAP simple Board). 393 forward; exclusion Test Fine motor control contacted, 59% of 63% using Grooved response. inclusion/exclusion pegboard Additional farmers criteria. Inclusion; Mental flexibility recruited through age 18-70y, having Trails B Stroop, advertising or reply worked in rural CALCAP choice to articles in area of SWest or Strategy making media. Initially North England. Verbal fluency 434 farmers came Retired on illhealth Verbal Ability forward; exclusion grounds. No WAIS-III of 67% using known exposure to comprehension inclusion/exclusion OPs. Exclusion on and vocabulary, criteria . Inclusion history of Graded naming age 18-70 y, living psychiatric or Visuospatial skills in SWest or North serious medical WAIS-II block England. Retired problems, design,WMS-III subjects on basis substance abuse spatial span of illhealth. (including alcohol) Verbal and visual Exposure to OPs or exposure to reasoning for minimum of 5 OPs. Mean age WAIS-III picture years prior to 51.73 (SD 7.36) arrangement, 1991. Exclusion on (68 male, 10 comprehension history of female). and similarities

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First Date Country Study Reference Health assessment Health Measure of Risk factors/ Statistical Author population population method outcome Exposure bias/ analysis variables confounders psychiatric, Primary reason for neurological or retirement was serious medical musculoskeletal problems injury (78%), substance abuse stress (7%), 15% (including alcohol) other (breathing or acute OP difficulties, gout, intoxication. Mean benign tumour, age 54.73 (SD chronic fatigue, 9.42) (102 male, arthritis) 25 female) Of the retired group, 51% had retired completely, remainder semi retired. For 77% reason for retirement was non-specific symptoms such as chronic fatigue, headaches, cognitive impairment, chemical sensitivity. For 23% reason was musculoskeletal injury, breathing difficulties and prostate problems Roldán- 2005 Spain 40 Green house 26 male controls Health assessment with A wide range of Structured Age and Logistic Tapia L sprayers from who had never emphasis on head trauma, tests were used. questionnaire to educational level regression Southeastern worked on farms medication, neurological The functional assess lifetime performed for Spain (March-April or had contact with diseases and lifetime domain pesticide use. dichotomous 1998) using OP toxic substances. alcohol, tobacco and drug classification by Years of working variables. Ors and/or carbamate All with up to 3 use. All underwent a these authors was with OP/carbamate and 95%Cis for pesticides, years education, complete physical different to other pesticides. Serum worst chronically from same examination. Blood investigators (BuChE) performance exposed (6month- demographic area samples taken for cholinesterase reported. 30 years) but working in different estimation of serum BuChE Tests of Attention measured. Linear without recorded professions (hotel, levels. Cholinergic Stroop regression for all poisoning. All restaurant staff, symptoms recorded. A Cancellation other test participants were maintenance Letter test measurements. male, of the same technicians, Exposed subjects Trails A and B Coefficients and

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First Date Country Study Reference Health assessment Health Measure of Risk factors/ Statistical Author population population method outcome Exposure bias/ analysis variables confounders ethnicity, culture factory workers, underwent Digit vigilance 95%Cis and at least 4years security guards). neuropsychological testing (Spanish reported. of education. The The response rate at their workplace or at a adaptation of authors didn’t for controls was community centre (private WAIS) Long-term (years report the not reported. school, produce Tests of Concept working with response rate or warehouse) located near to formation/reasoni pesticides) and full details of the agricultural areas. Data ng recent selection collected 2-7 days after last Picture OP/carbamate procedure. fumigation. completion exposure Similarities (BuChE) Verbal memory considered as Digit span relevant variable. forward/backward Base models Rey Auditory containing these Verbal learning variables were test constructed by Visual memory backwards Rey-Osterreich elimination Complex Figure (variable Benton Visual retained if Retention test p,0.10. Logical memory Age, BuChE Logical memory lelve and years test part A working with (Spanish pesticides were translation of scaled in WMS) regression Perception analysis by Benton Visual interquartile Form range. Linear Discrimination test logistic modlels Poppelreuter test were fitted to Stereognosis asses the Constructional relationship WAIS Block between Design cumulative Verbal expression exposure , or Boston Naming recent exposure test and neuropsychologi In addition the cal outcomes of investigators analyses shown assessed motor to be significant. performance (eg rhythm

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First Date Country Study Reference Health assessment Health Measure of Risk factors/ Statistical Author population population method outcome Exposure bias/ analysis variables confounders reproduction, coordination of hand movements) Ideomotor apraxia (Loss of ability to voluntarily perform a learned task when given the necessary objects.) Ideational apraxia (loss of ability to conceptualize, plan, and execute the complex sequence of motor actions)

Rothlein 2006 USA All attendees at 55 immigrant Neurobehavioral testing in Psychomotor Spot urine samples Age, sex, Association parent meetings, Hispanic workers evenings using similar functions; finger taken once during education in between who had a child from Newport, testing stations for both tapping, simple summer and in fall home country methylphosphate enrolled in thw Oregon (tourist exposed and controls. The reaction time, Adjusted to pH 3 (mostly Mexico) in house dust Migrant head Start coastal town with Behavioral Assessment progressive ratio, and stored -20oC till and thiomethyl program and were little agriculture). Research System Measures of analysis (samples metabolite currently working 10 excluded as (Spanish) was administered cognitive with low or high concentrations in fields, orchards they had worked in functioning: creatinine evaluated using or nurseries were landscaping/forestr (symbol-digit, digit excluded). House Spearman’s invited to y, had no formal span, selective dust samples (5g) correlation. participate. The education in attention, serial were obtained from Difference in response rate was Mexico or USA or digit learning and 26 homes during urinary not reported. 96 were not available continuous week urine samples thiomethyl Hood River, during scheduled performance) were taken.Dust metabolites Oregon Hispanic testing sessions. samples taken between summer farm workers during middle of T1 and fall T2 (aged 20-52 y) Controls were growing season analysed using who lived in recruited for the when pesticides Wilcoxon signed cabins, trailers, study by a were being applied rank test (T1 and single/multi family community (in particular T2 combined for homes alongside member with the azinphos-methyl) subsequent orchards were support and Dust analysed for analyses).

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First Date Country Study Reference Health assessment Health Measure of Risk factors/ Statistical Author population population method outcome Exposure bias/ analysis variables confounders recruited. They partnership of azinphos-methyl, The association had arrived in USA Hispanic diazinon, between from Mexico community chlorpyrifos, neurobehavioral from1970-1998. organisations malathion, methyl test scores and Centro de Ayuda parathion, phosmet average Mean age and Un Paso (azinphos methyl, thiomethyl- 29.7±6.89 Adelante. The phosphomet and phosphate Mean time since response rate was malathion levels metabolite levels arrival in USA 9.8y not reported. were summed). assessed Urine analysed for 5 accounting for Mean age dialkyl phosphates age, sex and 27.8±6.19 (19-48y) (DAP: diemthyl-, education. Mean time since diethyl-, Differences arrival in USA 7.3y dimethylthio-, between diethylthio-, agricultural (AG) dimethyldithio-) and non- agricultural (non-AG) groups assessed by multiple linear regression (adjusted for age, sex and education). Mean values for each test computed for a 25 y old subject with 6 years of education (in his/her country). A summary neurobehavioral index was calculated (11/16 test items) designed to provide equal representation of all measures. Summary index analysed to see if there was any correlation with thiomethyl

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First Date Country Study Reference Health assessment Health Measure of Risk factors/ Statistical Author population population method outcome Exposure bias/ analysis variables confounders metabolites

Salvi 2003 Brazil 37 tobacco No referent group Clinical assessment of Mini-mental and History of OP use Time and type of Comparison workers assessed symptoms and evidence for word span tests assessed and OP exposure, between the two in December 2001 cholinergic syndrome. for orientation, plasma acetyl use of protective evaluations (after 3 months Psychiatric assessment and immediate/short cholinesterase. clothing, performed using use of OPs) and evaluation for Parkinsonian term memory, activities with ANOVA and again in March syndrome. naming and OPs, history of Wilcoxon for 2002 (25 subjects Cognitive behavioural sequencing acute toxicity, scale scores. after 3 months not testing alcohol and exposed to OPs). tobacco use Subjects had many were noted as years experience characteristics of of applying OPs to the 25 subjects tobacco crops. who completed both evaluations; There was no possible bias description of the because affected selection subjects might procedure for the have enrolled 37 exposed more readily in subjects or the the study, and response rate. there is no unexposed comparison group Srivastava 2000 India All the 59 workers 17 workers Clinical, social and Digit span (verbal Exposure not Groups similar in Student’s t-test, exposed to engaged as tea occupational history memory), directly assessed. age, work chi-square test, chemicals during vendors, roadside obtained. Whole blood Digit symbol Information on history, physical Fisher’s exact manufacture of hawkers who were AChE and (visuomotor chemicals used and activity at work, test Quinalphos not exposed neurobehavioural testing speed), produced during social directly or Bourden Weirsma manufacture of characteristics indirectly to any vigilance test quinalphos provided and use of OP pesticides (selection of tobacco and groups of 4 dots alcohol. from jumbled groups, test of perceptual accuracy and fluctuations in vigilance). Tests administered in Hindi Steenland K 2000 USA Current and former Approximately half Demographic details and Neurobehavioural Subjects first Age, race, Linear

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First Date Country Study Reference Health assessment Health Measure of Risk factors/ Statistical Author population population method outcome Exposure bias/ analysis variables confounders termiticide of the exposed complete work history tests of a wide contacted by mail education, regression model applicators using subjects were (termiticide use, other range of functions and then by current smoking. adjusting for chlorpyrifos in a 12 asked to bring a pesticide use, solvent use) telephone. And possible county area of friend of same sex, taken. Participants asked to Buccal cells information on Variables not confounding North Carolina age (within 5 refrain from alcohol the isolated for termiticide use predictive of variables. from 1987-1997. years) (106) night before assessment determination of (including outcome Some had used A second non- (saliva alcohol test done). genotype for chlorpyrifos and included hours of Analysed a chlordane before exposed group The Neurobehavioural paraoxonase. chlordane) sleep the night variety of 1988. Included was chosen from Evaluation System (NES) gathered. before testing, subgroups termiticide blue-collar North was administered alcohol including applicators who Carolina state consisting of vocabulary Applicators who consumption the a) currently had used employees. 856 test, mood scales, digit had reported night before applying pesticides for a were mailed. span, continuous current exposure testing, current termiticide (128) year or more. Volunteers were performance, simple during telephone exposure to b) formerly 3,605 applicators included if they reactions time, digit symbol interview (105) solvents, coffee applying were identified matched the test, pattern memory. In collected urine consumption the termiticide from 246 overall age, race addition the investigators samples (first void). day of tests. c) self reported companies. 176 sex distribution of also administered Trails A 3,5,6-trichloro-2- poisoning to companies applicators and if and B tests. pyridinal (TCP-a chlorpyrifos contacted (which they had never specific metabolite d) workers with represented worked with for chlorpyrifos susceptible ‘screened pesticides or been absorbed dose) genotype. employees’). Of poisoned by was measured. Within applicator these companies pesticides. A total TCP also measured group trends 105 (60%) of 83 NC state in urine samples were assessed reported either blue collar workers from 52 by duration of current or past were tested. nonexposed exposure to chlorpyrifos use. participants. chlorpyrifos, Another 71 chlordane and companies were other pesticides. out of business Models were and 6 refused to also run participate (which restricting to represented subjects with ‘unscreened’ TCP values (log employees. Of TCP or TCP 2917 screened corrected for employees (688 creatinine) unscreened), 383 were reported to have applied termiticides for at least a year. Of these 239 were contacted, and 153

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First Date Country Study Reference Health assessment Health Measure of Risk factors/ Statistical Author population population method outcome Exposure bias/ analysis variables confounders were scheduled for test. The authors tracked a further 206 individuals from the unscreened group. Of these 43 were scheduled for testing. Of the 196 scheduled for tests, data were obtained for 193. Participants underwent testing at a central location within a 2h drive. Stephens 2004 UK 60 male orchard Two reference Neurobehavioural testing Subjective Urine collected for Study group Kruskal-Wallis sprayers from 53 populations using 7 tests providing data memory assessment of characteristics non-parametric businesses (males) were used. on 13 dependent variables. questionnaire urinary reported (no ANOVA for urine (Hereford, Pig farmers and The Automated Cognitive (SMQ), diethylphosphate differences in levels of OP Worcester, East construction Testing System (ACTS), as General Health (DEP) and age or education metabolites. For Anglia, Kent and workers. used in a previous study of Questionnaire diethylthiophosphat reported neuropsycho- Sussex) who had sheep dippers was applied. (GHQ). Simple e (DETP) although more logical tests, all been in an 263 pig farming Reaction Time orchard sprayers variables were occupational businesses A period of at least 2 (SRT), Digit Span, were university normally hygiene survey the approached. months between use of Symbol Digit educated (16%) distributed previous year. 41 Access to workers OPs and testing was subtests of the compared to 0% except GHQ (68%) were for 24 businesses imposed to ensure the Neurobehavioral in construction vulnerability to followed up but 4 agreed (site absence of acute OP Evaluation workers and psychiatric were excluded response rate 9%). effects System 2 (NES2), 12% in pig disorder (head injury and 3 38 subjects agreed The Syntactic farmers.. Weekly (categorical). with low blood to participate. Reasoning alcohol ANOVA followed AChE) Excluded 3 head Location consumption by pair wise Neurobehavioural injury, 1 missing Recognition, was similar comparisons. tests on 37,,mean urinalysis and 8 Category Search between orchard GHQ analysed age 45.49±12.05y aged 17-23 to age and Serial Word sprayers by chi squared. match with Learning subtests (12.35±13.37 Bonferroni The number of exposed. of the ACTS units) and pig corrections premises and Neurobehavioural farm workers undertaken to response rate tests on 26, mean (15.08±15.05) account for were not recorded. age 42.31±12.27y but was multiple significantly comparisons 41 construction higher in workers from 100 construction

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First Date Country Study Reference Health assessment Health Measure of Risk factors/ Statistical Author population population method outcome Exposure bias/ analysis variables confounders approached (41%). workers 2 excluded head (27.71±21.22) injury, 3 (previous (1 unit =10 ml) agricultural work, Authors did not use of mood employ any altering drugs, or covariates in the no recorded age). analyses as they Further 5 aged 19- argued group 24y excluded to inequalities in match age groups. alcohol Neurobehavioural consumption test on 31, mean would favour the age 39.45±10.12y null hypothesis.

6.B.4. Case series studies - none

6.B.5. Case reports - none

Table 7. NEUROPSYCHOLOGY RESULTS AND CONCLUSIONS

First Date Strengths / Major Findings Conclusions Author Published Limitations A. Acute Exposure with Chronic Effects 7.A.1. Cohort studies Delgado 2004 NICARAGUAN STUDY OF 53 SUBJECTS EXPOSED TO OP POISONING Strengths Severe acute OP Prospective design poisoning can EXPOSURE None of the subjects had clinically mild exposure. 31 subjects were considered with exposure result in short term to have had moderate occupational poisoning, which included symptoms of weakness, classification. 85% of deficits in dizziness, head ache or blurred vision, in combination with at least one symptom out of: poisoned subjects visuomotor and vomiting, sialorrhoea, fasciculations, abdominal pain, diarrhoea, miosis, wheezing or crepitus . were considered at short term Severe (15 individuals) also included diminished consciousness, or cyanosis. examination III memory (at Type of OP used (by cases): discharge) . Methamidophos 20 Limitations There is some Chlorpyrifos 17 No direct estimation limited evidence to Edifenphos 6 of exposure. suggest that

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First Date Strengths / Major Findings Conclusions Author Published Limitations Methyl parathion 4 Small group size. visuomotor effects Terbufos 3 Small referent group. persisted in the Phorate 1 Limited number of most severely Malathion 1 neurobehavioural exposed subjects Fenthion 1 tests applied

HEALTH OUTCOMES There were no statistically significant effects on performance of the Rey verbal test when assessed for exposure or the interaction of time and exposure. The deficit in the high exposure group at the time of discharge was -1.7 (95% CI -3.7-0.3) after adjustment for age, education and alcohol consumption in comparison with unexposed group. There was no deficit at 7 weeks or 2 years in this group.

A deficit in the adjusted digit symbol visuomotor performance was reported at 7 weeks in all groups (value for all exposed 7 weeks v discharge -5.07, 95%CI -9.00- -1.14). In the medium exposure group, the mean deficit was -7.89 units (95%CI -12.7- -3.0). This deficit had disappeared in this group after 2 years (-0.40,95% CI -8.16-7.37). The authors reported a considerable improvement in the unexposed group was responsible for the change in this deficit. This was likely a test- retest effect.

In the high exposure group visuomotor performance was depressed throughout the observation period, particularly after 2 years, but the CIs were wide and included positive values: -3.12 (95% CI -9.72-3.49) 7 weeks v discharge. -7.69 (95% CI -17.6-2.24) 2 years v discharge. -4.58 (95% CI -15.5-6.33) 2 years v 7 weeks

The P-value for interaction between time and exposure was 0.04 (unadjusted and adjusted) for all exposed, 0.20/0.23 (unadjusted/Adjusted) for low exposed, 0.001 (both unadjusted and adjusted) for medium exposed and 0.29/0.25 (Unadjusted/Adjusted) for high exposed. 7.A.3. Cross-sectional studies Chao 2010 STUDY RELATES TO GULF WAR VETERANS DURING THE KHAMISIYAH INCIDENT Strengths The authors Extensive conclude that EXPOSURE Derived plumes were matched to geographical co-ordinates for units during 10- neuropsychological sarin/cyclosarin 13 March 1991. Estimated exposure range 0.047-0.889 mg min/m3, ( 9 subjects with no evaluation and MR exposure was not exposure, 7 with moderate (0.0469-0.072 mg min/m3 and 24 with high exposure (>0.072 – Imaging of GW associated with 0.999 mg min/m3 . veterans exposed to deficits on sarin/cyclosarin. attention, memory, visuospatial HEALTH OUTCOMES Neuropsychology data are summarised below. Limitations abilities or manual

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First Date Strengths / Major Findings Conclusions Author Published Limitations The data suggested a marginally significant effect on visuospatial memory (Brief Visual Exposure modelled dexterity. Dose- Memory test) . However a significant malingering effect (group difference in Trial 2 for at unit level. related effects malingering ) was also reported. Exclusion of the 4 veterans who scored lower than 45 on trial Not possible to reported by 2 for malingering, eliminated any slight differences on visuospatial memory/abilities. estimate individual Proctor were not exposures. found in this The authors also conducted comparison of data for 32 exposed and 26 unexposed for whom Small group sizes study. The full test data were available. A significantly reduced performance on the California Verbal with limited power to absence of an Learning test II long delay was reported (P=0.04). However the effect was no longer detect effects. effect may be due statistically significant when the veterans who failed the malingering test were excluded. Findings possibly to the long interval confounded by between exposure Functional Neuropsychology Function All Exposed malingering. and testing (ca. 10 domain test assessed v Control y). significance The authors General WAIS -III Intelligenc 0.17 considered that verbal WRAT-III reading e 0.68 reduced GM intelligence Attention Continuous Sustained 0.23 volume observed Performance attention in sarin/cyclosarin Trail Making A Spatial 0.73 exposed veterans attention, was associated simple with deleterious visuopatial effects in some tracking neuropsychologic WAIS III Digit Simple 0.78 al tests. In Span attention, addition the concentrat ion, correlation tracking between WM Executive Trail Making B Spatial 0.99 volume and Function attention, performance on set shifting Block Design test Short Category Cognitive 0.57 led to the test flexibility, suggestion that abstract OP exposure reasoning affected WM Control oral word Verbal 0.33 association fluency which in turn Psychomotor Groove pegboard Performan 0.99 compromised function ce speed dominant, cognitive function in a fine 0.33 non- (more than a motor task dominant decade later). WAIS-III Digit Visual 0.23 Authors symbol matching perception considered that

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First Date Strengths / Major Findings Conclusions Author Published Limitations , effects were not psychomot confounded by or speed Chronic Mutli Visuospatial WAIS-III Block Spatial 0.17 symptom illness or abilities Design perception other factors , visual abstract associated with processing Gulf War Veterans , problem Illness. Authors solving suggest further Short-term California Verbal Verbal 0.27 follow-up with memory learning test episodic Short delay more subjects and memory 0.25 improved imaging Long delay systems. WMS-III Logical Recall of 0.49 Memory orally presented informatio n Brief Visual Visuospati 0.07 Memory test-R al memory Total recall 0.51 delayed recall Genuine Test of Memory Tendency 0.69 Trial1 Effort Malingering to 0.01 Trial2 purposeful 0.1 ly perform Retention poorly

Spearman’s correlation coefficients between hippocampal, total GM and WM volumes and neuropsychological test performance were presented.

In OP exposed veterans hippocampal volume correlated positively with Verbal Comprehension Index scores (r=0.48, p<0.01). Total GM correlated positively with performance on the Controlled Oral Word Association test (r=0.61, p<0.0001), the Block Design test (r=0.42, p=0.01) and negatively with Trail making test A (r= -0.35, p<0.05) and time to place all pegs in the Grooved Pegboard (non dominant) (r=-0.36, p=0.03). Total WM volume also correlated with the Controlled Oral Word Association test (r=0.43, p=0.01) and Block Design test (r=0.34,p=0.04). In unexposed veterans total GM volume correlated positively with Block Design test (r= 0.36, p=0.02) and negatively with time to complete Trail-making test A (r=- 0.38,p<0.05) while WM volume correlated positively with Verbal Comprehension Index (r=0.38, p<0.05).

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First Date Strengths / Major Findings Conclusions Author Published Limitations

Mittal 2011 3MONTH FOLLOW-UP OF PATIENTS WITH ACUTE OP POISONING (INDIA) Strengths Study provides Neuropsychology evidence of EXPOSURE: Means serum AchE was 0.35±0.28 IU/ml (normal range 1-2 IU/ml) testing of subjects persistent effects who had (3 month follow- HEALTHOUTCOMES experienced acute up) on verbal poisoning episode. fluency (executive Patients presented with a range of cholinergic symptoms (vomiting 96%), diarhea (36%), function), , visual salivation (100%), pinpoint pupils (84%), fasciculations (82%), tachycardia (89%) (other Limitations Small and verbal symptoms not listied here) size with 8 patients memory. The lost to follow-up. authors reported Data for 3 month follow up neuropsychological testing reported below Period of follow-up the impairment in (At discharge there were reduced performance in Trail B, verbal fluency, visual retention, was small. Potential BVMG visual recognition, verbal retention (data for 26 patients avaialble).) confounding by represented educational effects on Data at 3 months (for 18 patients) reported below achievement not perceptual motor considered. skills and Test Control (mean 3 months (mean p perceptual motor ±SD) ±SD) development. Trail A 52.4 (19.7) 50.8 (20.8) 0.688 Trail B 96.5 (37.9) 119.8 (39.46) 0.042 Verbal fluency 29.4 (3.25) 17.3 (4.7) 0.0001 Visual retention 9.7 (3.3) 9.29 (2.95) 0.121 Visual 8.4 (1.6) 9.33 (2.03) 0.005 recognition Verbal retention 11.0 (3.6) 10.9 (3.1) 0.001 BVMG 1.3 (1.5) 6.55 (3.63) 0.001 (not stated in paper to be a significant difference

Significant impaired performance in verbal fluency, visual recognition and verbal retention were reported. Poorer performance in BVMG is apparent from the tabled data. (Poorer performance on BVMG was also apparent at discharge (7.7 (1.5)),

Miyaki 2005 7 YEAR FOLLOW UP OF TOKYO SUBWAY WORKERS EXPOSED TO SARIN Strengths Authors claim that

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First Date Strengths / Major Findings Conclusions Author Published Limitations Prospective design psychomotor HEALTH OUTCOMES Finger tapping (dominant and non-dominant hands) was significantly of group exposed to function was reduced, with some p values <0.05, although the 95% CIs for ORs include 1.Finger tapping acutely toxic levels of reduced in dominant was reduced after accounting for confounders but linear trend test was not sarin subjects 7y post significant (p=0.062). Median numbers of forward digit span and Benton visual test were exposure to sarin., reported to be 1 unit reduced (not statistically significant) (No effect on Digit Span backwards Limitations and that reported) No changes in stabilometry, simple and choice reaction times. ORs were calculated Exposure combined 3y and and were above 1 but were not statistically significant. categorisation 7y data suggest undertaken on some reduced For combined 3y and 7y post exposure: assessment of memory function. Finger tapping intervals of both dominant and non dominant hands were significantly slower in severity of acute However, the high-exposure group compared to referents (after adjustment for age, post-exposure symptoms. although some p period and other confounders). Effect was significantly dose-dependent. Calculated ORs were values are <0.05, significant for the high- exposure group for finger tapping. Small group of Confidence Performance of Digit span (backward) was reduced in exposed. The trend for dose- subjects included in Intervals of dependence was marginally significant (p=0.055) after adjusting for age, post-exposure period 7 y follow-up calculated ORs and other confounding variables. There were no other significant changes. include 1, suggesting that Effects and risk of sarin exposure on subway workers 7 y: the significance of the reductions in Group Tapping (dominant) Tapping (non-dominant) function may be imsec msec borderline Geometric mean Geometric mean (geometric SD) (geometric SD) Exposed 117.0 (1.13) 136.3 (1.17) (p=0.079) (23) p<0.05 by t-testand after adjustment for confounders High exposure 123.3 (1.17) 157.6 (1.20) (5) (p,0.05 Student’s t-test) Low exposure 115.3 (1.12) 130.9 (1.14) (18) (<0.05) Referents 104.5 (1.17) 123.7 (1.16) (13) P for trend (score 0.062 Ns v exposure level) Exposed OR 4.38 (0.67-28.5) 1.18 (0.18-7.81) High exposure OR 15.0 (0.44-517) 3.15 (0.07-151) Low exposure OR 4.19 (0.64-27.4) 1.15 (0.17-7.58)

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First Date Strengths / Major Findings Conclusions Author Published Limitations

Effects and risks of sarin exposure combined 1998 (3y) and 2002 (7y) data: (post exposure period (3y=0, 7y=1) included as explanatory variable in multiple regression model or multiple logistic regression model):

Group Tapping Tapping (non Digit span (dominant) msec dominant) msec (backward) Geometric mean Geometric mean Median (geometric SD) (geometric SD) (range) Exposed 120.4 (1.18) 138.1 (1.20) 4 (2-8) (p<0.05 (80) (Wilcoxon rank) High 131.1 (1.19) 150.8 (1.22) 4 (3-6) exposure (p<0.05 by t-test (p<0.05 by t-test (30) and after and after adjusted adjusted for for confounders) confounders) Low 114.4 (1.15) 131.1 (1.17) 4(2-8) exposure (50) Referents 117.3 (1.24) 134.2 (1.22) 5(2-9) (65) P for trend 0.020 0.033 0.055 (score v exposure) Exposed OR 1.98 (0.88-4.43) 1.46 (0. 68-3.11) 2.14 (0.97- 4.70) High 3.44 (1.18-10.1) 2.77 (1.00-7.70) 2.57 (0.91- exposure 7.22) OR Low 1.40 (0.57-3.44) 0.99 (0.42-2.31) 1.90 (0.78- exposure 4.63) OR Post- 0.28 (0.11-0.73) 0.55 (0.22-1.34) 1.13 (0.45- exposure 2.88) period

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First Date Strengths / Major Findings Conclusions Author Published Limitations Nishiwaki 2001 STUDY OF FIRE RESCUE STAFF AND POLICE OFFICERS EXPOSED TO SARIN IN THE TOKYO SUBWAY INCIDENT

HEALTH OUTCOMES Neurobehavioural and stabilometry data:

Test High Low exposure Referents exposure(25) (29) (52) Mean (SD) Mean (SD) Mean (SD) Psychomotor function Tapping 132.7 (1.2) 114.3 (1.1) 120.7 (1.2) dominant (p<0.05 in ((msec) multiple regression including GHS score) Tapping non 149.4 (1.2) 130.3 (1.2) 137 (1.2) dominant (msec) Simple 255.5 (1.2) 242.1 (1.1) 246.9 (1.1) reaction time (msec) Choice 607.7 (1.3) 558.6 (1.2) 591.7 (1.3) reaction time (msec) Stabilometry Centre of foot 96.7 (1.2) (eyes open) Length (p<0.05 t-test, 83.5 (1.2) (cm) 84.3 (1.4) <0.05 multiple regression) Sway X length 68.3 (1.2) 57.3 (1.2) 58.2 (1.4)

No effects on vibration perception thresholds reported.

A marginally significant reduction in digit span number (backward) was reported

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First Date Strengths / Major Findings Conclusions Author Published Limitations High Low exposure Referents exposure (25) (29) (52) Forward digit 6.12 (1.51) 6.52 (1.43) 6.38 (1.48) span Mean (SD) Backward 4.24 (0.72) 4.69 (1.37) 5.00 (1.71) digit span P=0.07 Mean (SD) Forward digit 60% 51.7% 57.7 span maximal OR 1.15 OR 0.73 OR 1.0 number(≤6) (0.40-3.34) (0.27-1.94) (Prevalence) Backward 68.0% 51.7% 46.2 digit span OR 3.19 1.17 (0.42- OR 1.0 maximal (1.06-10.38) 3.23) number (≤4) (Prevalence)

The prevalence of poor performers was statistically higher in the high dose group.

In a further analysis with members of police staff with known exposure to solvents and reagents omitted, the maximal digit span (backward) in the high dose group was lower than the referent group. No effect on finger tapping is reported in this re-analysis.

High Low exposure Referents exposure (25) (22) (44) Digit span 4.24 (0.72) 4.64 (1.43) 5.16 (1.74) backwards p=0.07 Mean (SD) Wilcoxon rank test

None of the psychological tests showed any association with hypoxia

Negative results from Benton Visual retention test. Test High exposure Low exposure Referents Benton visual 2.76 (1.54) 2.69 (1.69) 2.71 (1.55) (correct answers) Benton visual 3.60 (3.13) 3.48 (3.15) 3.38 (2.91)

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First Date Strengths / Major Findings Conclusions Author Published Limitations (errors) Benton visual 0.52 (95% CI 0.54 (95% CI 1.0 (correct, cut 0.13-2.03) 0.14-1.97) off≤3) Benton visual 1.29 (95% CI 1.05 (95% CI (errors, cut off 0.41-4.08) 0.36-3.05) ≥3)

Ohtani 2004 FOLLOW UP OF VICTIMS TREATED AT ONE EMERGENCY DEPARTMENT AFTER THE TOKYO SUBWAY SARIN INCIDENT

HEALTH OUTCOMES PTSD (n=11) and non-PTSD (n=23) groups did not differ in age or sex. 6 subjects in the PTSD group had other mental disorders (2 agoraphobic, 2 panic disorder, one major depression and one with depression/agoraphobic)

Mean Visual memory was lower in PTSD group (97.6±13.1) compared to non PTSD group (108.4 ±10.4 ) P<0.05

WMS-R correlated with Impact of Event Scale Revised P<0.01.

No correlation with clinician administered PTSD with WMS-R Proctor 2006 FOLLOW UP OF GULF WAR VETERANS INVOLVED IN THE KHAMISIYAH INCIDENT

EXPOSURE Derived plumes were matched to geographical co-ordinates for units during 10- 13 March 1991. 4 modelled hazard areas, one for each day, were produced. The estimated doses for the 11 units ranged from 35-144 μg min/m3 . High exposure (n=23) >72 μg min/m3, Moderate exposure (n=47)>12.96-≤72 μg min/m3 (12.96 μg min/m3 equates to General Population Level set by the US Army and Centre for Disease Control and Prevention). Low or No exposure (n=70) <12.96 μg min/m3 (subjects not in modelled plume, mostly in Saudi Arabia coastal cities during exposure period)

HEALTH OUTCOMES Higher exposure was associated with ambidextrous/left handedness, lower PTSD symptomatology, psychological symptomatology and psychiatric diagnoses.

Dose-dependent effects on psychomotor and visuospatial abilities were reported (compared to low-no-exposure group). No effects on attention, executive function or short term memory.

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First Date Strengths / Major Findings Conclusions Author Published Limitations

Dose-dependent reduction in performance on Purdue Pegboard (timed, fine manual dexterity) and Block Design (visuospatial construction with a motor component). However a significant improvement in Finger Tapping was reported. Models for Purdue Pegboard were re-run to adjust for possible confounding due to gross motor abilities. The linear trend analysis for Purdue Pegboard (dominant) adjusting for Finger Tapping performance was -1.3 (95% CI (- 1.9- -0.75) P<0.0001. The adjusted parameter estimate for Purdue Pegboard (non dominant) was -0.57 (95% CI -1.0- -0.09), P= 0.02. For both hands -0.66 (95% CI-1.3- -0.07), P=0.03. Higher exposure was not significantly related to mood states (fatigue, tension, depression, anger, and confusion)

Test High/Moderate Results Significance Exposure (adjusted Group with 95%CI) Purdue High -0.93 0.005 Pegboard (-1.6- -0.28) (dominant) Moderate -0.55 0.003 (-0.92- -0.19) Purdue High -0.48 0.03 Pegboard (-0.92- -0.04) (non- dominant) Moderate -0.24 0.40 (-0.81-0.32) Finger High 2.4 0.001 Tapping (0.96-3.8) (dominant) Moderate 2.7 0.0007 (1.1-4.2) Finger High 2.2 0.002 Tapping (0.83-3.6) (non- dominant) Moderate 2.0 0.02 (0.33-3.6) WAIS-R High -4.0 <0.0001 Block design (-5.8- -2.2) Moderate -1.9 0.01 (-3.4- -0.47)

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First Date Strengths / Major Findings Conclusions Author Published Limitations Negative results

Test High/Moderate Results Significance exposure (adjusted with group 95%CI) Continuous High 0.54 (-16.8-17.8) 0.95 Performance (mean response time) Moderate -8.8 (-19.8-2.3) 0.12 Trail making A High -1.8 (-3.7-0.17) 0.07 (time to completion) Moderate 1.1 (-0.84-3.0) 0.28 WAIS-R Digit High 0.32 (-0.13-0.78) 0.16 Span forward (score) Moderate 0.11 (-0.36-0.58) 0.64 WAIS-R Digit High 0.40 (-0.07-0.86) 0.10 Span backward (score) Moderate -0.10 (-0.59- 0.69 0.40) Californian High -0.06 (-1.4-1.2) 0.92 verbal recall (short term) Moderate -1.08 (-2.3-0.15) 0.09 Californian High -0.05 (-1.3-1.3) 0.94 verbal recall (long term) Moderate -0.84 (-1.8-0.16) 0.10 Verbal paired High 0.07 (-0.32-0.46) 0.72 associate, difficult, delayed Moderate -0.006 (-0.27- 0.96 0.26) WMS visual High 0.62 (-0.65, 1.9) 0.34 reproduction (immediate)

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First Date Strengths / Major Findings Conclusions Author Published Limitations Moderate -0.50 (-1.5-0.45) 0.30 WMS visual High 0.09 (-0.98-1.2) 0.87 reproduction (delayed) Moderate -0.38 (-1.2-0.42) 0.35

Roldan- 2006 STUDY OF CHRONIC EFFECTS RESULTING FORM ACUTE INTOXICATION OF Tapia GREENHOUSE WORKERS, SPAIN

EXPOSURE: (Four categories of exposure were assumed : aucte posioning>chhronic high>chronic low>control.

HEALTH OUTCOMES;

Symptoms reported in acute intoxication were reported

Nicotinic symptoms Muscariniic symptoms Central symptoms Poisoned (24) Poisoned (24) Poisoned (24 Dizziness (85%) Respiratory problems Nerviosism (16%) Tremors (70%) (77%) Dysarhria (8%) Fasciculation (16%) Myosis (70%) Sialorrhea (56%) Blurred vision (54%) Abdominal pain (47%) Perspiration (46%) Vomiting (39%) Dyspnea (23%) Diarrhea (16%) Exposed (39) Exposed (39) Exposed (39) Cephalea (6%) Abdominal pain (2%) None Paraesthesia (5%) Vomiting (3%) Asthenia (5%) Rhinitis (3%) Fasciculation (3%) Conjunctivitis (1.6%) Diarrrhea (1%) Dyspnea (0.5%)

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First Date Strengths / Major Findings Conclusions Author Published Limitations

Characteristics of study participants were reported.

Poisoned High Low Control Sig exposed exposed Age 36.87 36.65 27.20 36.73 0.017 (years) (14.55) (8.38) (7.91) (12.53) poisoned v low, high exposure v low, control v low exposure Education 2.83 2.80 3.35 3.26 BuChE 11.297.67 4885.70 5162.79 7396.92 0.000 (2836.39( (903.89) (2275.40) (1692.01) poisoned v high exposure, poisoned v low exposure, poisoned v control high exposed v control, low exposed v control.

The mean BuChE immediately after intoxication was within normal levels and was highly variable (mean 7902.0 (SD 3580.44). Three months later the level in acutely poisoned group had increased above the normal level. The authors found the number of recorded poisoning events varied from 1-7, and positively correlated with plasma cholinesterase levels recorded at

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First Date Strengths / Major Findings Conclusions Author Published Limitations the time of admission at the emergency unit (Pearson 0.719, p =0.002) and 3 months later (Pearson 0.736, p=0.002)/ After 12 months BuChE had returned to normal levels.

Neuropsychological tests in poisoned subjects 3 months after intoxication, and in sprayers and control groups.

Tests of Attention

Test Poisoned High Low Control Sig (24) exposed exposed (26) (20) (20) Digit 3.37 3.90 3.95 3.84 0.168 span (1.13) (1.25) (0.88) (1.22) (backw ard) Stroop 48.30 47.15 49.40 43.96 0.280 Test (7.70) (6.67) (6.11) (11.75) ‘A 2.79 2.60 2.80 2.73 0.790 cancell (0.50) (0.68) (0.52) (0.53) ation Trails A 2.65 2.70 3.00 2.76 0.474 (0.71 (0.57) (0.00) (0.42) Trails B 2.08 1.80 2.45 2.23 0.400 (0.90) (0.89) (0.82) (0.86) Digit 8.54 9.60 10.40 10.00 0.272 Symbol (3.09) (2.90) (1.93) (2.38)

Concept forming reasoning

Test Poisoned(24) High Low Control Sig exposed exposed (26) (20) (20) Similaritie 11.08 (2.73) 11.00 11.50 11.26 0.582 s WAIS (1.71) (3.28) (2.08)

Memory

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First Date Strengths / Major Findings Conclusions Author Published Limitations Poisoned( High Low Control Sig 24) exposed exposed (26) (20) (20) Digit span 3.37 3.90 3.95 3.84 0.938 (forward) (1.13) (1.25) (0.88) (1.22) RAVL * 35.29 40.50 43.95 40.15 0.007 sum trial 1- (7.70) (7.70) (7.07) (7.51) 5 RAVL* 7.08 8.80(2.83 9.10 8.15 0.938 (after (3.10) ) (2.26) (3.05) delay)0.51 5 Logical 10.75 12.50 13.50 12.96 0.515 memory A (3.16) (3.51) (3.81) (2.95) (immediate recall) Logical 9.04 11.00 12.15 11.15 0.755 memory (3.12) (4.15) (4.04) (3.22) (delayed recall) ROFC ** 19.33 22.90 48.30 41.61 0.225 (short (25.24) (26.89) (33.20) (31.06) term) ROFC ** 18.12 22.80 50.25 40.65 0.113 (long term) (25.41) (29.17) (30.71) (30.98) BVRT*** 10.91 11.65 13.00 12.61 0.027 (2.41) (2.32) (0.91) (2.46) *RAVL= Rey Auditory Verbal Learning test. ** ROFC= Rey Osterrieth Figure Complex *** BVRT= Benton Visual Retention Test

Perception

Poisoned( High Low Control Sig 24) exposed exposed (26) (20) (20) Picture 9.45 (2.46 10.75 11.80 completio (2.129) (2.06) n

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First Date Strengths / Major Findings Conclusions Author Published Limitations BVRFT* 27.58 28.35 31.00 ( (4.44) (2.47) Poppelreu 9.91 10.00 ter Test (0.28) (0.00) Stereogn 4.95 5.00 osis (0.20) (0.00) *BVRFT= Benton Visual Recognition Form Test

Language

Poisoned( High Low Control Sig 24) exposed exposed (26) (20) (20) Boston 48.91 51.00 50.75 51.96 0.331 Naming (4.72) (4.61) (5.27) (4.20) Test

Visuomotor

Poisoned( High Low Control Sig 24) exposed exposed (26) (20) (20) *ROCF 37.83 41.90 60.40 65.96 0.015 copy time (27.83) (28.66) (25.32) (25.36) *ROCF 56.29 65.60 77.80 76.42 0.050 quality (33.19) (26.46) (19.46) (22.78) copy Block 8.70 10.85 11.50 11.26 0.031 Design (3.41) (2.08) (3.60) (1.80) Coordinati 1.62 1.85 2.00 1.73 0.349 on (0.49) (0.36) (0.00) (0.45) movemen ts

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First Date Strengths / Major Findings Conclusions Author Published Limitations Rhythm 9.00 10.35 10.14 10.23 0.084 reproducti (2.87) (1.42) (1.49) (1.94) on Altern 1.54 1.70 1.70 1.49 0.737 movemen (0.50) (0.47) (0.47) (0.47) ts * ROCF= Rey Osterrieth Complex Figure

Mood states

Poisoned( High Low Control Sig 24) exposed exposed (26) (20) (20) Beck 7.08 5.55 3.75 5.69 0.356 Depressio (6.44) (6.67) (5.00) (6.13) n Inventory Taylor 19.16 12.60 13.20 13.34 0.002 Anxiety (9.26) (7.68) (6.62) (6.91) Scale

At 3 months after intoxication

Results showed significant difference in some tests for assessment 3 months after poisoning related to memory (Rey Auditory learning test, Benton Visual Retention Test and recall of Rey Osterrieth Figure Complex) but overall domain was not significantly affected (F(24,207=1.11, p0.326). Significant changes in perceptive and visuomotor domains were reported.

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First Date Strengths / Major Findings Conclusions Author Published Limitations Perceptive domain (F(9,222)=2.74, p=0.005); Benton Visual Recognition Form Test, Picture completion Visuomotor domain (F (9,222)=2.31, p=0.003) Block design and quality and time of copy of Rey Osterrieth Complex Figure.

Trend analyses were undertaken to evaluate a dose-response of acute poisoning>high exposure chronic, low exposure chronic>control.

In memory domain the analysis of Rey Auditory Verbal Learning test showed a quadratic rend, and the Benton Visual Retention Test showed a linear trend.

There was also a trend for time taken to copy the Rey Osterrieth Complex Figure acutely poisoned and chronic high exposed subjects required more time to complete the figure. Assessment of quality of copy (visuoperceptive praxis) showed a linear trend. Performance of the Benton Visual Form Discrimination Test showed a linear trend. Block Design showed a linear trend. Taylor Anxiety also showed a linear trend..

Results of the assessment undertaken at 1 year are given below (only data for tests giving statistically significant changes were reported) . The authors did not report the number of subjects with 1 year data in the poisoned exposed and control groups.

Test F Df Sig Picture 2.888 3,72 0.041 (low completion significant (perception) scores in poisoned group) Rey Auditory 5.779 3,72 0.01(low Verbal Learning significant Test scores in poisoned group) Logical memory 9.051 3,72 0.00(low (immediate) significant scores in poisoned group) Logical memory 5.051 3,72 0.003(low (delayed recall) significant scores in poisoned group) Rey-Osterrieth 2.969 3,72 0.037(difference

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First Date Strengths / Major Findings Conclusions Author Published Limitations Figure Test s in poisoned (memory) and high exposed group compared to low exposed and control group) Rey-Osterrieth 2.798 3,72 0.046 Figure Test differences in (quality of copy) poisoned and (visuo motor) high exposed group compared to low exposed and control group) Benton Visual 11.683 3,72 0.000 Form Test differences in (visuo poisoned and motor/memory) high exposed group compared to low exposed and control group)

For acutely poisoned subjects, 1 year after discharge These data showed reduced performance in a test of perception (Picture completion) , tests of memory (Rey-Auditory Verbal learning, Logical memory and Rey-Osterrieth Figure Test, and visuomotor components of tests (Rey-Osterrieth Figure Test and Benton Visual Form Test). At this 1 year evaluation, the previously increased anxiety score was no longer evident.

Spencer 2001 STUDY REPORTS ON GULF WAR VETERANS AND THE KHAMISIYAH MUNITIONS DUMP Too few details No conclusions DETONATION presented to assess regarding OP exposure can be EXPOSURE Khamisiyah veterans were present within a 50km radius of Khamisiyah when the drawn from this munitions dump was detonated. study

HEALTH OUTCOMES Some significant differences (Simple Reaction Time, Oregon Dual

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First Date Strengths / Major Findings Conclusions Author Published Limitations Task, Tapping) reported between Khamisiyah and non- Khamisiyah veterans. Differences in psychological tests (Penn PTSD, Mississippi PTSD, multiple scales of SF36 – a multi-purpose health survey giving physical and mental health summary measures - and Beck Depression scale. However, the authors also reported that statistical differences were found between veterans from different cities and among ethnic groups and that it had not been possible to extract information independent of regional differences.

Interviews were undertaken in October 1998-April 1999 but it wasn’t stated when neurobehavioural testing was undertaken Wesseling 2002 STUDY OF COSTA RICAN BANANA WORKERS WITH A HISTORY OF OP POISONING Strengths Evidence for a Comprehensive mild deficit in EXPOSURE: Poisonings classified as OP related for 54 subjects and carbamate for 24 (23 neurobehavioural Digit-symbol of which were carbofuran). OPs cited were terbufos (18), fenamiphos (6), ethoprophox (6), test battery used (visuomotor test) diazinon (2), carbofuran and chlorpyrifos (1 each). All of poisoned subjects reported reported in poisoning not sufficient to require hospitalisation but needed to seek medical attention Weaknesses individuals with Data presented as evidence of There were no differences between mean temperature adjusted red blood cell combined previous mild cholinesterase levels in poisoned and non-poisoned individuals. The mean value of plasma OP/carbamate cholinesterase cholinesterase levels in workers with recent contact with cholinesterase inhibitors was lower poisoned individuals. poisoning than the mean for workers without recent contact (2.11 U./ml versus 2.26 U/m,l p=0.01). Limited information for OP alone HEALTH OUTCOMES exposure. Possible There were no differences in age or education between the groups. More of the tests for the selection bias non-poisoned group were undertaken in the afternoon (73.1% compared to 46.9% in the poisoned group). More of the poisoned group had loss of consciousness for >1h (8.6% compared to 2.3% in the non-poisoned group).

The authors reported and tabulated data for combined OP and carbamate poisoned individuals. These performed less well than controls in 13 out of the 14 tests administered, but differences were small. The largest deficits were tests of psychomotor and visuomotor functions, language and affect. Poisoned subjects performed less well on Digit symbol and in addition reported more neuropsychiatric symptoms than did non-poisoned workers using Questionnaire 16 and Brief symptom inventory.

Deficits were more clearly seen in data for OP exposed subjects than carbamate exposed subjects. (Data presented graphically)

Deficits were observed in both subjects with or without recent handling of pesticides (3 months) but were more evident in the subset of workers with recent contact with

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First Date Strengths / Major Findings Conclusions Author Published Limitations cholinesterase inhibitors.

Analyses restricted to the subgroup of control workers who had never experienced poisoning symptoms in connection with pesticides yielded results similar to those for all controls.

Data for combined OP/carbamate exposed subjects:

Neurobehavioral Poisoned Non- Crude Regression 95% CI test Mean poisoned Difference coefficient (SD) Mean of means (n=81) (SD) (n=130) Memory Benton visual 6.3 (2.2) 6.9 (2.1) -0.5 -0.4 -1.0,0.2 retention (<0.10) (no.correct) Rey verbal 8.5 (2.9) 8.6 (2.5) -0.1 -0.2 -0.9,0.6 learning (no. after distraction) Attention Digit vigilance (s) 218 (49) 218 (55) 0 -9 -24.7 Digit span 4.2 (1.6) 4.5 (2.0) -0.3 -0.1 -0.7,0.4 (forward) Psychomotor Santana dexterity 53.02 54.7 (8.5) -1.7 -1.3 -3.7,1.2 (both hands) (7.9) Pursuit aiming 60.8 63.3 -2.5 -5.3 -14.2, (no. correct dots) (14.1) (16.4) 3.6 Finger tapping 92.1 94.0 -1.9 -2.4 -6.4,1.7 (both hands) (14.4) (13.2) Mean simple 314 (78) 301 (65) 13 21 (<0.10) -1,43 reaction time (ms) Visuomotor Digit symbol 28.3 30.8 -2.5 -2.7 -5.3, (8.7) (12.0) (<0.10) (<0.05) -0.1 Trails A (s) 82.3 75.5 9.8 7.1 -2.4, (34.31) (31.5) 16.7 Block Design 14.0 15.3 (7.8) -1.2 -1.5 -3.6,0.7 (8.0) Language 26.2 29.2 -3.0 -3.1 -7.4,1.2 Vocabulary (12.9) (16.5) Neuropsychiatric Questionnaire 16 9.1 (4.2) 6.5 (3.8) 2.6 1.7 (<0.05) 0.5,3.0

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First Date Strengths / Major Findings Conclusions Author Published Limitations (no yes answers) (<0.05) Brief Symptom 45.8 26.8(40.7) 19.0 15.7 5.5,25.8 Inventory (grand (25.3) (<0.01) (<0.01) total)

7.A.4. Case series studies Dahlgren 2004 REPORT OF EFFECTS ON FAMILY OF ACUTE EXPOSURE TO DIAZINON Strengths Acute exposure to Neurobehavioural apparently high EXPOSURE On day 8 after the spraying surface samples detected diazinon was widespread deficits found in a levels of diazinon throughout the house, from 0.048 μg/cm2 (base of child’s toy and back of two legs of plastic number of individuals are associated chair) to 9.932 μg/cm2 (playroom by closet). On day 24 0.2 μg/cm2 (hockey equipment in with acute exposure with chronic garage) to 1.1 μg/cm2 (child’s room toy in bedroom). Air samples on day 23 were up to 10 to apparently high neurobehavioural μg/m3 in playroom. Samples from 2nd laboratory on day 24 reported up to 18.3 μg/m3. Bulk concentrations of deficits samples reported detectable levels of diazinon at 6.5 months post spraying ( e.g. sofa material diazinon at 3 years from family room near kitchen, near floor 4.72 mg/kg, and toy from floor of child’s room near after exposure. garage 1.55 mg/kg). Limitations HEALTH OUTCOMES Patients 1 and 6 returned 4h post application of diazinon. Patient 6 Although detailed crawled on treated surfaces whilst they were wet. Patient 1 attempted to mop up excess, but surface and air splashed her legs and arms (felt a burning sensation). Patient 6 experienced rhinitis, sampling was lacrimation, severe headaches, muscle pain and erythema on face. Patients 3,4,5 returned undertaken it is not home 5h after diazinon application. Patients 3 and 4 had acute headaches, patient 4 repeated clear what levels of vomiting. Patient 2 came home later that evening. The next evening patient 2 played hockey exposure were using contaminated uniform and experienced vomiting, nausea, coughing, dizziness and experienced or when headache. The family evacuated the home and didn’t return for 11 months. the family actually left the house. The family were assessed at the clinic in August 1999. Patient 1 (mother aged 37 y) had The study relates to persisting fatigue, insomnia, and decreased short-term memory. Patient 2 (father aged 39y) indoor application of had continuing acute symptoms and also insomnia, lack of concentration, decreased short- a pesticide, where term memory, difficulty driving, mood swings and depression. Patient 3 (11y female) had exposure might be persistent severe headaches, patient 4 (8y female) had intermittent erythema . Patient 5 (6 y considered to be male) had headaches, decreased concentration and memory. Patient 6 (1 y male) had more intense and erythema, skin rash and lacrimatory conjunctivitis. prolonged than in outdoor applications The family returned in August 2002 and underwent neuropsychological testing. because of the confined space, and Patient 1 reported decreased concentration and short-term memory. Testing revealed the possibility that prolonged choice reaction time. Tests revealed cognitive disorder, psychomotor and residues remain

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First Date Strengths / Major Findings Conclusions Author Published Limitations functioning impairment. A clinical diagnosis of toxic encephalopathy was reported. contained within the house Patient 2 had blurred vision, rhinitis, headache, insomnia, lack of concentration, decreased short-term memory, driving confusion, mood swings. Testing revealed cognitive disorder, psychomotor dysfunction and functional impairment.

Patient 3 (now 14 y) had experienced a complex partial seizure in March 2002. She had developmental delay (e.g delayed menarche and bone development). Neurological testing revealed abnormal colour vision, prolonged sway speed, prolonged Trails A and B. Tests revealed cognitive disorder, word-finding anomia, left-sided auditory imperception, proactive imperceptions in verbal learning, and relative weakness in visual discrimination of complex stimuli.

Patient 4 had decreased memory, headaches, mood swings and skin rash. Testing revealed abnormal colour discrimination, prolonged simple and choice reaction times, prolonged sway speed, prolonged pegboard, prolonged Trails A and B and abnormal perimetry. The results revealed cognitive disorder, oromotor-sequencing dysfunction, word-finding anomia, left-sided auditory imperception, and mild astereognosis.(astereognosis is the inability to identify an object or discriminate between objects by touch without visual input). Patient 5 has continuous symptoms of headaches. Testing revealed abnormal colour discrimination, prolonged simple and choice reaction times, prolonged sway speed, prolonged peg board time, prolonged Trails A and B times, and abnormal right eye perimetry. The tests revealed cognitive disorder, psychomotor and sensorimotor functioning impairment, and oromotor sequencing dysfunction.

Patient 6 (now 4y old) had continuing symptoms of erythematory pinpoint macules on the skin around his left eye and white spots on cheeks where the red rash of pesticide exposure occurred. He did not undergo neurological testing. Neuropsychological evaluation revealed cognitive disorder, oromotor sequencing dysfunction, and attention/executive dysfunction.

Patient 7 was exposed in-utero and was aged 2 at assessment. He had delays in sensory processing, mainly proprioception, and was slow to speak. At 23 months of age he was identified as having a severe expressive communication developmental disability. At 36 months of age neuropsychological tests identified a severe expressive language disorder, oromotor sequencing disorder, articulation disorder, and a range of mild cognitive impairments.

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First Date Strengths / Major Findings Conclusions Author Published Limitations Results of neuropsychological testing are given below (100= normal. Percent predicted values in excess of 100 indicate abnormal values):

Patient Color Reaction Reaction Balance Balance vision time time test test simple Choice Eyes Eyed open closed Patient 89 106 130 100 115 1 Patient 115 117 91 70 84 2 Patient 132 111 103 122 119 3 Patient 133 135 185 127 117 4 Patient 152 192 158 137 133 5 Mean 124 132 133 111 113

Patient Pegboard Pegboard Trails Trails Right peg Left peg A B Patient1 94 94 116 106 Patient2 97 100 99 83 Patient3 96 98 120 129 Patient4 119 139 131 124 Patient5 141 146 119 138 Mean 110 115 93 116

7.A.5. Case reports Loh 2010 REPORT ON SEARGANT EXPOSED TO SARIN AFTER HANDLING EXPLOSIVE DEVICE Strengths Authors report IN IRAQ Comprehensive reduced psychological information EXPOSURE 3 to 5ml of sarin were identified in the explosive device handled by the seargant. testing. processing speed,

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First Date Strengths / Major Findings Conclusions Author Published Limitations poor focused and HEALTH OUTCOMES Acute symptoms included confusion, dyspnea, blurred vision and Limitations divided attention. severe headache. Following exposure RBC-ChE was 39% of pre-deployment level. The unit Single case report Difficulty in returned to the USA after 3 months. He experienced progressively worsening short-term speeded bilateral memory loss, dys-coordination, episodic imbalance. On clinical examination at 8 months, he manual motor complained of these symptoms. Short-term memory loss consisted of mostly names and coordination. tasks. He had not experienced weakness, numbness or tingling. He also complained of post- Patient did not exertional headaches. He denied alcohol, tobacco or illicit drug use. He admitted to some have subjective difficulty with sleep but denied mood changes, lability, irritability or personality changes. complaints of PTSD. On physical examination he was well developed, well nourished and in no acute distress. Vitals were stable. On neurological examination he was fully orientated and language was Overall authors normal. He had difficulties with rapid alternative finger tapping and recall (e.g. digit sequences, considered that words beginning with the letter F). There were no effects on biochemistry, haematology, causal relationship toxicology, MRI of brain/spine, electromyography/nerve conduction, or PET. between sarin exposure and Neuropsychological testing revealed a mild cluster of impairments subtle deficits could not be Reduced speed of information processing (WAIS-III, Processing speed index score 86). substantiated Poor focused and divided attention (Auditory Consonant Triagrams ACT 18" and 36" (scores 38 and 34)) and Trial 1 of the Californian Verbal Learning test (CVLT) (score 4). Difficulty in speeded bilateral manual motor coordination (grooved pegboard test) (32 (R ), 29 (L).

His problem-solving, mental flexibility, naming, new learning, recall, visuoperceptual integration were normal. He showed delays on timed tasks that require rapid mental processing of information. Certain aspects of attention were affected, with greatest impairment on divided attention tasks.

Minnesota Mulitphasic Personality Inventory did not reveal the presence of emotional distress or any significant mood, anxiety or thought disorder. B. Chronic Low-Level Exposure 7.B.1. Cohort studies Albers 20004b PROPSECTIVE COHORT STUDY OF CHEMICAL WORKERS ENGAGED IN Strengths No evidence of MANUFACTURE OF CHLORPYRIFOS Prospective design neuropsychologic with good al abnormalities in EXPOSURE Historical personal air sampling data. Historic cumulative chlorpyrifos exposure assessment of chlorpyrifos calculated. Chlorpyrifos workers had significantly longer duration of working with chlorpyrifos historical chlorpyrifos exposed workers

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First Date Strengths / Major Findings Conclusions Author Published Limitations than sarin referent workers (9.72 vs 0.10 years; P<0.0001) Historic cumulative exposure was exposure. but extent of also greater in chlorpyrifos workers (64.16 vs 0.69 mg/m3*days: P<0.0001)Chlorpyrifos assessment very exposure during the 1 year follow-up period was also assessed by urinary excretion of 3,5,6 Limitations; Extent of limited. trichloro-2-pyridinol (TCP a metabolite of chlorpyrifos) (4 overnight collections), BuChE neuropsychology (monthly) and AChE (at start and second examination). These measures showed significant assessment very differences in exposure between the chlorpyrifos worker group and referents. limited. TCP/Cr 192.2 vs 6.2 ug/g P<0.0001. The authors calculated a daily exposure of 576-627 ug/day (approximately 30% of that received by a typical worker exposed at the permissible limit of 200 ug/m3 Average BuChE 7155 vs 8183 mu/ml P<0.01) (ratio of lowest BuChE activity during the year to pre-exposure or baseline level (0.75 vs 0.88 P=0.0008. AChE levels were similar between groups aty baseline (6923 vs 6966 mu/ml P=0.77) and second examination (7149 vs 7253; P=0.48)

HEALTH OUTCOMES: There were no significant differences between chlorpyrifos exposed and referents in response to questions (compared to 10 years ago) at either baseline or at the second examination (1 year later)

Questions included

Statement( Baseline Baseline P-value Second Second P-value compared CPF Referent CPF Referent to 10 years (Mean Mean (Mean Mean ago) (SD) (SD) (SD (SD) My memory 3.1 (1.1) 3.1 (1.0) 0.90 3.1 (1.0) 3.1 (1.0) 0.11 is as good My reading 3.9 (1.0) 3.9 (0.8) >0.99 3.9 (0.9) 4.0 (0.9) 0.52 skills are as good I have more 2.6 (1.1) 2.4 (1.0) 0.30 2.5 (1.0) 2.5 (1.1) 0.77 trouble staying focused My problem 2.3 (0.9) 2.1 (0.8) 0.25 2.1 (0.7) 2.3 (1.0) 0.28 solving skills are not as good.

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First Date Strengths / Major Findings Conclusions Author Published Limitations Likert scale 1= strongly agree, 2=agree, 3=not sure, 4=disagree, 5=strongly disagree.

No difference in MMSE scores were reported.

MMSE Baseline Baseline P-value Second Second P-value CPF No referent CPF No Referent No No Orientatio 0 0 0 0 n (>2 errors) Attention/c 4 6 0.75 2 8 0.10 alculation (≥2 errors) Recall (>2 0 0 0 2 0.23 errors) Language 0 0 0 0 (>2 errors) MMSE 0 0 0 0 score <24

My memory is goo Finkelstein 2010 PRELIMINARY DETAILS OF COHORT STUDY OF ISRAELI SUBJECTS EXPOSED TO OPs Strengths: No conclusions Retrospective cohort can be reached EXPOSURE Not stated. design regarding this Limitations: Too few study. HEALTH OUTCOMES: Authors report impaired performance in Trails B and Digit Symbol. details reported to Details of results not presented. make any assessment.

Starks 2012a STUDY OF NEUROBEAVIOURAL TESTS IN SUBJECTS FROM AGRICULTURAL HEALTH Strengths No consistent STUDY Prospective design evidence for an with good adverse effect of EXPOSURE: Frequency and cumulative use of OPs are given below. Ever use ranged from characterisation of OP exposure on 77% for malathion to <10% for dimethoate, tebupirimfos and tetrachlorvinphos. specific OP pesticide neurobehavioural use patterns test performance Pesticides Number % Mean SD (Authors report that (ever used) cumulative (cumulative) other studies have OPs demonstrated that

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First Date Strengths / Major Findings Conclusions Author Published Limitations Acephate 166 24 85 90 AHS participants Chlorpyrifos 418 60 75 103 provide accurate and Coumaphos 94 13 74 245 reliable information Diazinon 302 43 55 93 on pesticide use) Dichlorvos 128 18 443 1064 Diemthoate 66 9 46 68 Quantitative Disulfoton 110 16 43 42 measure of NB test Ethorprop 121 17 45 50 function Fonofos 201 29 64 84 Limitations Malathion 541 77 99 201 Highly selected Parathion 147 21 103 272 sample ( subjects Phorate 230 33 70 130 had to complete all Phosmet 101 14 61 83 AHS questionnaires) Tebupirimph 69 10 51 46 and average age of os study population was Terbufos 356 51 101 116 older than other Tetrachlorvi 69 10 65 99 studies. nphos (Authors report that Summary participants were All OPs 682 97 420 663 similar to non- All 700 100 1604 1617 participants in age pesticides and total life-time days ofpesticide Lifetime days of all Ops and lifetime days of all pesticides were similar between Iowa and use). North Carolina. Authors report that Demographics study didn’t capture Briefly among 701 participants, 51% from Iowa, 49% from North Carolina (NC) the full range of OP Mean age was 61 years (SD 12years), and approximately half reported completing more than exposures as sample a high school education. At the most recent AHS interview 78% (542) participants were still sites were limited. applying pesticides, 69% (484) were still farming. Over 20% reported past head injury with or without loss of consciousness and eight (1%) reported previous physician-diagnosed pesticide poisoning)

HEALTH OUTCOMES

NB test data were available for between 671-699 subjects depending on test.

The authors reported that specific pesticides were associated some NB tests. Lifetime days of

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First Date Strengths / Major Findings Conclusions Author Published Limitations all OP use was not significantly associated in either direction with any NB test. Ever-use of ethoprop and life-time days of malathion were associated with poorer performance of the digit symbol test. Ever use of disulfoton, ethoprop and terbufos were significantly associated with poorer performance on Sequence A test. In contract better test performance was reported for three Auditory Verbal learning tests for chlorpyrifos, coumaphos, parathion, phorate and tetrachlorvinphos. Coumaphos was associated with better performance on a test of motor speed and visual scanning and parathion was associated with better performance on a test of sustained attention.

A significant pesticide state by pesticide interaction suggesting differential effects for chlorpyrifos (significantly lower score Digit symbol in Iowa compared to NC), coumaphos (Improved score AVLT recognition in NC compared to Iowa) and malathion (improved score Groove pegboard in Iowa compared to NC)

Only the statistically significant regression coefficients (P≤0.05) are reported below

EVER USED OP PESTICIDES (Significant changes. Total of 144 OP results reported in published paper)

Test Significant results (regression coefficient β and SE) Continuous performance (692)* No significant changes Digit Symbol (691)* Ethoprop (-3.66 SE1.84) Finger Tapping dominant No significant changes Grooved pegboard (699)* Chlorpyrifos (3.47, SE 1.53) (Improved performance) Auditory Verbal learning Test Coumaphos (1.25, SE 0.48) (AVLT) (total recall) (696) (improved performance.) Tetrachlorvinphos (1.24, SE 0.55) (Improved performance) Ethoprop (-0.86, SE 0.44) AVLT (delayed recall)(695) No significant changes AVLT (recognition)(694) No significant changes Sequences A* Disulfoton (-2.55, SE 1.31) Ethoprop (-3.27, SE 1.25) Terbufos (-1.74, SE 0.90) Sequences B* No significant changes * Regression coefficients multiplied by -1 so that lower scores indicate poorer performance

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First Date Strengths / Major Findings Conclusions Author Published Limitations

CUMULATIVE LIFETTIME DAYS OF OP PESTICIDE USE (Significant changes. Total of 144 OP specific results reported in published paper and 9 results for total OP exposure)

Test Significant results (regression coefficient β and SE) Continuous performance (692)* Parathion (4.65, SE 2.32) (Improved performance Digit Symbol (691)* Malathion (-1.75, SE0.75) Finger Tapping dominant No significant changes Grooved pegboard (699)* No significant changes Auditory Verbal learning Test Coumaphos (0.82, SE 0.34) (AVLT) (total recall) (696) (improved performance) AVLT (delayed recall)(695) Chlorpyrifos (0.22, SE 0.11) (improved performance) AVLT (recognition)(694) Phorate (0.25, SE 0.12) (improved performance) Sequences A* Ethoprop (-1.65 , SE 0.81) Sequences B* Coumaphos (3.05, SE 1.28) (improved performance)

Regression coefficients multiplied by -1 so that lower scores indicate poorer performance *

The authors reported that simultaneous inclusion of correlated pesticides in the models did not attenuate any statistically significant associations between pesticide exposures and NB outcome measures.

No difference in results occurred when 57 participants with medical conditions or medications which may influence NB test performance were excluded. When 8 individuals with a history of diagnosed pesticide poisoning were removed from the analyses, the parameter estimate of the association between ever ethoprop use and Digit-Symbol test performance was reduced from - 3.66 (p=0.05) to -3.19 (p=0.09). 7.B.2. Case-control studies Jamal 2002a UK STUDY OF SHEEP FARMERS WHO UNDERWENT NEUROLOGICAL ASSESSMENT Not possible to No conclusions No results were detailed in this publication assess the can be reached The authors report significant changes in neuropsychological test results, particularly for sheep neuropsychological farmers with probable/definite peripheral neuropathy, which inferred greater investigations anxiety/depression. reported in this

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First Date Strengths / Major Findings Conclusions Author Published Limitations publication 7.B.3. Cross-sectional studies Abdel 2008 STUDY OF ADOLESCENT EGYPTIAN COTTON FIELD SPRAYERS EXPOSED TO OPs Strengths Adolescents who Rasoul AND OTHER PESTICIDES Comprehensive apply OPs in battery of cotton fields show EXPOSURE Four pesticide application cycles (5-11 days), two of which involved Chlorpyrifos neuropsychological neurobehavioural applications using 20L backpack sprayers. There was approximately one week between spray tests. deficits.(Authors periods. The other pesticides used were Bacillus thuringiensis and pyrethrins (or other Exposure suggest that both carboxylate). Spray cycle had been used for 10 years. Children did not mix pesticides. PPE demonstrated by applicators and was not commonly used. serum AChE controls worked measurement. long hours in hot HEALTH OUTCOMES There were no significant differences between applicators and controls Limitations humid conditions regarding smoking, age, years education. BMI of older control subjects (16-19y) was Exposure not limited and thus work significantly higher than applicators (26.9±4.1 controls, compared to 23.2±0.6 applicators). For to OPs; conditions were the older group mean days worked in season was 21.4±6.7, and years worked 7.2±1.5. A applicators also unlikely to be significantly lowered serum AChE was reported for applicators (combined age groups). exposed to Bacillus responsible for thuringiensis and the observed Significantly reduced neurobehavioural performance was reported for all tests administered in pyrethrins (or other results. Authors the 16-19y group: carboxylate). report findings Serum AChE similar to those Test B- 95% CI p-value Effect size measurement at only reported in adult coefficient corrected one time point. cotton workers) Information -1.8 -3.0 to-0.6 0.005 0.1 Many results Arithmetic -3.6 -4.7 to -2.5 <0.001 0.2 reported as Similarities -3.0 -3.6 to -2.4 <0.001 0.4 combined BVRT -1.7 -2.2 to -1.2 <0.001 0.2 child/adolescent Digit Span -1.9 -2.3 to -1.6 <0.001 1.0 exposure group (Forward) Digit Span -2.0 -2.5 to -1.5 <0.001 1.0 (Backward) Digit Span -3.7 -4.5 to -3.0 <0.001 0.5 (Total) Block -7.7 -9.6 to -5.8 <0.001 0.1 Design Digit -8.4 -10.5 to -6.2 <0.001 0.4 Symbol Trail Making 6.3 4.1-8.6 <0.001 0.3 A

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First Date Strengths / Major Findings Conclusions Author Published Limitations Trail Making 6.8 3.5-10.1 <0.001 0.1 B

Effect size from 0.1-1.0 Applicators (16-19y) scored higher than controls on neuroticism and extraversion scales.

A number of analyses were reported for the whole applicator group (i.e. combined younger and older children 9-19 y):

A significant correlation between days worked during the season was reported for 6/11 measures (Information, Arithmetic, Similarities, BVRT, Block Design and Trail Making B). A significant correlation between years worked and 3/11 indices was reported (Similarities, Block Design, Trail Making B). A significant correlation was reported between serum AChE and 5/11 measures (Information, Digit Span Forward, Backward and Total, and Trail Making B). Analyses controlled for age.

Significantly more neurological symptoms were reported in applicators (including difficulty in concentration, trouble remembering, feeling depressed/irritable). Applicators scored higher for neuroticism and extraversion. Neurological symptoms were also correlated with days worked and years worked Bayrami M 2012 STUDY OF 40 HORTICULTURE FARMERS, IRAN Strengths No evidence for neuropsychological effects of OP EXPOSURE: The plasma AChE (KU/L) was lower in farmers compared to controls testing in subjects exposure on (35.73±4.89 in control and 31.24±7.11 in exposed P=0.001) with exposure to cognitive function, anticholinesterases but assessment HEALTH OUTCOMES; agents. method limited.

There were no differences between exposed and controls regarding subscales of the MMSE. Limitations, selection process not reported. MMSE indice Controls Farmers P value Small size. Exposure Orientation 8±2.39 7.94±2.03 0.91 data not gathered. Registration 2.81±0.65 2.91±0.29 0.42 Attention/calculat 3.1±0.88 3.33±1.88 0.52 ion Recall 1.32±1.28 1.58±1.15 0.406 Language 7.06±1.86 7.12±1.75 0.9 Total 22.19±6.36 23.73±5.3 0.72

Bazylewicz- 1999 STUDY OF 26 POLISH WOMEN WORKING IN GREENHOUSES Strengths Chronic Walczak Neuropsychology, occupational

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First Date Strengths / Major Findings Conclusions Author Published Limitations EXPOSURE data reported as total OPs (combined dermal/respiratory exposure) on days 1-6 profile of exposure to after the restriction period ,a period of 1-3 days after spraying of pesticides when workers may mood/emotion and pesticides not enter the sprayed area. Most frequently used compounds were Dichlorvos, subjective symptoms including a Methamidophos, Methidathion and Pirimiphos-Methyl. Additional exposures to carbamates, assessed both pre number of OPs is synthetic pyrethroids and dithiocarbamates Exposure was seasonal, each worker being in and post-spray associated with contact with OPs for approximately 7-46 days. There were cycles of 4-7 days of spraying with season. reduced aninterval of approximately 3 days between spray applications. The daily cumulative exposure Inhalation and perceptual-motor (combined inhalation/dermal) on 6 consecutive days after the restriction period was between dermal exposure to functioning. 0.001-0.009 % of the toxic dose (based on dermal LD50s). The duration of spraying varied OPs reported. However between 1-24 years (mean 11.9y SD 6.8y). Exposed- reference evidence is groups matched for insufficient to HEALTH OUTCOMES NCTB results were obtained pre- and post-season to assess the effect age, education draw a definite of one season. Apart from errors in the Aiming test, there was no deterioration in cognitive and (years schooling), conclusion psychomotor function or in emotional states or subjective symptoms over one season. Some smoking, alcohol tests showed improvement (Digit symbol, Digit Span, Santa Ana Dexterity) over one season consumption and Significant improvement in mood scales (tension, depression, confusion) was also reported use of drugs over one season. Limitations The only increased subjective symptoms were fatigue and gastric symptoms but these were Small size. not statistically significant. There was a decrease in other symptoms between pre- and post spray season assessments. No investigation of The between group analyses (exposed compared to reference group (cumulative exposure) dose-response or found a significant slow-down of perceptual-motor functions (simple reaction time- fastest p = duration of exposure 0.04 ) and lower hand movement efficiency (Aiming errors p=0.02). Exposed women had a higher degree of anxiety, anger, depression and fatigue-inertia. They also reported more complaints relating to ‘absent-mindedness’ Exposed women reported more neurological symptoms (central but not specified) than controls. No effects between groups for Digit Symbol, Digit Span (forward), Santa Ana dominant and non dominant. Exposed subjects reported more subjective symptoms (fatigue and gastrointestinal) in the second assessment while controls reported more complaints in the first assessment

Exposed Exposed Control Control pre-season post – Pre-season Post-season Mean 26 season Mean 25 Mean 25 Mean 26 Simple 290.15±48.0 288.81±43.9 275.64±33.3 268.68±25.2 reaction 0 7 3 0 time-mean Simple 211.08±31.9 209.54±22.4 198.00±29.2 190.80±32.0 reaction 8 8 2 9

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First Date Strengths / Major Findings Conclusions Author Published Limitations time- Fastest Digit symbol 45.50±11.02 49.69±10.50 49.40±8.73 52.72±11.58 (WAIS) Digit span- 4.92±0.89 5.27±1.15 5.08±0.81 5.20±0.76 forward Digit span- 3.69±1.12 3.88±0.95 4.00±0.76 4.19±0.80 backward Benton 8.50±1.50 8.69±1.22 9.24±1.16 8.88±1.20 visual retention Santa ana- 39.73±5.78 41.00±5.19 38.24±4.91 41.12±5.96 dominant Santa ana- 37.85±5.20 39.42±5.21 37.04±4.81 37.96±4.49 non- dominant Aiming- 234.54±32.9 234.96±33.1 245.12±35.3 240.32±45.4 correct dots 4 8 9 1 Aiming- 2.77±3.36 4.35±5.43 7,64±9.80 9.96±9.25 errors Aiming- total 237.31±33.1 239.31±32.7 256.76±43.7 254.28±43.7 dots 6 3 2 3

Browne 2006 STUDY OF NEUROPSYCHOLOGICAL EFFECTS OF OPs IN INDIVIDUALS LIVING NEAR Strengths Authors TO FIELDS, SOME OF WHOM WERE ALSO AGRICULTURAL WORKERS Neuropsychological considered that evaluations of a the specific EXPOSURE Exposure to cholinesterase inhibitors confirmed at all distances from the field population with finding of where spraying occurred. OPs routinely used included fenitrothion, chlorpyrifos, confirmed exposure deficiencies in monocrotophos, ethion and azinphos-methyl) to cholinesterase visual recall was inhibitors suggestive of an Biochemistry data were available for 30 subjects in the exposed group (including 10 effect of agricultural workers). Serum AChE was lower in exposed (41% of control, P<0.001) Limitations cholinesterase Paraoxonase and arylesterase were significantly higher in exposed (447% and 441% of Levels of exposure inhibitors on contro,l P<0.001) were likely to be performance substantially different HEALTH OUTCOMES ANOVA for immediate memory was nearly significantly altered for between residents exposed (P=0.056) and was significant for delayed memory (P<0.05) of the Weschler Memory and agricultural

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First Date Strengths / Major Findings Conclusions Author Published Limitations scale (visual reproduction-delayed) workers but information on dose Visual memory Exposed (%tile Control (%tile and duration not score) score) presented. Immediate 28.56±17.6 36.13±20.7 Differences in Delayed 25.04±12.6 37.43± 23.7 performance of neuropsychological Data for most neuropsychological tests performed were not reported. Negative results were tests between these reported for Tower of Hanoi, Serial Reaction Time, Continuous performance, Digit Span, Rey two groups were not Auditory learning. investigated Farahat 2003 STUDY EXAMINES EXPOSURE OF EGYPTIAN COTTON WORKERS TO OPs Strengths Evidence that Comprehensive pesticide EXPOSURE Cotton fields regularly treated (ca. every 15 days) from early June to early neuropsychological exposure September with OPs (profenofos, chlorpyrifos, triazaphos and phorate) and a range of other evaluation of group including OPs pesticides (carbaryl, thiodicarb, esfenvalerate, flufenoxuron, chlorfuazuron, hexaflumuron and of agricultural was associated Bacillus thuringiensis workers with with effects on Pesticides applied as mixtures of one to three of OPs, carbamates, pyrethroids. Spraying by exposure to OPs visuo motor knapsack or tractor. Applicators were seasonal workers. .Also present in fields were speed, and verbal agricultural engineers, assistants, whose main route of exposure was inhalation, and mixers, Limitations abstraction, whose main route was dermal and inhalation. Mechanics were exposed by inhalation, skin Exposure not attention and contact and occasionally though ingestion when they were repairing old machines. measured. memory. However Exposure would effects were not HEALTH OUTCOMES There were no statistical differences between exposed and referent have been to a wide correlated with groups regarding age, duration of working, degree of education, BMI, smoking or coffee/tea range of pesticide acetylcholinestera intake. active ingredients se level but were correlated with Mean serum AChE was lower in exposed compared to control (exposed 87.34 U/ml, control duration of work 108.25 U/ml, p=0.0001). Multiple regression showed that serum AChE was associated with duration of exposure (β = -21.34, SE 3.94, 95%CI -29.18 to – 13.50), but not with age, education or BMI.

After adjustment for confounders and multiplicity, performance of the exposed was significantly lower on Similarities, Digit Symbol, Trailmaking part A and B, Letter Cancel, Digit Span Forward and Backward, and Benton Visual Retention test (BVRT).

Neurobeh Control Exposed Holm 95% CI avioural Mean Mean adjusted for Test (SEM) (SEM) p value difference Similaritie 10.91 9.68 0.003 -1.88 to

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First Date Strengths / Major Findings Conclusions Author Published Limitations s (0.23) (0.24) -0.57 Digit 27.19 23.85 0.001 -4.97 to Symbol (0.60) (0.62) -1.72 Trailmaki 56.43 60.02 0.030 1.15 to ng A (0.90) (0.93) 6.02 Trailmaki 113.18 119.97 0.015 2.58 to ng B (1.56) (1.61) 11.01 Block 22.41 20.68 0.124 -3.39 to Design (0.61) (0.64) -0.07 PASAT 19.65 19.40 0.568 -0.69 to (0.16) (0.17) 0.20 Letter 2.83 3.52 0.037 0.19 to Cancel (0.18) (0.19) 1.18 Digit 4.87 4.38 0.037 -0.84 to Span (0.13) (0.13) -0.14 Forward Digit 3.64 3.09 0.003 -0.84 to Span (0.10) (0.10) -0.28 Backward BVRT 5.48 4.82 0.003 -1.01 to (0.13) (0.13) -0.31 Story 17.93 17.76 0.570 -0.76 to recall A (0.22) (0.22) 0.42 Story 3.09 2.76 0.052 -0.59 to recall B (0.10) (0.10) -0.07

In the Eysenck Personality Questionnaire mean neuroticism was significantly higher in exposed compared to control (9.90 (1.6) exposed compared to 9.24 (1.61) in control (p=0.01). Symptoms of dizziness (27% exposed, 4% control, p=0.008) and numbness (25% exposed, 2% control, p=0.003) were significantly higher in exposed compared to controls.

Most of the reported neurological symptoms and signs were significantly higher in older workers with the greatest duration of exposure. Serum AChE showed no significant differences between those with positive or negative neurological symptoms and signs Keifer 2000 US STUDY OF A SEASON OF EXPOSURE IN APPLE ORCHARD THINNERS Strengths: The authors Prospective design consider that no EXPOSURE Coefficients for exposures and confounders for first year results and changes in Application of Core consistent effect results from first to second year were reported. The authors reported that the number of hours Neurobehavioural of a season of thinning in 1994 had a clear effect on cholinesterase activity (type of cholinesterase not Test Battery. thinning on

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First Date Strengths / Major Findings Conclusions Author Published Limitations reported). neurobehavioural Included estimates of parameters was HEALTH OUTCOMES The authors grouped tests into those affected by Peabody Vocabulary potential found. They score and those not affected. confounders in believe that the analyses. results of their With regard to tests not affected by Peabody score, the effects of the previous seasons Authors report that study suggest thinning (difference between 2nd and 1st year) was significant for the Santa Ana pegboard (non work history low-level, non- dominant hand) test, which is a measure of rapidity of motor skills. The authors note there questionnaire intoxicating were no effects on other tests of motor function. probably under- exposure to OP estimated potential pesticides does Results (coefficients for effect in multilinear regression) of first year tests and changes from first exposure. not have a to second year (∆ values) are shown in the table below. Tests used are those where previous significant impact education is unlikely to affect outcome Limitations on Small size with 47 neurobehavioural individuals lost to 2nd parameters Thinning hours Pre P val e for year follow-up. 1994 199 (thinning model seasons) No assessment of Vibration (hand) -0.07 -0.06 0.58 multiple comparisons Vibration (foot) 0.07 -0.05 0.53 Santa Ana -0.21 -0.07 0.23 (dominant) Santa Ana (non- -0.25 -0.21 0.23 dominant) ∆ Vibration 0.21 0.05 0.67 (hand) ∆ Vibration foot 0.27 0.08 0.1 ∆Santa Ana -0. 6 0.16 0.31 dominant ∆Santa Ana 0.09 -0.26 0.02 (non-dominant) (P<0.05) ∆Reaction time -0.00 0.11 0.88 Acetylcholineste -0.18 Not avai able 0.00 rase yr1 (type (p<0.05) not stated) Model includes gender, age, haemoglobin, thinning hours’94 and seasons thinning.

With regard to tests affected by Peabody score, past seasons of thinning was predictive of performance in Trails A and Digit span (backward) but not in other tests.

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First Date Strengths / Major Findings Conclusions Author Published Limitations

Coefficients for effect in multilinear regression for first year results and changes in results from first to second year (∆ values) are shown in the table below. These are tests where previous education probably affects outcome

Peabody Thinning Pre 1994 P value for score hours in 94 t inning model seasons Trails A -0.59* 0.11 -0.26 <0.00 (P<0.0 ) Digit symbol 0.64* -0.10 -0.18 <0.00 Reaction -0.32* -0.18 -0.08 0.05 time Pursuit 0.48* -0.16 0.22 0.00 aiming (good) Paired 0.18 0.08 -0.14 0.22 associations tough Paired 0.28* 0.21 -0.21` 0.08 associations easy Digit span 0.18 -0.11 -0.13 0.04 forward Digit span 0.57* -0.07 0.24 0.01 backward Block 0.54* -0.01 -0.02 0.01 design Benton 0.46* -0.06 -0.11 0.00 ∆Trails 0.42* 0.23 0.12 0.06 ∆Symbol -0.00 -0.15 0.10 0.09 digit forward ∆Pursuit -0.34* 0.04 0.27 0.19 aiming (good) ∆Paired -0.18 0.12 0.06 0.62 associations tough Paired -0.10 0.00 0.23 0.52

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First Date Strengths / Major Findings Conclusions Author Published Limitations associations easy ∆Digit span 0.01 -0.06 0.18 0.93 forward ∆Digit span 0.03 0.17 -0.35 0.38 backward (P<0.05) ∆Block -0.12 0.08 -0.01 0.97 design ∆Benton -0.15 0.01 0.10 0.76 Model includes gender, age, haemoglobin, Peabody Picture Vocabulary score, thinning hours 94 and seasons thinning. * P<0.05

The authors report that paraoxonase, chlorpyrifos oxonase and diazinon oxonase did not affect these analyses. Kilburn 1999 STUDY OF SUBJECTS EXPOSED TO CHLORPYRIFOS Strengths Impaired Comprehensive psychological EXPOSURE For the 22 chlorpyrifos-exposed subjects studied, no direct measure of exposure neurobehavioural functioning was available. Chlorpyrifos levels in clothing for patients 21 and 22 had 0.21-0.4 μg/ft2 and evaluation (cognitive, rugs for patients 12 and 13 had 23.7-125 μg/ft2 and 193-197 μg/ft2. perceptual motor Limitations speed, recall and There was no difference in mean age between exposed (47.7±13.0) and referents (46.6±20.6). Patients were either long term The mean educational level was higher in exposed (15.3±3.1 y exposed, 12.9±2.3 y referents, self-referred or memory) in a P<0.0001). attorney referred. All group of patients attributed their with documented HEALTH OUTCOMES Results of neurobehavioural tests are shown in the table below. Mean symptoms to but variable percentage of predicted (adjusted) and SD assessed by analysis of variance chlorpyrifos. exposure and Exposure not exposure duration Exposed (n=22) Unexposed(n=2 P value measured and to chlorpyrifos Mean SD 64) assumed to be low. Mean SD Exposure duration Simple reaction 105.8±66.5 99.9±23.7 0.0001 varied considerably time between patients Choice reaction 104.6±65.1 100.0±12.5 0.0001 and was not time considered in the Cognitive analyses Culture Fair A 85.4±30.2 101.2±20.0 0.004 Digit symbol 83.5±23.6 103.8±18.8 0.0001 Vocabulary 87.2±31.1 99.2±30.8 0.047

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First Date Strengths / Major Findings Conclusions Author Published Limitations Perceptual motor speed Pegboard 86.6±23.3 101.8±25.7 0.009 Trails A 107.6±11.7 100.3±8.3 0.0002 Trails B 105.8±6.1 100.4±7.5 0.0015 Recall Story immediate 73.5±22.9 99.8±31.1 0.0002 Story delayed 68.5±36.6 99.9±41.3 0.041 Finger writing errors Right 102.1±9.1 100.0±7.5 0.296 Left 104.3±9.3 100.0±7.8 0.040 Long-term memory Information 75.4±39.5 101.5±39.4 0.005 Picture 79.1±38.0 99.3±32.2 0.011 completion Similarities 102.5±33.9 98.1±41.2 0.637 Profile of mood states Mean score 89.7±36.6 21.0±31.6 0.0001 Depression 15.3±3.4 12.9±2.3 0.0002 mean score

No patient had elevated alcohol. Only the agricultural worker had evidence of acute exposure to OPs. Half of the exposed had evidence of peripheral neuropathy.

Impaired balance and simple/choice reaction times were reported along with reduced grip strength, colour discrimination, visual field performance in both eyes. Hearing was diminished in 4 patients.

Testing revealed a perceptual motor function impairment (peg board, Trails A and B were all decreased). There were finger writing errors in the left (but not right) hand. Long term memory functions of information, picture completion diminished (but similarities was not). POMS/depression score was elevated.

The number of neurobehavioural abnormalities was not different between self-referred (10) and attorney referred (12) patients.

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First Date Strengths / Major Findings Conclusions Author Published Limitations 33 out of 35 symptoms were elevated. Most elevated included impaired concentration, recent memory loss, headache, extreme fatigue, sleep disturbances, skin redness, itching, irritability, dizziness and disturbed balance. Depression score was elevated but no significant increase in psychiatric diagnoses was reported. However 63% of exposed had been prescribed tranquilizers (psychotropic drugs not taken on day of testing). Frequency of alcohol ingestion was less than weekly in all patients. Two had partial motor seizures but were not taking anticonvulsants.

No patient had a pre-existing history of nervous system disease, head trauma, unconsciousness or prolonged general anaesthesia.

All occupational histories were negative for chemical or solvent use or previous pesticide exposures, although patient 1 may have had exposure to other pesticides in the field he worked in, and patient 15 had applied herbicides, pesticides including other OP compounds, and had used photographic chemicals whilst exposed to chlorpyrifos.

Authors considered results unlikely to be stress-mediated, or litigation-determined, and the possibility of intentional falsification was unlikely

Mackenzie 2010 STUDY COMPARES SHEEP FARMERS AND CONTROL GROUP OF RURAL POLICE Strengths Cognitive deficits Ross OFFICERS IN THE UK, INCLUDING SOME SUBJECTS WHO HAD RETIRED FROM ILL Comprehensive were identified in HEALTH neuropsychological a population of evaluation of a group working and EXPOSURE Information is given below: of sheep dippers with retired sheep exposure to OP dippers Exposure Mean SD Range sheep dips indices Limitations No of years Selection procedure spent working preferentially with OPs included sheep Working 23.05 10.72 8-49 farmers with chronic group illhealth. (Authors Retired group 26.11 15.17 5-66 excluded data from No of days potential spent working malingerers). with OPs Possible use of Working 3.77 6.90 0.5-30 inappropriate control group group (but authors Retired group 2.84 3.54 1-21 compared data to Years since normative standards)

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First Date Strengths / Major Findings Conclusions Author Published Limitations last dip Working 9.48 8.78 0-37 Group Retired group 11.26 7.65 0-42

HEALTH OUTCOMES 33.8% of working and 50.9% of the retired groups reported throughout their working life they suffered repeated episodes of flu-like symptoms (fatigue, muscle pain, headaches, general malaise) following use of OPs. The primary reason given for retirement (77%) was a constellation of non-specific symptoms including chronic fatigue, headaches, cognitive impairment, muscular and joint pain, numbness and chemical sensitivity. A quarter of these farmers attributed their symptoms to pesticide (sheep dip) poisoning. Remainder (23%) retired on other ill health grounds such as musculo-skeletal injury, breathing difficulties and prostate problems.

Farmers (both working and retired) were significantly impaired on measures of memory, response speed, fine motor control, mental flexibility and strategy. There were no impairments on verbal abilities, visuo-spatial abilities and visual and verbal reasoning. A significant effect of exposure was reported for Full Scale WAIS but was due to patchy under-functioning on certain WAIS subtests. General intellectual ability was reported to be well preserved.

Memory tests:

Cognitiv Exposed Mean Control Mean p value e area N (SD) N (SD) Working <0.001 memory Digit 125 9.36 76 11.21 <0.001 span (2.36) (2.71) DS 124 4.6 76 5.32 <0.001 backwar (1.16) (1.33) d Letter- 127 9.48 78 11.69 <0.001 number (2.62) (2.44) Arithmeti 122 11.43 75 11.48 NS c (2.78) (2.89) Visual <0.001 memory Visual 127 90.91 78 98.71 <0.001 immediat (15.95) (16.65) e Visual 125 93.04 77 101.34 <0.001

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First Date Strengths / Major Findings Conclusions Author Published Limitations delayed (14.78) (14.45) Auditory <0.01 memory Auditory 127 98.52 78 107.32 <0.001 immediat (16.07) (13.69) e Auditory 125 99.87 78 107.23 <0.001 delayed (14.86) (13.98) Auditory 125 101.08 78 <0.01 recogniti (15.69) 106.03(1 on 3.3)

The authors report that there was no effect of working status on cognitive variables.

Response and mental flexibility:

Cognitiv Expose Mean(S Control Mean p value e area d D) N (SD) N Respons e speed Digit 126 8.84 75 10.81 <0.001 symbol (2.55) (2.15) Trails A 127 41.03 74 32.27 <0.001 (15.3) (13.05) CALCA See P text simple below* Fine <0.001 motor control Groove 124 92.65 74 75.08 <0.001 d (24.51) (11.89) pegboa rd (domina nt) Groove 123 96.49 73 81.12 <0.001 d (22.47) (13.92) pegboa

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First Date Strengths / Major Findings Conclusions Author Published Limitations rd Non- domina nt Mental Flexibility Trails B 124 92.26 77 71.03 <0.001 (44.74) (30.79) Stroop See text below* CALCA See P text choice below* Strategy making Verbal 127 32.88 77 44.21 <0.001 fluency (11.51) (10.47)

For CALCAP simple a higher proportion of retired farmers performed abnormally compared to controls (p<0.05) (working farmers and controls performed similarly). A significantly higher proportion of working (p<0.01) and retired farmers (p=0.001) performed abnormally on the Stroop test compared to controls.

The above analyses were repeated using normative comparison standards and similar results were reported.

Analyses were re-run with effects of mood taken into account and similar results were reported.

The same areas of deficit remained when participants with a history of ‘dippers flu’ were removed.

There were no significant effects on tests of verbal ability, visuo-spatial ability, verbal/visual reasoning. The WAIS-III full scale IQ was 104.79 (11.76) in exposed (n=122) and 110.03 (10.83) p<0.01

To analyse for the relationship between cognitive tests and exposure duration composite z scores were generated for each test domain. Significant (Spearman) negative correlations were found for auditory memory (p<0.05), visual memory (pP<0.01), verbal ability (p<0.01) and strategy making (p<0.05). A significant positive correlation was reported for fine motor control,

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First Date Strengths / Major Findings Conclusions Author Published Limitations which is indicative of poorer performance (p<0.05).

The authors reported that although differences were found between working and retired farmers on subjective, self report measures of mental and physical health, no significant differences were found on measures of cognitive function. It was concluded that individuals who retired on ill health grounds were not at an increased risk of suffering cognitive impairment. (data for comparison of working and retired sheep farmers were not presented)

The following results were reported for neuropsychological domains which were not affected by exposure:

Exposed Mean Control Mean P value number (SD) number (SD) Verbal ability Vocabular 125 10.33 76 10.96 NS y (2.41) (1.87) Compreh 119 10.84 75 11.35 NS ension (2.64) (2.12) Graded 127 12.36 76 12.78 p<0.05 naming (1.28) (1.1) Visuo- spatial ability Block 125 11.98 76 12.17 NS design (2.84) (3.19) Spatial 126 10.07 78 10.87 NS span (2.64) (3.19) Verbal/vis ual reasoning Picture 122 9.9 (2.67) 69 10.96 p<0.05 arrangem (2.78) ent Similaritie 124 10.47 76 10.92 NS s (2.6) (1.87) Compreh 119 10.84 75 11.35 NS

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First Date Strengths / Major Findings Conclusions Author Published Limitations ension (2.64) (2.12) Intelligenc 122 104.79 74 110.03 p<001 e WAIS (11.76) (10.83) full scale IQ

Roldán- 2005 SPANISH STUDY OF GREENHOUSE WORKERS. Strengths The authors Tapia Comprehensive conclude that EXPOSURE. Exposure was to a mixture of pesticides mainly OP/carbamates. neuropsychological exposed subjects Data were reported along with other characteristics of participants. assessment and had a lower duration of exposure neuropsychologic Control (26) Exposed (40) Significance reported. al performance in Age mean (SD) 36.30 (12.47) 31.92 (9.36) 0.108 tasks of Education mean 3.30 (1.08) 3.07 (0.76) 0.311 Limitations Testers integrative (SD) were not blinded to perception BuChE level 9363.42 10026.03 0.197 exposure status, the (Benton visual mean (SD) (1959.71) (2002.50) assessment of form recognition) Years working 0 10.86 (7.49) Not compared. exposure was to total and visuo- with pesticides pesticides constructional mean (SD) (predominantly praxis* (Rey- OPs/carbamates) Osterreich figure Results of tests reported below in functional areas and small study size. test). difficulty in Attention Authors don’t provide reproducing Test Cut off point Control Sprayers details of subject 3dimensional Digit span 3-5 3.84 (1.22) 3.92 (1.07) selection for the figures. (backward) study. The authors Stroop

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First Date Strengths / Major Findings Conclusions Author Published Limitations Similarities

Perception

Control Sprayers Benton visual 30-32 30.92 (1.23) 29.67 (2.33) form discrimination Poppelreuter 9+/-1 9.88 (0.43) 10.00 (0.00) test Steregnosis* 5 5.00 (0.00) 5.00 (0.00) *the faculty of perceiving and understanding the form and nature of objects by the sense of touch

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First Date Strengths / Major Findings Conclusions Author Published Limitations

Praxis

Cut off point Control Sprayers Rey-Osterreich

Expressive Language

Cut off point Control Sprayers Boston naming 42-59 52.00 (4.34) 50.87 (4.88) test

Motor Performance

Cut off point Control Sprayers Hands 0 0.26 (0.45) 0.07 (0.26 coordination movements Rhthym 10+/-2 10.26 (1.97) 10.25 (1.44) reproduction Movements and 0 Results not Results not hand sequences legible in paper legible in paper Alternative 0 Results not Results not sequences legible in paper legible in paper (graphics)

Emotional condition

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First Date Strengths / Major Findings Conclusions Author Published Limitations Cut off point Control Sprayers Beck depression >10.9 5.81 (6.54) 4.65 (5.89) inventory Taylor anxiety 31+/-15.3 15.04 (6.16) 12.90 (7.08) scale

Mean values for test measurements in these populations were over the cut-off points except for Stroop, immediate/delayed recall of Rey-Osterreich figure and slope of learning and recall after delay in Rey-auditory verbal test, for both groups.

Age and education were significant predictors of Digit span (forward/backward), Trails A and B, Digit symbol, Picture completion, similarities, Rey-auditory verbal learning test (immediate/delayed recall), Logical memory Test (immediate and delayed recall), Benton visual recognition and Discrimination Tests, time and quality of copy of Rey-Osterreich figure and Block design.

Recent exposure was a significant predictor of quality of copy of Rey-Osterreich figure (p=0.019). There were no significant differences between exposed and control groups with regard to BuChE levels. Cumulative exposure was a significant predictor of recall after delay in the Rey-auditory Verbal Learning test (a test of memory), quality and time of copy of Rey- Osterreich Figure (a test of praxis), Benton Visual Form Discrimination (a test of perception) and Taylor Anxiety Scale.

Coefficients and Odds Ratio for significant predictors of test performance and emotional status

Measure, covariate Estimate (95% CI) Digit Span (backward); educational -0.25 (-0.49 to -0.01) level Trail A ; age 1.98 (1.63 to 32.47) Trail B; educational level 0.36 (0.17 to 0.75) Digit symbol; age, educational level -0.67 (-1.18 to -0.17), 1.072 (0.458 to 1.68) Picture completion; educational 1.35 (0.042 to 2.66) level Similarities; educational 0.94 (0.26 to 1.62) Digit span (forward) education 0.32 (0.03 to 0.62) Rey-auditory verbal (sum trial 1-5); -2.76 (-4.29 to -1.22) age Rey-auditory verbal (after delay); 0.83 (0.09 to 1.05),

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First Date Strengths / Major Findings Conclusions Author Published Limitations education, years working with 054 (0.03 to 1.05) pesticides Logical memory (immediate recall); 1.18 (0.26 to 2.11) education Logical memory (delayed recall); 1.83 (0.81 to 2.84) education Benton visual retention test; age -0.72 (-1.15 to -0.28) Bento visual form discrimination; 0.58 (0.03 to 1.13), education, years working with -0.61 (-0.99 to -0.236) pesticide Rey-Osterreich figure copy time; -5.29 (-10.32 to -0.26), age, years working with pesticides -5.22 (-10.44 to -0.01) Rey-Osterreich figure copy quality; 6.07 (1.05 to 11.10), BuChE level, years working with -3.71 (-8.02 to 0.60) pesticides Block design; age, education -0.68 (-1.30 to-0.05), 0.65 (-1.10 to 1.41) Taylor Anxiety Scale; years working -1.45 (-2.79 to -0.12) with pesticides

In further analysis, outcomes were converted to dichotomous variables (over versus below cut off points) and predictors were stratified showed the following results.

Cumulative exposure (years working with pesticide) and recent exposure (BuChE levels) with neuropsychological performance and emotional status (ORs and 95%Cis)

Exposure Rey Rey- Rey- Benton Taylor assessme auditory Osterreic Osterreic visual Anxiety nt verbal h figure h figure form scale (after copy copy time discrimina delay) quality tion Years working with pesticides 2-4 0.30 0.69 3.93 0.96 0.23 (0.06- (0.068- (0.87- (0.08- (0.04- 1.41) 7.06) 17.72) 10.47) 1.31)

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First Date Strengths / Major Findings Conclusions Author Published Limitations 5-10 0.94 0.00 3.50 1.44 1.23 (0.17- (0.00) (0.63- (0.12- (0.22- 4.99) 19.23) 16.42) 6.67) 11-30 0.56 5.00 4.12 6.93 0.26 (0.17- (1.22- (1.18- (1.52- (0.68- 1.85) 20.40) 14.39) 31.51) 1.02) BuChE levels 5022- 5.69 8474 (0.48- 67.62) 8475- 8.14 9493 (0.74- 89.28) 9494- 2.53 10804 (0.11- 54.66) Reference is control group or workers with less than 1 year working with pesticides.

Rothlein 2006 STUDY OF IMMIGRANT MEXICAN FARMWORKERS IN PORTLAND, OREGON EXPOSED Strengths Correlation TO OPs Comprehensive between OP neuropsychological exposure There were no significant differences between the Agricultural and non-Agricultural groups with assessment assessed by regard to age. The non-Agricultural group averaged 1.1 y more education (P=0. 04, 0. 026-2.2 Biological estimation urinary excretion y more education). of absorbed dose of of dimethylthio- OPs. phosphate EXPOSURE At least one OP was detected in each of the 26 homes studied. Phosmet was Environmental metabolites and identified in 25/26 (mean 5.2 ±4.1 μg/g) and azinphos-methyl in 18/25 (mean 5.9±4.5 μg/g). sampling of homes some indicators of Other OPs were found in 62-92% of homes but mean concentrations ranged between 0.20- for OPs psychomotor and 0.38 μg/g. cognitive Limitations functions There were 84 urine samples at the summer sampling (T1) and 68 in the fall (T2) where Complexity of creatinine levels were considered to be in the normal range. Dimethylthio- phosphate was adapting above the LOD in ≥99% of samples. The median concentration of combined thiomethyl neurobehavioural phosphate metabolites (dimethylthio- and dimethylditio-) was 0.43 μmol/L at T1 and 0.48 tests for Spanish μmol/L (not statistically different). speakers.

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First Date Strengths / Major Findings Conclusions Author Published Limitations 23 carpet dust samples could be paired with urinary thiomethyl- metabolite levels. A modest The response rate correlation was reported rs =0.47, p = 0.013. Metabolite levels tended to be higher in males. for selection of exposed and HEALTH OUTCOMES Neurobehavioural test data were available for 92 farmers (51% male) controls was not and 45 controls (60% male). After adjusting for age, sex and years of education poorer reported. performance in 5/16 test indices was associated with higher levels of average combined thiomethyl- metabolites. Selective attention latency (p=0.011), symbol digit latency (p=0.005), preferred hand finger tapping (p=0.012), alternate hand finger tapping (p=0.029), continuous performance hit latency (p=0.042), and summary index (p=0.047). (negative findings for Digit span (forward/backward), Progressive ratio, Reaction time, Selective attention trials, selective attention inter stimulus interval, serial digit learning, finger tapping non-preferred hand, continuous performance %hits, % correct rejects, False alarm latency.)

Overall non-agricultural workers performed better in 12/16 neurobehavioural measurements. The authors reported a significant interaction between agricultural status and the covariate for the serial digit learning test (Agricultural Group (AG) x age p=0.049, AG x sex p=0.041), for the symbol digit test (AG x education) (p=0.043), and preferred-hand finger tapping (AG x sex) (p=0.031). The summary index of 11/16 measures also showed an AG x sex interaction p=0.012. The tabulated information relates to the mean response for a 25 y old with 6 years of education.

Test AG group Non-AG group One-sided p Mean SE Mean SE value Digit span 4.12 ±0.17 4.37±0.19 0.10 b forward a Digit span 3.86±0.19 4.53±0.21 <0.01 b backward a Progressive 600.40±14.53 600.22±16.44 0.50 ratio a Reaction time a 340.95±10.50 327.77±11.89 0.13 b Selective 450.27±10.03 456.16±11.48 0.31 b attention trials Selective 397.85±13.45 386.19±15.40 0.23 b attention ISI a Selective 323.00±6.64 315.15±7.60 0.15 b attention latency Serial digit learning a Male 11.36±1.31 8.36±1.57 0.93 Female 9.33±1.09 11.56±1.66 0.13 b

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First Date Strengths / Major Findings Conclusions Author Published Limitations Symbol-digit a 3034.58±113.74 2973.38±158.3 0.38 b 8 Finger tapping preferred hand a Male 99.80±2.69 96.88±3.39 0.75 Female 81.68±2.31 90.41±3.60 0.02 b Finger tapping, 89.22±2.51 90.75±2.84 0.30 b non preferred hand a Finger tapping , 52.25±3.00 46.72±3.42 0.95 alternate hand a Continuous performance % Hits a 0.90±0.02 0.88±0.02 0.84 % correct 0.95±0.01 0.97±0.01 0.26 b rejects Hit latency 407.82±10.38 396.55±11.63 0.17 b False alarm 483.36±21.40 494.16±24.88 0.67 latency Summary index Male 1.01±0.32 0.18(0.38) 0.95 Female -1.00±0.25 -0.04 (0.39) 0.02 b

a included in summary index b non AG performed better than AG Salvi 2003 STUDY OF BRAZILIAN TOBACCO WORKERS EXPOSED TO OPs Strengths No evidence for The average age of the 25 tobacco workers who completed the follow-up examination was Prospective design neuropsychologic 37.0±13.5 years (13 male, 12 female). al effects, but Limitations study too limited EXPOSURE Mean duration of exposure was 17.8±11.8 years, 5.4±0.9 hours/day. Activities Small size with to draw definite included preparation (84% of subjects), application (88%), transport (84%) and collecting limited conclusions. (100%). PPE was worn by a minority of subjects (gloves (16%), mask (4%), clothes (12%) and neuropsychological boots (4%)). Predominant pesticides used in past 4 years were chlorpyrifos and acephate. testing undertaken. (Authors reported Lack of effects on motor HEALTH OUTCOMES Clinical signs reported included fatigue (12 subjects), headache (5), cholinesterase functions and hypertension (3), dermatitis (3). 13 of subjects had lifetime history of cholinergic syndrome, one depression suggests psychiatric illness hospitalised. None reported acute symptoms of cholinergic syndrome within previous year. limited low exposure in this study) Plasma acetylcholinesterase at both time points (December 2001, and March 2002; 4.7±0.9U/l to OPs occurred but and 4.5±1.1 U/l respectively) were within the normal range (3.2-9.0 U/l). this is inconsistent with the description Mini-mental and word span scores were within the expected range for this population and were of pesticide

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First Date Strengths / Major Findings Conclusions Author Published Limitations not influenced by exposure application undertaken with Parameter On On Off P value limited or no PPE. exposure exposure Exposure No referent group (37 (25 (25 Possible exposure to subjects) subjects) subjects) other pesticides. Dec 2001 Dec 2001 March 2002 Mini- 24.86±3.77 24.56±3.71 25.16±2.97 0.33 mental Word 5.62±1.32 5.92±2.18 5.44±1.12 0.37 span

Srivastava 2000 STUDY OF WORKERS EXPOSED TO CHEMICALS DURING MANUFACTURE OF Strengths No definite QUINALPHOS Neurobehavioural conclusions can testing in subjects be drawn from EXPOSURE Exposure would have been to a range of chemicals used or produced during exposed to a single this study manufacture as well as to quinalphos itself. This would include o-phenylene-diamine, glyoxalic OP. methyl hemi-acetal reacted to give 2-hydroxyquinoxaline (refluxed with sodium hydroxide to Limitations form sodium salt). Final step is reaction with diethyl thiaryl phopshorocyanide to prepare Exposure was to a quinalphos. mixture of reagents and intermediates.. The exposed and referents were of similar age (30.0±6.61 exposed, 28.9±4.5 y) height, weight, Study did not control income, cigarette and alcohol use. There was a higher proportion of graduates in the referent for effects of group (15 (25.5%) in exposed, 8 (47.1%) in control). education (higher proportion of HEALTH OUTCOMES There were no significant differences in whole blood AChE levels graduates in control between exposed and referents. Whole blood AChE was not statistically different between group) which may exposed and controls. Three exposed subjects had whole blood AChE lower than the control have been important range, and one had a higher value. The subject with a low blood AChE was shifted to a job with no OP exposure.

Complaints of weakness significantly higher in exposed subjects, but no subject with acute symptoms of OP poisoning.

Significantly reduced performance in neurobehavioural tests in exposed was reported.

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First Date Strengths / Major Findings Conclusions Author Published Limitations Test Exposed (59) Controls (17) P value Mean SD Mean SD Memory (digit 8.61±1.29 10.4±1.34 <0.05 span) Learning 51.0±10.85 62.4±13.73 <0.05 (digit symbol) Vigilance 49.79±9.5 56.0±7.14 <0.05 Bourdon Weirsma vigilance test

Steenland 2000 US STUDY OF TERMITICIDE APPLICATORS EXPOSED TO CHLORPYRIFOS Strengths The authors Comprehensive report generally EXPOSURE neurobehavioural negative results testing in well apart from Exposure characteristics of 191 termiticide applicators. defined exposed performance of population with large Groove pegboard Characteristic Value sample size (a test of Applied termiticide in last week (n) 76 (40%) psychomotor Median No (range) termite jobs in 4 (1-41) Limitations. Possible performance) last week if any selection bias (38% Applied termiticide in current year 128 (67%) of termiticide They caution (n) applicators could not against Ever applied chlordane 65 (34%) be traced). Exposure generalising the Median years (range) applied 4.5 (0.5-28.5) duration for results form this chlordane (65) chlorpyrifos was discrete group). Mean years (SD) applied chlordane 7.0 (6.3) relatively short. (65) Median years (range) applied 1.8 (0.1-10.3) chlorpyrifos (n 191) Mean years (SD) applied 2.4 (2.2) chlorpyrifos (191) Meadian years applied other 1.6 (0.5-11.3) pesticides (n=173) Mean years (SD) applied other 2.5 (2.5) pesticides Median (range) TCP level in uring 172.7 (5.7-13,009) (ug/L) termiticide applied last week (65) Mean TCP level (SD) in urine (ug/L) 629.5 (1,636.6)( see (a) below for

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First Date Strengths / Major Findings Conclusions Author Published Limitations termiticide applied last week (65) creatinine corrected values) Median (range) TCP level in urine 28.1 (1-946) (ug/L), no termiticide applied in last week (n=40) Mean TCP level (SD) in urine 119.0 (196) (ug/L), no termiticide applied last week (n=40) Mean TCP level (SD) in urine (ug/L) 6.2 (6.1) in non exposed subjects Self-report of chlorpyrifos poisoning 8 (n) Creatinine corrected values for applicators exposed in last week, not exposed in last week and nonexposed were 331, 55 and 3 ug/g creatinine respectively.

Mean level of chlorpyrifos TCP metabolite in random sample of 929 US adults 4.5 ug/L (from Hill R Environ Res, 71, 88-108, 1995)

HEALTH OUTCOMES

The investigators did not report actual values for tests.

Exposed group did not perform as well in Pegboard (dominant (p=0.07). This effect was apparent when applicators were compared to state employees controls (p=0.005) but not when compared to nonexposed friends (p=0.43) Similar results were reported for Pegboard (non dominant) Eight applicators with self-reported poisoning had significant decrease in Pegboard (non dominant) (p=0.01) and a borderline decrease for the dominant hand (p=0.09). Former applicators performed less well for the Pegboard dominant hand (p=0.01)

There were no associations between any exposure variable and either Trail A and Trail B. (R2 0.16 and 0.32 respectively)

There were no significant differences between exposed and non exposed for the neurobehavioural tests (R2 values expressed as percentage); Simple reaction time (5%) Digit symbol (34%) Continuous performance (7%) Digit span forward (12%)/ backward (16%), Pattern memory (13%) Vocabulary (31%)

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First Date Strengths / Major Findings Conclusions Author Published Limitations The level of TCP did not significantly predict performance in any test except for Vocabulary , for which subjects with more TCP did significantly worse (p=0.02)

There were no associations for current v former exposure, duration of use of chlorpyrifos, chlordane or other pesticides.

Self-reported poisoning by chlorpyrifos was associated with decrease in Continuous performance test (p=0.0001) and on Simple reaction time (p=0.06)

With regard to mood scales exposed reported more tension/fatigue than nonexposed.

Stephens 2004 UK STUDY OF ORCHARD SPRAYERS EXPOSED TO OPs Strengths Evidence for Orchard workers slowed EXPOSURE Urine DEP/DEPT metabolites were similar in each group (p=0.207), 0-35 were considered well processing speed nmol/mmol creatinine in orchard sprayers, 0-12.19 nmol/mmol creatinine in pig farm workers matched except for in OP exposed and 0-11.48 nmol/mmol creatinine in construction workers. sociocultural factors. orchard sprayers. Alcohol consumption Orchard sprayers regularly used Chlorpyrifos and had participated in an HSE survey. They by construction Authors were found to have used Chlorpyrifos for a median of 5d/year (range 0.5-13 d/yr) for a median workers would tend considered that of 14 years (range 2-25 yrs) at an intensity sufficient to produce median summed DEP and to reduce the the lack of an DETP metabolites of 10.20 nmol/mmol creatinine (range 0-65.0 nmol/mmol creatinine). chances of detecting underlying The predominant pesticide sprayed at the time of the study was Chlorpyrifos. an OP related effect. neurotoxic Education level in mechanism The majority (73%) of orchard sprayers reported previously using pesticides in applications orchard workers was precludes outside of spraying top fruit in orchards: spraying soft fruit 18, non- fruit crops 12, dipping slightly higher which interpretation of sheep 7, treating other farm animals 9, spraying to control insects 6, spraying amenity land 2, would predict better the study results commercially spraying in households 2. performance.

The majority (73%) of pig farmers reported previously using pesticides: spraying soft fruit 2, Selection was non- fruit crops 10, dipping sheep 4, treating other farm animals including pigs 17, spraying to originally for control insects 3, spraying amenity land 4, commercially spraying in households 2. occupational health study and authors Two construction workers reported using pesticides (control of insects 1 and commercially considered selection spraying households 1) bias unlikely to have occurred. POPULATIONS There were no differences in age and educational level. However it is noted there were 16% of orchard sprayers educated to graduate level, 12% of pig farmers, and 0% Limitations of the construction workers. Weekly alcohol consumption was substantially higher in Similar performance construction workers (27.71±21.22 un its (10ml alcohol), as compared to 12.35±1.37 in of pig farm workers

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First Date Strengths / Major Findings Conclusions Author Published Limitations orchard sprayers and 15.08±15.05 in pig farm workers. compared to orchard workers may reflect HEALTH OUTCOMES On neuropsychological tests two significant differences between the greater sociocultural occupational groups were reported. similarity (authors suggest pig farm The ACTS Syntatic Reasoning accuracy where pig farm workers had higher accuracy than workers may also orchard sprayers (p=0.012) and construction workers (p<0.001). There was no difference exhibit pesticide- between orchard sprayers and construction workers. On the ACTS Category Search related effects). Recognition accuracy orchard sprayers performed significantly better than construction workers (p=0.006), and pig farm workers performed significantly better than construction workers Lack of effect when (p=0.021) (no difference between orchard sprayers and pig farm workers). compared to There was no difference between groups regarding ACTS Syntactic Reasoning latency (after cumulative exposure adjustment for type 1 error inflation) but the uncorrected p value was 0.044. The authors indices (authors undertook further analyses. Each item on ACTS Syntactic Reasoning has two properties which suggest exposure affect performance; voice (passive or active) and positivity (whether stimulus is positively or misclassification negatively phrased). For each of the ACTS Syntatic Reasoning latency and ACTS Syntatic possible) Reasoning accuracy properties, a mixed factorial 3x2x2 ANOVA was carried out. A significant study group interaction with negative statements was reported for orchard sprayers ( F(1,91)=7.507, MS Wcell=3.859, p=0.012 corrected) and pig farm workers (F (1,91) =6.124, MS Wcell=3.859, p=0.024 corrected) compared to construction workers, which was still evident (in analysis of orchard workers (F(1,90)=5.132, MS Wcell=4.265, p=0.042 corrected) after accounting for effects of differences in alcohol consumption. Group analysis of positivity for the ACTS Syntactic Reasoning accuracy was not significant.

The authors calculated lifetime exposure to Chlorpyrifos as lifetime days used Chlorpyrifos x level of DEP/DETP in urine. There was no association between this estimate of cumulative Chlorpyrifos exposure and ACTS Syntactic Reasoning latency.

Neuropsychological data:

Orchard Pig farm Construction Uncorrected sprayers workers workers P value Mean SD Mean SD Mean SD Attention Simple 0.29 (0.04) 0.29 (0.04) 0.29 (0.03) 0.960 reaction time Digit span 4.43 (1.69) 5.27 (1.66) 5.23 (2.13) 0.116 (backward) Processing speed

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First Date Strengths / Major Findings Conclusions Author Published Limitations Digit symbol 2.30 (0.44) 2.22 (0.35) 2.24 (0.51) 0.769 latency Syntactic 5.60 (1.78) 5.67 (1.55) 4.75 (1.34) 0.044 reasoning latency Syntactic 59.76 70.01 54.33 <0.001 reasoning (14.51) (14.34) (12.23) accuracy Short term memory Digit span 5.76 (1.30) 6.00 (1.13) 6.37 (1.38) 0.158 forward Location 1.15 (0.23) 1.15 (0.20) 1.13 (0.26) 0.947 recognition latency Location 70.68 (8.21) 72.82 (6.14) 71.67 (5,87) 0.485 recognition accuracy Long term memory Category 1.04 (0.2) 1.06 (0.24) 1.16 (0.48) 0.292 search latency Category 85.81 83.27 69.46 0.002 search (17.07) (20.85) (21.44) Accuracy Serial word 27.35 (6.76) 28.12 (8.79) 28.52 (5.01) 0.784 learning(No items/45) Subjective 144.14 138.58 143.35 memory (17.89) (12.64) (14.43) questionnaire (max 215)

Table 8. EXPOSURE SCENARIO AND NEUROPSYCHOLOGICAL ABNORMALITIES

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A. ACUTE EXPOSURE WITH CHRONIC EFFECTS

Table 8.A.1. Cohort Studies

First Author and Date Test Name Delgado Delgado 2004 2004 7-week 2-year follow up follow up Intelligence Attention Executive Function Psycho-visuomotor Digit Symbol + + Visuospatial Memory Rey auditory verbal learning - - Language

Profile of Mood States (or other assessment of psychiatric status

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Table 8.A.3. Cross-sectional studies

Attention Continuous performance - - A Cancellation - Digit vigilance - Trail making A - - - - - Stroop test WAIS-III Digit span (forward) ------WAIS-III Digit span - - - - + (backward

Executive Function Control oral word - Short category test - Trail making B - - - - Verbal fluency +

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Psycho-visuomotor Simple reaction time - + - - - Choice reaction time - - - Finger tapping dominant - + + + + + Finger tapping non-dominant + - + + Groove pegboard - Purude pegboard dominant + Purude pegboard non + dominant Pursuit aiming - Santa ana Dexterity - WAIS-Digit symbol + - Benton Visual retention-time of copy + Coordination Movements - Rhythm reproduction - Altern Movements -

Perception Picture Completion WAIS +

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Visuomotor praxis Rey-Osterreich figure copy + time Rey-Osterreich figure copy quality +

Visuospatial WAIS Block Design - + + -

Language Boston naming test - Language

Verbal reasoning Similarities -

Memory

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First Author and Date Wesseling Roldan- Mittal Spencer Proctor Chao Nishiwaki Ohtani Miyaki Miyaki 2002 Tapia 2011 2001 2006 2010 2001 2004 2005 2005 Banana 2006. Acute Gulf war Gulf war Gulf war Tokyo Tokyo Tokyo Tokyo workers Acute poisoning veterans: veterans veterans subway subway subway subway 2y10mth-3y with acute poisoining cases follow up 3.5-5year 10year 5 year 7 year combine 9mnth follow Test Name cholinergic Spain. admitted not stated: follow up follow up up. Fire follow up. follow d 3y+7y poisoning 1year to [raw data rescue staff Subjects up. data (at leat 1 follow up hospital, not and police treated at Subway Subway year post India 3 presented] officers one workers workers OP Months emergency poisoning) after centre discharge Profile of mood states (or Brief No effects Deployed Lower No Mental visual scores in scores in other measure of symptom on Beck had higher levels of differenc heath memory GHS and GHS and psychiatric status eg inventory, a Deression levels of PTSD e in assessed reduced in IES IES General Health measure of index or PTSD and among PTSD or as normal subjects (measur (measur Survey(GHS)). Evidence neuropsych Anxiety were more high depressi in GHS with PTSD e of e of for Post Traumatic Stress iatric sclaes likely to be exposed on survey PTSD) PTSD) Disorder symptoms (increased hospitalise compared between higher in higher in was anxiety d for to exposed/ exposed exposed significant seen at 3 depressio moderate, non- workers workers in poisoned months)> n. low exposed cases. exposed. groups Test for malingering +

Test 1 Test 2

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Case series studies First Author and Date Test Name Dahlgren 2004 USA Series of 7 cases Attention Trails A + Executive function Trails B + Psycho visuomotor Simple reaction time + Choice reaction time + Peg placement + Perception Colour discrimination +

Table 8.A.5. Case reports

First Author and Date Test Name Loh 2010 Intelligence WAIS-III Full scale - WAIS Verbal - WAIS Performance - WAIS Processing speed + Wide Range Achievement test - III reading - Atteniton/executive function Auditory consonant trigrams + WAIS Digit span - Seashore rhythm - Trail A - Winconsin card sort - Psychomotor Finger tapping - Groove pegboard + Visuoconceptual Rey complex figure - Hooper visual organisation - Memory Californain Verbal Learning test - Wechler memory scale III - Rey complex figure recall -

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B. CHRONIC LOW-LEVEL EXPOSURE

Table 8.B.1. Cohort studies

First Author and Date Albers Albers Starks 2004b 2004b 2012a US US Pesticide Chlorpyrifos Chlorpyrifos applicators Test Name manufacture manufacture in Baseline 1-year Agricultural follow up Health Study (Total OP exposure) Intelligence

Attention Likert scales (staying focused) - - MMSE (attention/calculation) - - Continuous Performance - Sequence A -

Executive function Likert scales (problem solving) - - Sequence B - Psycho-visuomotor Digit symbol - Groove pegboard, dominant - Visuo-spatial

Memory Likert scales (memory 10y ago) - - MMSE(recall) - -

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Auditory verbal learning (total recall, delayed and recognition) - Language Likert scales (reading) - - MMSE (comprehension) - -

Composite tests (orientation memory, naming, sequencing - - MMSE total score - - Profile of mood states (or other assessment of psychiatric status)

Table 8.B.3(i). Cross-sectional studies

First Author and Date Stephens Mackenzie Keifer 2000 Keifer 2000 Salvi 2003 Salvi 2003 Steenland Rothlein 2006 Farahat 2004 Ross 2010 Apple orchard Apple orchard Tobacco Tobacco 2000 Oregon farm 2003 Cotton Test Name Orchard Sheep dippers thinners, US. thinners, US. workers after 3 workers 3 Termiticide workers US field sprayers England Thinning in Pre 1994 months months post applicators US sprayers England 1994 cumulative spraying US exposure US Egypt

Intelligence WAIS -III Intelligence/Information WAIS -III total score +

Attention/Working Memory A' cancellation

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WAIS-III Arithmetic - Bourden-Wiersma vigilance Continuous Performance - + Digit Span (forward) - + - - - - + Digit Span (backward) - + - + - - + Letter cancel (errors) + Paced Auditory Serial Attention - Selective Attention + Stroop - Trailmaking A + - + - +

Executive Function/Mental flexibility CALCAP Choice - Syntatic reasoning Trailmaking B + - +

Psycho-visuomotor ACTS Syntatic Reasoning latency - ACTS Syntatic Reasoning accuracy + Aiming errors CALCAP simple - Choice reaction time Culture Fair A Digit Symbol - + - + + Finger writing errors Finger tapping (dominant) + Finger tapping (non-dominant) + Groove pegboard (dominant) + -

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Groove pegboard (non-dominant) + - Hands coordination movements Pursuit aiming - - Progressive ratio - Rythmn reproduction Santa ana dexterity (dominant) - - Santa ana dexterity (non-dominant) - + Simple reaction time - - - - Tower of Hanoi

Perception Benton visual form discrimination Poppelreuter test Stereognosis

Praxis Rey-Osterreich figure copy time Rey-Osterreich figure copy quality Ideomotor apraxia Ideational apraxia

Visuospatial WAIS Block Design - - - - WAIS Spatial span -

Memory ACTS Location recognition latency -

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ACTS Location recognition accuracy - ACTS Category search latency - ACTS Category search accuracy - ACTS Serial word learning - WMS auditory (immediate) + WMS auditory (delayed) + WMS auditory (recognition-delayed) + Benton Visual Retention - - + Category search Letter number + Location recognition Logical memory (immediate recall) Logical memory (delayed recall) Paired associates (tough) - - Paired associates (easy) - - Pattern memory - Picture completion Rey auditory learning scale Rey auditory verbal (sum trial 1-5) Rey auditory verbal (after delay) Rey-Osterreich figure recall (5 min delay) Rey-Osterreich figure recall (15 min delay) Serial word learning Story recall A - Story recall B - Subjective memory questionnaire - WMS Visual (immediate memory) + WMS Visual (delayed memory) +

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Language Boston namming test Verbal Fluency + WAIS -III Vocabulary WAIS -III Comprehension Graded naming + Vocabulary -

Verbal reasoning WAIS -Picture arrangement + WAIS -III Comprehension - Picture completion Similarities - +

Composite (memory, naming, sequencing) MMSE Total - Word span -

Profile of mood states General Increased Not assessed Not assessed Not assessed Not assessed Boderline Not assessed Personality health anxiety in depression questionnair question- exposed among e: naire 3 sprayers. Neuroticisi sprayers m in above exposed psychiatric threshold (7 pig farmers, 9 construction workers

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Table 8.B.3(ii). Cross-sectional studies continued

First Author and Date Abdel Rasoul Bazylewicz Bazylewicz Browne 2006 Kilburn, 22 Roldan-Tapia Srivastava Bayrami 2008 Cotton 1999 Gdn/ 1999 Gdn/ Agricultrl subjects with 2005 2000 Manufac 2012 Test Name field sprayers grnhse workers grnhse commnty Israel chlorpyrifos Greenhouse of Quinalphos Horticulture Egypt Pre-season workers exposure. USA sprayers, India farmers, Iran Poland Poland Post- Spain season

Intelligence WAIS -III Intelligence/Information + + WAIS -III total score

Attention/Working Memory A' cancellation - WAIS-III Arithmetic + Bourden-Wiersma vigilance + Continuous Performance - Digit Span (forward) + - - - + Digit Span (backward) + - + Letter cancel (errors) Paced Auditory Serial Attention Selective Attention Stroop - Trailmaking A + + -

Executive Function/Mental flexibility CALCAP Choice Syntatic reasoning Trailmaking B + + -

Psycho-visuomotor ACTS Syntatic Reasoning latency ACTS Syntatic Reasoning accuracy Aiming errors +

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CALCAP simple Choice reaction time + Culture Fair A + Digit Symbol + - + - + Finger writing errors + Finger tapping (dominant) Finger tapping (non-dominant) Groove pegboard (dominant) Groove pegboard (non-dominant) Hands coordination movements Pursuit aiming Progressive ratio Rythmn reproduction Santa ana dexterity (dominant) - Santa ana dexterity (non-dominant) - Simple reaction time + Tower of Hanoi -

Perception Benton visual form discrimination + Poppelreuter test - Stereognosis -

Praxis Rey-Osterreich figure copy time + Rey-Osterreich figure copy quality + Ideomotor apraxia - Ideational apraxia -

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Visuospatial WAIS Block Design + - WAIS Spatial span

Memory ACTS Location recognition latency ACTS Location recognition accuracy ACTS Category search latency ACTS Category search accuracy ACTS Serial word learning WMS auditory (immediate) WMS auditory (delayed) WMS auditory (recognition-delayed) Benton Visual Retention + - Category search Letter number + Location recognition Logical memory (immediate recall) - Logical memory (delayed recall) - Paired associates (tough) Paired associates (easy) Pattern memory Picture completion + Rey auditory learning scale - Rey auditory verbal (sum trial 1-5) - Rey auditory verbal (after delay) -

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Rey-Osterreich figure recall (5 min delay) - Rey-Osterreich figure recall (15 min delay) - Serial word learning - Story recall A + Story recall B + Subjective memory questionnaire WMS Visual (immediate memory) - WMS Visual (delayed memory) +

Language Boston namming test Verbal Fluency WAIS -III Vocabulary + WAIS -III Comprehension Graded naming Vocabulary

Verbal reasoning WAIS -Picture arrangement WAIS -III Comprehension Picture completion Similarities - -

Composite (memory, naming, sequencing) - MMSE Total Word span

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Profile of mood states Increased Not assessed Not assessed Subjects with Profile of mood No evidence No data Somatisation neurological anxiety, states and for reported. Most higher in symptoms depression depression depression in manufacturers exposed including excluded from score raised. sprayers. reported farmers. difficulty in study Trait anxiety fatigue and concentration, showed weakness irritability and tendency with depression in >5 y exposed exposure, but relationship not consistent

Table 9. OVERVIEW OF NEUROPSYCHOLOGY TESTS

WHO CORE TEST BATTERY

Simple reaction time Response speed Digit Span Auditory attention/memory Santa Ana Dexterity Fine motor control Digit symbol Perceptual speed Benton visual retention Visual perception/memory Pursuit aiming Motor steadiness Profile of mood states Current experienced affect

TESTS CITED IN COT DRAFT DISCUSSION PAPER AND ANNEXES

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The subdivision of tests into neuropsychological domains is based predominantly on the information given in papers which have been summarised. It is noted that many tests examine multiple functions, so the citation of a particular test might be relevant to more than one domain. The information is summarised here to aid members in interpreting the neuropsychology studies

Intelligence

Test Description WAIS full scale WAIS-III comprises 14 subtests. The overall result of these tests is the full scale IQ. Two composites of the subtests measure verbal IQ and performance IQ. WAIS can also give 4 indices based on verbal, comprehension, perceptual organisation and processing speed WAIS-III- Verbal IQ Comprised of 7 subtests; digit span, vocabulary, comprehension, information, arithmetic, similarities and letter number sequence WAIS-III-Performance IQ Comprised of 7 subtests: picture completion, picture arrangement, block design, object assembly, digit symbol, matrix reasoning and symbol search WAIS III-Processing speed index Comprised of digit symbol and symbol search WAIS-III- Reading Reading ability is assessed as part of the WAIS working memory index Wide Range Achievement Test- Word memory test WRAT is an achievement test combining reading words, comprehending sentences, and spelling coupled to mathematics problems Word memory test A computer-based test that is designed to measure both verbal memory and biased responding (i.e. malingering). It measures memory on a number of dimensions and contains hidden scales, which serve to check the validity of the person’s test scores. (See also WMS-auditory memory)

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WAIS Subscales

A short overview of the abilities and traits measured in the individual subtests is given below (abstracted from Groth-Monart G. Hand book of Psychological Assessment Fifth Edition, 2009, Published John Wiley & sons Inc, ISBN 978-0-470-08358. The information presented in this text refers to the WAIS-IV which was the version of Intelligence testing which replaced WAIS-III.

Verbal comprehension Index

Similarities: Logical abstract reasoning, verbal concept formation or conceptual thinking, distinguishing essential from nonessential details, associative ability combined with language facility.

Vocabulary: Language development, word knowledge, general verbal intelligence. Language usage and accumulated verbal learning ability, rough measure of subject’s optimal intellectual efficiency, educational background, range of ideas, experiences or interests that the subject has aquired.

Information: Range of general factual knowledge, old learning or schooling, intellectual curiosity or urge to collect knowledge, alertness to day-to-day world, long term memory.

Comprehension: Demonstration of practical knowledge, social maturity, knowledge of conventional standards of behaviour, ability to evaluate past experience (that is, proper selection, organisation and emphasis of facts and relationships); abstract thinking and generalisation, social judgement (common sense or judgement in practical social situations), grasp of one’s social milieu (information and knowledge of moral codes, social rules and regulations), reality awareness (understanding and alertness to the day to day world).

Word reasoning; Verbal reasoning, verbal abstraction, deductive reasoning, ability to develop alternative concepts, synthesising ability, verbal comprehension

Perceptual reasoning Index

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Block Design: Analysis of whole into component parts, spatial visualisation, nonverbal concept formation, visuomotor coordination and perceptual organisation, capacity for sustained effort (concentration), visual-motor spatial coordination, manipulative and perceptual speed.

Matrix reasoning: Visual-spatial reasoning, abstract reasoning, visual organisation, simultaneous processing of visuospatial information, analysis of wholes into component parts.

Visual puzzles; Visual recognition and identification, perception of the parts in relation to the whole, visual spatial reasoning, analysis of wholes into component parts, capacity for sustained visual effort (concentration), fluid reasoning

Figure weights: Non verbal mathematical reasoning, quantitative and analogical reasoning, visual concentration combined with an ability to visually organise material, capacity for sustanined effort.

Picture completion: Visual alertness, visual recognition and identification (long-term visual memory), awareness of environmental detail (reality contact), perception of the whole in relation to its parts (visual conceptual ability), ability to differentiate essential details form nonessential details, visual concentration combined with ability to visually organise material.

Picture concepts: Nonverbal concept formation, perceptual recognition, abstract categorical reasoning.

Working memory index

Digit span: Immediate rote recall, reversibility; ability to shift thought patterns from digits forwards to digits backwards, concentration or attention, auditory sequencing, rote learning.

Arithmetic: Computational skill, auditory short-term memory, sequencing ability, numerical reasoning and speed of numerical manipulation, concentration and attention/low distractability, reality contact and mental alertness (i.e. active relationship to outside world), school learning (earlier items) (acquired knowledge), logical reasoning, abstraction and analysis of numerical problems (later items)

Letter Number Sequencing: Auditory short-term memory, sequencing ability, concentration and attention.

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Processing speed index

Coding (Previously called Digit Symbol): Psychomotor speed, ability to follow directions, clerical speed and accuracy, visual short- term memory, paper-pencil skills, ability to learn an unfamiliar task (capacity for learning and responding to new visual material), some degree of flexibility (ability to shift mental set), capacity for sustained effort, attention, concentration and mental efficiency, associative learning and ability to imitate newly learned visual material, sequencing ability.

Symbol search: Speed of visual search, speed of processing information, planning, encoding information in preparation for further processing, visuomotor coordination, learning ability.

Cancellation: Perceptual recognition, perceptual discrimination, perceptual scanning ability, speed and accuracy, attention and concentration, visuomotor coordination.

Attention/Working Memory

Test Description WAIS Arithmetic 14 mental arithmetic brief story type problems. Tests distractibility as well as numerical reasoning ‘A’ Cancellation test Letter cancellation tasks are paper and pencil tests widely used in clinical and research settings as quick measures of attention/concentration, visual-spatial scanning abilities, and visual-spatial dysfunctions such as spatial neglect. Auditory consonant trigrams This test is used to test levels of memory and attention. The client listens to a string of three consonants (the consonant trigram) immediately followed by a mental task such as counting backwards. After that task, the client is asked to recall the trigram Bourden-Wiersma vigilance The Bourdon-Wiersma Test is a commonly used test of combined visual perception and vigilance. The Bourdon-Wiersma Test in the Cognitive Function Scanner system is composed of 37 rows of 25 dot groups of either three, four, or five dots. The subject is asked to search the rows and mark all the four-dot groups. The test is done on the drawing pad with a ballpoint pen with ink. The inkfilled pen is used in order to provide visual feedback and prevent confusion. As focus is on the time spent, time is measured for each row so that the time variation can be used as a measure of vigilance. In

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Test Description addition the number of errors is recorded for each row Continuous performance Clients are presented with a repetitive, "boring" task and must maintain their focus over a period of time in order to respond to targets or inhibit response to task. Tests may use numbers, symbols, or even sounds Several variables may be derived from the CPT including errors of omission and commission (omission errors measure inattention, commission errors measure impulsivity) CVLT Trial 1 and 2 (see also California The California Verbal Learning test: Scores for CVLT Trial 1 (immediate encoding of Verbal Learning under memory) novel words) and recognition discriminability (recognition of familiar vs. novel words) Digit span Digit-span test is a task that is often used for measuring working-memory and attention. Participants are read a series of digits (e.g., '8, 3, 4') and must immediately repeat them back. If they do this successfully, they are given a slightlly longer list (e.g., '9, 2, 4, 0'), and so forth. The length of the longest list a person can remember in this fashion is that person's digit span. While the participant is asked to enter the digits in the given order in the forward digit-span task, in the backward digit-span task the participant needs to reverse the order of the numbers

Digit vigilance test (DVT) The DVT is a simple task designed to measure vigilance during rapid visual tracking and accurate selection of target stimuli. It is sensitive to subtle changes in neuropsychological status, but relatively insensitive to the effects of either repeated administrations or practice. The DVT appears to isolate alertness and vigilance while placing minimal demands on two other components of attention: selectivity and capacity FTMS (Failure to Maintain set) FTMS is a subscore of the Wisconsin card sort tests. It measures the loss of the correct sorting rule during performance (see Wisconsin card sort test) Letter cancel The Letter cancellation test is a test of attention/concentration, visual-spatial scanning abilities, and visual-spatial dysfunctions such as spatial neglect. A single letter test consists of one 8.5"x11" sheet of paper containing 6 lines with 52 letters per line. The stimulus letter H is presented 104 times. The page is placed at the patient's midline. The patient is told to put a line through each H that is found on the

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Test Description page. The time taken to complete the test is recorded. The score is calculated by subtracting the number of omissions (H's that were not crossed out) from the possible perfect score of 104 (0 to 53 on the left and 0 to 51 on the right)

Likert Scales (Staying focused) A five response type scale used in Albers et al 2004 to measure attention (also used for recall, reading performance) MMSE (Mini–Mental State Examination) The most commonly applied test of cognitive function. It is a brief 30-point questionnaire test that is used to screen for cognitive impairment, divided into subscores for orientation, attention, recall (short term memory) and language. A score below 24 is used as a cut off for mild cognitive impairment. The MMSE is composed of 11 major items: temporal orientation (5 points), spatial orientation (5 points), immediate memory (3 points), attention/concentration (5 points), delayed recall (3 points), naming (2 points), verbal repetition (1 point), verbal comprehension (3 points), writing (1 point), reading a sentence (1 point), and constructional praxis (1 point). The MMSE has maximum score of 30, with five different domains of cognition analysed: (1) Orientation, contributing a maximum of 10 points, (2) Memory, contributing a maximum of 6 points, (3) Attention and calculation, as a measure of working memory, contributing a maximum of 5 points, (4) Language, contributing a maximum of 8 points, and (5) Design copying, contributing a maximum of 1 point. Individuals scoring two points below the maximum in any independent domain (except design copying) were considered to be impaired

Paced Auditory Serial Addition Test The PASAT is a test of sustained attention. In PASAT, patients are trained to add 60 (PASAT) pairs of single digits so that each number is added to the one immediately preceding it. Patients report the sum orally. The digits are presented by audiotape, first at a rate of 3 seconds per digit (PASAT3), then, in a second trial, at a rate of 2 seconds per digit (PASAT2). Scores are the sums of correct responses for the 3- and 2- second forms of the task Seashore rhythm (Rhythm test) Rhythm test: Thirty pairs of tape-recorded, non-verbal sounds are presented. For each pair, individuals decide if the two sounds are the same or different, marking "S" or "D"

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Test Description respectively on their answer sheets. The pairs are grouped into three subtests. This test is also called the Seashore Rhythm Test, and is based on the Seashore Tests of Musical Ability. It evaluates auditory attention and concentration, and the ability to discriminate between non-verbal sounds Selective attention SATs can be either auditory or visual. In the auditory test, the instrument was constructed as a paper-and-pencil approach to evaluate sustained attention utilizing different distractor conditions in the study of voluntary or intentional aspects of attention Sequence A and B Assumed to be the same as Trails A and B. Trailmaking A and B Both parts of the Trail Making Test consist of 25 circles distributed over a sheet of paper. In Part A, the circles are numbered 1 – 25, and the patient should draw lines to connect the numbers in ascending order. In Part B, the circles include both numbers (1 – 13) and letters (A – L); as in Part A, the patient draws lines to connect the circles in an ascending pattern, but with the added task of alternating between the numbers and letters (i.e., 1-A-2-B-3-C, etc.). The patient should be instructed to connect the circles as quickly as possible, without lifting the pen or pencil from the paper. Time the patient as he or she connects the "trail." If the patient makes an error, point it out immediately and allow the patient to correct it. Errors affect the patient's score only in that the correction of errors is included in the completion time for the task. It is unnecessary to continue the test if the patient has not completed both parts after five minutes have elapsed. The TMT is a measure of attention (A), speed (A/B) and mental flexibility (B) Wisconsin card sort test The WCST was originally developed to assess abstract reasoning and ability to shift cognitive strategies in response to environmental changes. Over the years, it has gained popularity as a clinical neuropsychological instrument. Unlike other tests of abstraction, the WCST provides objective measures not only of overall ability, but also of particular sources of difficulty--e.g., inefficient initial conceptualisation, perseveration, failure to maintain set, and inefficient learning across several stages of the test. In addition, it is one of the very few tests that have shown specific sensitivity to brain lesions involving the frontal lobes. Accordingly, it can be very helpful in discriminating frontal from nonfrontal lesions. The test uses stimulus and response cards that show various forms in various colours and numbers. Individually administered, it requires the client to sort the cards according to different principles (i.e., by color, form, or number). As the test progresses, there are

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Test Description unannounced shifts in the sorting principle which require the client to alter his or her approach

Executive Functions

Test Description CALCAP Choice reaction time California Computerized Assessment Package (CalCAP, a collection of computerised reaction time tests). Subjects are asked to press a key as soon as they see a specific number such as '7', otherwise they are to do nothing. This procedure adds a simple element of memory to the reaction time task (See definition in Psychomotor section) Control Oral Word Association The Controlled Oral Word Association (COWA) Test is a brief and sensitive measure of executive cognitive dysfunction. In addition, the Controlled Oral Word Association Test (FAS test) is another executive functioning exercise in which the examinee is asked to generate as many words as they can in a one minute span of time for the letters F, A, and S. Individuals with learning and attentional impairments often show a significant difficulty in terms of generating words starting with these letters, while also exhibiting strong vocabulary abilities

Short Category Test The Short Category test is available from Western Psychological Services. Based on the HRB category test, the SCT is a complex nonverbal task assessing concept formation and abstract reasoning Stroop The Stroop test is a test of attention and mental flexibility. The subject reads aloud the colours presented but when challenged with the word green written in red, the correct answer is red. Directed attention requires inhibition of the initial response which

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Test Description is to read the word as written, i.e. in this case green (Automated Cognitive Test system (ACTS) Syntactic Reasoning The ACT system is a key-press, menu-driven system for selecting, administering, and storing raw data from a series of specially designed psychological tasks. Associated task analysis programs process the raw data and store the resulting summary data for later statistical analysis. The system utilizes a cognitive approach to assessments of marginal toxicity by employing multiple performance parameters to specify a profile of deficits that, on the basis of a task's internal structure, can be related to functionally discrete cognitive systems. The tasks have been developed from a consideration of current cognitive theory and the areas of cognition include those of learning, memory, attention, reasoning, verbal, and spatial abilities

Trailmaking B See description given above Wisconsin card sort See description given above

Psycho-visuomotor

Test Description CALCAP Simple reaction time An investigation of changes in reaction time and speed of information processing WAIS Digit symbol Digit symbol is a subtest of the Wechsler Adult Intelligence Scale. It is a complex timed fine motor test, measuring a range of abilities including processing speed and memory. Digit symbol test: the digit symbol test worksheet contains a list of numbers that are associated with certain simple symbols and a list of random digits from one through nine with blank squares below each digit. The subject is required to fill the blank squares with the symbols paired to their corresponding digits

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Test Description and to do so as quickly as possible for 90 s Finger tapping Individuals place their dominant hand palm down, fingers extended, with the index finger resting on a lever that is attached to a counting device. Individuals are instructed to tap their index finger as quickly as possible for ten seconds, keeping the hand and arm stationary. This trial is repeated five to ten times, until the examiner has collected counts for five consecutive trials that are within five taps of each other. Before starting the test, individuals are given a practice session. They are also given brief rests between each 10-second trial, and one to two-minute rests after every third trial. This entire procedure is repeated with the non-dominant hand. The test takes approximately ten minutes to complete. Interpretation (tapping interval measured in msec) should also consider education level, intelligence, fatigue, general weakness or lack of coordination, depression, and injuries to the shoulders, arms, or hands. This test should only be interpreted in combination with other tests in the battery

Groove pegboard The Grooved Pegboard is a manipulative dexterity test consisting of 25 holes with randomly positioned slots. Pegs with a key along one side must be rotated to match the hole before they can be inserted. This test requires more complex visual- motor coordination than most pegboard tests. Some common uses are student labs, screening procedures in industry and evaluating lateralized brain damage Progressive ratio A schedule of reinforcement that is characterised by requiring the subject to make progressively more responses in order to obtain reinforcement. The subject is required to work for a reinforcement on a fixed-ratio (FR) schedule that consistently gets longer. The pattern of increment is determined in advance by the experimenter. For example,

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Test Description the schedule may start at FR 2 (two responses must be made), then FR 4, FR 8, FR 16, and so on. At some point, the demand of the schedule will be too high, and the subject will quit responding. This point is called the breaking point,, which is defined as the last completed ratio. So, if the subject made 64 responses, got the reinforcement, but then stopped responding, the breaking point would be 64. The progressive ratio schedule is a very useful measure of how motivated the subject is to obtain the reinforcement

Purdue pegboard Tests dexterity. Measures two types of activities: one involving gross movement of hands, fingers and arms; and the other involving fingertip dexterity. The Purdue Pegboard is a dexterity test to aid in the selection of employees for industrial jobs such as assembly, packing, operation of certain machines, and other manual jobs. It measures dexterity for two types of activity: one involving gross movements of hands, fingers, and arms, and the other involving primarily what might be called “fingertip” dexterity Pursuit aiming Pursuit aiming test: the pursuit aiming test requires the subject to use a pencil to place one dot inside each circle following the pattern given on the printed pursuit aiming test sheet. This task is to be performed as quickly as possible for 60 s Simple Reaction time Simple reaction time is the time taken between a stimulus and movement. In a simple reaction time experiment, the subject is presented with one simple stimulus, such as a light, and instructed to perform one simple response, such as pressing a button. In a discrimination reaction time experiment, the subject is presented with one of two or more different stimuli, such as a red light and a green light, and instructed to perform a response to only one of the stimuli, such as pressing a button when the

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Test Description red light is presented but not when the green light is presented Choice Reaction time Another type of reaction time, choice reaction time, is the time taken between stimulus and action which requires a choice. Choice Reaction Time can be improved by practice and training. Choice Reaction Time (CRT) is a 2-choice reaction time test which is similar to the Simple Reaction Time (SRT) test, except that stimulus and response uncertainty are introduced by having two possible stimuli and two possible responses. It is useful for testing general alertness and motor speed Santa Ana Dexterity Santa Ana dexterity test: in the Santa Ana dexterity test a plastic base plate with pegs fitted in rows of 12 was used. Each peg was to be removed, turned 180 degrees and replaced in its slot. The objective is to turn as many pegs as possible in 30 s. The test is repeated twice with the dominant hand and twice with the nondominant hand. The number of pegs successfully turned is recorded as the test score Tower of Hanoi The Tower of Hanoi Test is used in studies of problem solving and strategy development. Performance on the Tower of Hanoi may reflect implicit memory, strategy development, and/or higher order cognitive functioning

Visuospatial

Test Description WAIS Block Design Involves putting sets of blocks together to match patterns on cards. The WAIS IQ tests measure your non-verbal reasoning by requiring you to organize blocks as per the given patterns on cards. The colourful blocks design tells how much performing reasoning you have Hooper visual organisation The Hooper Visual Organization Test (VOT), a commonly

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Test Description applied neuropsychological test of visual spatial ability, is used for assessing patients with suspected right hemisphere, or parietal lobe involvement. Patient identifies 30 objects represented in line drawings as puzzle pieces. Test assesses neurological impairment through a quick measure of visual integration

Rey-Osterreich Complex Figure The Rey–Osterrieth Complex Figure Test (ROCF), which was developed by Rey in 1941 and standardized by Osterrieth in 1944, is a widely used neuropsychological test for the evaluation of visuospatial constructional ability and visual memory. Recently, the ROCF has been a useful tool for measuring executive function that is mediated by the prefrontal lobe. The ROCF consists of three test conditions: Copy, Immediate Recall and Delayed Recall. At the first step, subjects are given the ROCF stimulus card, and then asked to draw the same figure. Subsequently, they are instructed to draw what they remembered. Then, after a delay of 30 min, they are required to draw the same figure once again. The anticipated results vary according to the scoring system used, but commonly include scores related to location, accuracy and organization. Each condition of the ROCF takes 10 min to complete and the overall time of completion is about 30 min.

Rey complex memory (also referred to as Rey Complex Figure RCFT is a measure of visuospatial constructional ability (Copy trial) trial) and visuospatial memory (Immediate Recall, Delayed Recall, and Recognition trials). Results of factor analysis suggest the RCFT captures five domains of neuropsychological functioning: visuospatial recall memory, visuospatial recognition memory, response bias, processing speed, and visuospatial

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Test Description constructional ability. It reliably discriminates among brain- damaged, psychiatric, and normal subjects WAIS Spatial span Spatial span requires examinee to repeat a number of tapping sequences following a demonstration by the examiner, with the sequence getting longer with each trial. Similar to Digit span, both forward and backward sequences can be used

Perception

Test Description Benton Visual Discrimination test More than 50 years of proven clinical utility is the hallmark of Benton Visual Retention Test.® This test has proven its sensitivity to reading disabilities, nonverbal learning disabilities, traumatic brain injury, Attention-Deficit Disorder, Alzheimer's, and other forms of dementia. Besides easy administration, the Benton Visual Retention Test also features updated normative data, expanded scoring examples, and a detailed review of research conducted with the test.

Easy Administration Each of the 3 test forms consists of 10 designs presented one- by-one. The examinee reproduces the drawings in the Response Booklet-Record Form. The 3 alternate, equivalent forms of the Benton Visual Retention Test allow for retesting while minimizing practice effects. Interrater scoring is highly reliable (r = .95 to .97).

Poppelreuter test Overlapping figures used in the assessment of visual perceptual deficits comprise two or more line drawings that partly overlap.

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Test Description The German neuropsychiatrist Walter Poppelreuter (1886-1939) produced one example of overlapping figures The Poppelreuter figure, sometimes known as the Ghent or Poppelreuter-Ghent figure, may be characterised (in Gestalt terms) as a figure/ground discrimination task, which is acknowledged to be problematic for patients with apperceptive (but not associative) visual agnosia, especially dorsal simultanagnosia, usually associated with right posterior hemisphere lesions. Stereognosis Stereognosis tests the individual’s ability to perceive and integrate a variety of sensory modalities and to interpret the stimuli to identify small objects placed in the hand.

Expected findings - The individual can successfully identify 90- 100% of all objects placed in his/her hand within 2-3 seconds of placement.

Memory

Test Description Automated Cognitive Test system ACTS Category Search Subtest of ACTS see above Automated Cognitive Test system ACTS Location recognition Subtest of ACTS see above Automated Cognitive Test system ACTS Serial Word Learning Subtest of ACTS see above WMS-Auditory Wechsler Memory Scale 3rd Edition (WMS III Test) updates the WMS-R and provides subtest and composite scores that assess memory and attention functions using both auditory and visual stimuli. There are now eight Primary Indexes: 8 Primary Indexes of the WMS III: Auditory Immediate, Visual Immediate, Immediate Memory, Auditory Delayed, Visual Delayed, Auditory

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Test Description Reception Delayed, General Memory, and Working Memory Benton Visual retention test The Benton Revised Visual Retention Test is a widely used instrument that assesses visual perception, visual memory, and visuoconstructive abilities. Because it measures perception of spatial relations and memory for newly learned material, it is used in clinical diagnosis of brain damage and dysfunction in children and adults, as well as in research. The Benton, as it is usually called, has three alternate forms, each of which consists of ten designs. In addition, there are four possible modes of administration. The Benton Visual Retention Test is an individually administered test for ages 8-adult that measures visual perception and visual memory. It can also be used to help identify possible learning disabilities. The subject is shown 10 designs, one at a time, and asked to reproduce each one as exactly as possible on plain paper from memory. The test is untimed, and the results are professionally scored by form, shape, pattern, and arrangement on the paper. Number of correct/incorrect answers can be scored Brief visual memory test The Brief Visuospatial Memory Test - Revised or BVMT-R can be used as a criterion measure of visuospatial memory, within a large battery of neuropsychological tests; as a screening measure within a brief, neuropsychological battery; or as a repeat measure to document changes in neurocognitive skills over time. In this test, patients are presented with an 8 x 11 inch plate containing six geometric visual designs in a 2 x 3 matrix. The stimulus is presented for 10 seconds and patients are instructed to reproduce as many designs as possible after the stimulus is removed from view California verbal learning test The California Verbal Learning Test (CVLT) is a neuropsychological test which can be used to assess an individual's verbal memory abilities. The tester reads aloud a list,

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Test Description called "Monday's shopping list". The list contains sixteen common words, each of which belongs to one of four categories: thus, there are four fruits, four herbs and spices, etc. The subject is then asked to recall as many of these items as possible

There are several components to this test. First, the tester records how many items the subject remembers over several repeated trials. Additionally, the tester records whether or not the subject is making use of category information. For instance, suppose the four fruit items are Apples, Bananas, Oranges, Cherries, and suppose the subject can only remember Apples, Bananas and Oranges. If the subject cannot remember the fourth item, but guesses that it is another fruit (e.g., Grapes), the tester concludes that the subject understood the category information in the list. If the subject guesses an unrelated word (e.g., Chicken), the tester concludes that the subject was not able to understand the category information in the list. Next, the tester may give a second list ("Tuesday's shopping list"), and see if the subject is able to keep the items from each list separate, or if the two lists become confused.

Finally, there is a short delay of 20 minutes, during which the subject is given other tasks to perform, and then the tester again asks the subject to recall Monday's list.

Because it contains so many different components, the CVLT is fairly popular as a neuropsychological test of many aspects of verbal learning and memory Location recognition A different variety of memory test is recognition testing. In recognition testing, the subject views stimuli such as words or pictures or locations

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Test Description WMS-Logical memory The Logical memory subtest of WMS-III uses an oral presentation of a story for immediate (LM1) and delayed (LM2) recall and a recognition test MMSE recall Ask the patient if you may test his memory. Then say the names of three unrelated objects, clearly and slowly, about one second for each. After you have said all three, ask the patient to repeat them. This first repetition determines the patient’s score (out of 3) but keep saying them until the patient can repeat all three (up to six trials). If he/she does not eventually learn all three, it is unlikely that recall can be meaningfully tested. Recall is tested after the attention/calculation sections of MMSE. Ask the patient if he/she can recall the three words you previously asked him/her to remember. Score one for each correct answer Oregon Dual Task a forced-choice measure of recognition memory Paired associates This challenging test assesses visual memory and new learning, and is a useful tool for assessing individuals with questionable dementia, mild cognitive impairment, Alzheimer's Disease, and age-related memory loss.

Boxes are displayed on the screen and are opened in a randomised order. One or more of them will contain a pattern. The patterns are then displayed in the middle of the screen, one at a time, and the participant must touch the box where the pattern was originally located. If the participant makes an error, the patterns are re-presented to remind the participant of their locations. The difficulty level increases through the test. In the clinical mode, the number of patterns increases from one to eight, which challenges even very able participants Rey complex figure recall See Rey complex figure above Rey auditory verbal learning The Rey Auditory Verbal Learning Test (RAVLT) is an efficient neuropsychological instrument for evaluating episodic

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Test Description declarative memory. It provides scores for assessing immediate memory, new verbal learning, susceptibility to interference (proactive and retroactive), retention of information after a period of time, and memory recognition Serial word learning Word-list verbal learning and memory tests with appropriate normative data can be highly sensitive to cognitive decline. Serial word learning is a key part of the Rey auditory verbal learning. The AVLT is a serial word learning task in which 15 words are presented over five learning trials, followed by a second learning list, and then free-recall of the original list of 15 words Story recall A and B The story recall test (SRT) is one of the most reliable neuropsychological assessments for evaluating verbal memory function in order to distinguish between individuals with normal aging, mild cognitive impairment (MCI), and Alzheimer's disease (AD). The SRT is analogous to the logical memory test in Wechsler Memory Scale-III, The Story Recall Test used to be known as the Auditory Comprehension Test. It consists of 30 short stories, which were recorded in a professional studio and which are now available in digital form. The stories can be played via computer speakers or headphones. It is important to use more than one or two stories to get a reliable measure of immediate or delayed story recall. Five stories was found to be the minimum needed for reliability. Those with impaired immediate story recall tend to have unusually large fluctuations from one story to another and it is easy to miss deficits in story recall if only one or two stories are used

Subjective memory questionnaire Questionnaire based approach to self assessment. Examples: How would you rate your memory overall? Poor 1 2Good 3 4 5 Excellent 6 7

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Test Description

How often do these present a problem for you? Always1 2 Sometimes3 4 5 Never 6 7 • names 1 2 3 4 5 6 7 • faces 1 2 3 4 5 6 7 Total score…..

WMS-visual memory A subtest of WMS-III (now replaced by WMS-IV Visual reproduction test).

Visual Reproduction scores – Immediate Recall – scaled score – Delayed Recall – scaled score – Delayed Recognition – cumulative percentage

Language

Test Description Boston naming (60) This 60-item test helps determine the extent of visual confrontation naming abilities. A 15-item short form and a multiple-choice version of the test can be used to retest comprehension of any words missed on the confrontation naming exercise MMSE comprehension See description of Mini mental State Examination above Thurstone verbal fluency Similar to controlled oral word test. Task 1 -subjects must write as many words as possible beginning with the letter "S" in five minutes(1 rule). Task 2- subjects must write as many words as possible beginning with the letter "C" in four minutes BUT the words must be four letters only. Successful performance on these tests depends on the subject's ability to organise output in terms of clusters of

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Test Description meaningfully related words WAIS-vocabulary Subtest of WAIS, see above explanation of WAIS-IV subtests

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References

http://faculty.washington.edu/chudler/java/ready.html Encyclopedia of Mental Disorders (www.mindisorders.com) http://www.psychpage.com/learning/library/intell/wais_history.html# http://wilderdom.com/personality/intelligenceWAISWISC.html http://www.crs.dk/function.html Johnson SC J Int Neuropsychol,7,55-62,2001 http://www.neurobs.com/ex_files/expt_view?id=218 http://www.ncbi.nlm.nih.gov/pubmed/11935454 http://www.medicine.mcgill.ca/strokengine-assess/module_slct_intro-en.html http://neuro.psychiatryonline.org/cgi/content/full/22/4/451-w.e38 http://www.brainmetric.com/ http://www.ncbi.nlm.nih.gov/pubmed/1484803 http://www.granddriver.net/data/media/docs/UIowa_trailMaking.pdf http://www.howardlas.com/adhd-article5.php http://www.sciencedirect.com/science/article/pii/0892036296000323 http://www.lafayetteevaluation.com/product_detail.asp?ItemID=167 http://www.camcog.com/en/science/tests/crt http://www.personality-and-aptitude-career-tests.com/wais-iq-test.html http://journals.cambridge.org/action/displayAbstract?fromPage=online&aid=270606 http://cps.nova.edu/~cpphelp/BVRT.html http://www.matrics.ucla.edu/meetings/september-2003/RAND_Panel_VisualLearn-8-31-03.pdf http://www.memorylossonline.com/glossary/californiaverballearningtest.html http://www.psywww.com/intropsych/ch06_memory/tests_of_recognition.html http://www.psycneuro.org/index.php/psycneuro/article/viewFile/74/318 Loring DW J of International neuropsych soc, 14, 394-400, 2008 http://155.100.238.116/cacir/docs/Loring_JINS08_LTE.pdf http://www.tandfonline.com/doi/abs/10.1080/13825585.2010.530221 http://www.wordmemorytest.com/srt.php http://neuro.psyc.memphis.edu/neuropsyc/np-test1.htm http://www.pearsonassessments.com/HAIWEB/Cultures/en-us/Productdetail.htm?Pid=015-8027-507&Mode=summary

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Sells R and Larner AJ. Progress in neurology and Psychiatry, 15, 17-21, 2011http://onlinelibrary.wiley.com/doi/10.1002/pnp.193/pdf

Essentials of Neuropsychological Assessment. http://books.google.co.uk/books?id=UOrOPZR_tfkC&pg=PT125&lpg=PT125&dq=Short+Category+Test+description&source=bl&ots =ErLD86aBfp&sig=e-wg3L6KZpB2K1bi-zcZwDPCnUg&hl=en#v=onepage&q&f=false http://snre.umich.edu/eplab/demos/st0/stroopdesc.html

Neuropsychological interpretation of objective psychological tests. Edited Golden CJ, Espe-Pfiefer P, and Wechsler-Felder J, pub 2000, Kluwer Academic USA, ISBN 0-306-46224-9. http://books.google.co.uk/books?id=7O66Q2- Oa9gC&pg=PA124&lpg=PA124&dq=WAIS+Digit+symbol&source=bl&ots=9RqVoZ5Muu&sig=BXSNjBP8gAyQ37VmrHWfQrNbUE g&hl=en#v=onepage&q=WAIS%20Digit%20symbol&f=false

Encyclopedia of Psychology. http://www.enotes.com/gale-psychology-encyclopedia/reaction-time

Clinical Interpretation of WAIS-III and WMS-III, Editied Tulsky DS et al, Elsevier, pub 2003. http://books.google.co.uk/books?id=8Q19rYe9JiUC&pg=PA122&lpg=PA122&dq=WAIS+Spatial+span&source=bl&ots=tMEPIyp9rn &sig=3BV7rPX9HSoIvBkWfZzUnnYPQtY&hl=en#v=onepage&q=WAIS%20Spatial%20span&f=false

Shin MS et al Nature Protocols, 1, 892-899, 2006

Members may wish to visit the following internet site where it is possible to undertake some of these tests. http://www.cogtest.com/tests/cognitive_int/ads.html http://www.intelligencetest.com/mindgames/hanoi.htm

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