Sarah Mackenzie Ross

Neuropsychological and psychiatric functioning in sheep farmers exposed to low levels of organophosphate pesticides.

The study aim was to determine whether low level exposure to organophosphate pesticides (OPs) causes neuropsychological or psychiatric impairment. Methodological weaknesses of earlier studies were addressed by: recruiting participants who had retired on ill health grounds; excluding participants with a history of acute poisoning, medical or psychiatric conditions that might account for ill health; and exploring factors which may render some individuals more vulnerable to the effects of OPs than others. Performance on tests of cognition and mood of 127 exposed sheep farmers (67 working, 60 retired) was compared with 78 unexposed controls (38 working, 40 retired) and published test norms derived from a cross section of several thousand adults in the general population. Over 40% of the exposed cohort reported clinically significant levels of anxiety and depression compared to less than 23% of controls. Exposed subjects performed significantly worse than controls and standardisation samples on tests of memory, response speed, fine motor control, mental flexibility and strategy making, even after controlling for the effects of mood. The pattern was similar for both working and retired groups. The cognitive deficits identified cannot be attributed to mood disorder, malingering, a history of acute exposure or genetic vulnerability in terms of PON1(192) polymorphisms. Results suggest a relationship may exist between low level exposure to organophosphates and impaired neurobehavioural functioning and these findings have implications for working practice and for other occupational groups exposed to OPs such as aviation workers and Gulf War veterans.

Neurobehavioral problems following low-level exposure to organophosphate pesticides: a systematic and meta-analytic review

Meta-analysis was carried out to determine the neurotoxic effects of long-term exposure to low levels of organophosphates (OPs) in occupational settings. Concern about the effects of OPs on human health has been growing as they are increasingly used throughout the world for a variety of agricultural, industrial and domestic purposes. The neurotoxic effects of acute poisoning are well established but the possibility that low-level exposure causes ill health is controversial. It is important to get a clear answer to this question as more individuals are at risk of low-level exposure than acute poisoning. Although a number of reviews on this topic have been published in the past, authors have come to conflicting conclusions. To date, none of these reviews have attempted quantitative evaluation of study findings using meta-analysis. This paper reviews the available evidence concerning the neurotoxicity of low-level occupational exposure to OPs and goes on to report the results of a meta-analysis of 14 studies which fulfilled criteria for this type of statistical analysis (means and standard deviations of dependant variables reported). Data were assimilated from more than 1600 participants. The majority of well designed studies found a significant association between low-level exposure to OPs and impaired neurobehavioral function which is consistent, small to moderate in magnitude and concerned primarily with cognitive functions such as psychomotor speed, executive function, visuospatial ability, working and visual memory. Unresolved issues in the literature which should become the focus of further studies are highlighted and discussed.

Cognitive function following exposure to contaminated air on commercial aircraft: A case series of 27 pilots seen for clinical purposes

Background. Cabin air on commercial aircraft is sometimes contaminated with hydraulic fluids, synthetic jet engine oils and combusted or pyrolized materials. The incidence of contaminated air events is hard to quantify as commercial aircraft do not have air quality monitoring systems on board. In the UK, around 350 aircrew have advised their union that they may be suffering physical and psychological ill health following exposure to contaminated air. Design. This paper presents a case series of 27 pilots referred for psychological assessment. The general aim of the assessment was to determine whether pilots show evidence of cognitive impairment and whether this relates to exposure history. Materials and method. All pilots underwent neuropsychological and adult mental health assessment, undertaken by 12 examiners, instructed to search for alternative explanations other than exposure to toxic fumes for any symptoms reported. Results. Pilots reported alarming cognitive failures at work such as being unable to retain or confusing numerical information from Air Traffic Control. Nine pilots were excluded from further analysis because they had a medical or psychiatric condition which might otherwise explain these difficulties. In the remaining 18 pilots, language, perceptual skills and general intellectual ability were preserved, but performance on tests of psychomotor speed, attention and executive functioning was below expected levels. Conclusions. The cognitive deficits identified in this cohort of pilots cannot be attributed to factors such as mood disorder or malingering. However, the evidence available in this study does not enable firm conclusions to be drawn regarding a causal link with contaminated air; the cohort of pilots was self-selected and only crude indices of exposure were available. Further research is warranted given the scientific uncertainty regarding the health effects of inhalation of heated or pyrolized engine oil.

Profound retrograde amnesia following mild head injury: organic or functional?

This paper describes a 56 year old female patient (JJ) who suffered a minor head injury at work and presented with profound retrograde amnesia for both public events and autobiographical material spanning her entire life. In addition, she complained of word-finding difficulties and anterograde memory impairment and neuropsychological assessment found evidence of mild executive dysfunction. Neurological investigations (CT and EEG) were essentially normal although changes indicative of small vessel disease were noted on MRI brain scan. Various forms and aetiologies of remote memory loss were considered including, simulated, psychogenic and organic amnesia, but differential diagnosis proved difficult. It is proposed that criteria used in clinical practice to differentiate functional and organic complaints are limited and this may be because (1) both factors can be involved in the aetiology of amnesia, and (2) a similar underlying brain mechanism, such as a retrieval deficit could underlie many instances of organic and psychogenic amnesia. Future research, complemented by functional brain imaging, is needed to explore the nature of retrieval deficits.

An emerging concern: Toxic fumes in airplane cabins

Toxicology is a new science, the complexities of which have been highlighted in the papers contained within this special section. Our understanding of the mechanisms through which various chemicals interfere with nervous system function is constantly evolving and research is unable to keep up with the speed with which new chemicals are produced and put onto the market. Thus there are often controversies surrounding the health-effects of commercially available compounds and disagreement around what constitutes safe exposure limits. This article will introduce readers to an emerging concern in this field, the potential risk to health of toxic fumes in airplane cabins. We explore the challenges and methodological issues encountered by researchers who have tried to investigate this issue and highlight the need for further research on this topic. We hope this article will promote discussion amongst academics and clinicians, and lead to the identification of creative solutions to the methodological issues encountered to date.

Anxiety and depression following cumulative low-level exposure to organophosphate pesticides

Previous research suggests that individuals with a prior history of pesticide poisoning are at increased risk of psychiatric disorder (Freire and Koifman, 2013), but findings regarding the impact of cumulative low-level exposure are inconsistent. The aim of the current study was to investigate whether sheep farmers with a history of low-level exposure to organophosphate pesticides (1) report a higher level of psychological distress on subjective symptom questionnaires, compared to unexposed controls (2) also meet internationally agreed diagnostic criteria for a psychiatric disorder more often than unexposed controls. 127sheep farmers were evaluated and compared to 78 unexposed controls, matched in terms of gender, education, level of intelligence, working status and area of residence. Both self-report measures and structured clinical interviews were used to assess mental health. The exposed cohort reported significantly higher rates of anxiety and depression when self-report questionnaires were used to evaluate mood, even when stressful life events, demographic and physical health factors were taken into account. However, when diagnostic interviews were used to assess mood, this pattern only held true for anxiety.

Delayed cognitive and psychiatric symptoms following methyl iodide and manganese poisoning: Potential for misdiagnosis

This paper describes two patients who were exposed to toxic substances in the workplace, but for whom diagnosis proved difficult, particularly in case 2. Case 1 was exposed to methyl iodide and case 2 to manganese. Poisoning was characterised by delayed onset of symptoms following exposure and symptom progression after cessation of exposure. The clinical consequences of exposure to these substances include cerebellar and Parkinsonian symptoms followed by the development of cognitive impairment and the late appearance of psychiatric disturbances. Both cases were evaluated by physicians with little training in toxicology. Apart from abnormal liver function in case 1 and decreased power, coordination and proprioception in case 2, results of most routine medical investigations were normal. Both cases were referred for MRI brain scan and neuropsychological assessment. Abnormalities were noted on MRI but reported as being absent initially in case 1and of unknown significance in case 2. There was evidence of cognitive impairment in both and personality change in case 1 of sufficient severity to prevent both cases from returning to work and to impact on family life. There is no antidote to methyl iodide or manganese poisoning. Successful treatment requires early diagnosis and cessation of exposure, but neurotoxic syndromes are difficult to diagnose when a time lag exists between exposure and symptom onset and there is no biomarker of exposure. These syndromes may initially be confused with other neurodegenerative conditions, infectious processes, and psychiatric disorders. Clinicians lack of familiarity with the potential toxicity of environmental and industrial chemicals can lead to misdiagnosis and mismanagement, and this lack of recognition can lead to continued exposure. These cases highlight the importance of taking a detailed occupational history in patients who present with atypical neurological symptoms.This paper describes two patients who were exposed to toxic substances in the workplace, but for whom diagnosis proved difficult, particularly in case 2. Case 1 was exposed to methyl iodide and case 2 to manganese. Poisoning was characterised by delayed onset of symptoms following exposure and symptom progression after cessation of exposure. The clinical consequences of exposure to these substances include cerebellar and Parkinsonian symptoms followed by the development of cognitive impairment and the late appearance of psychiatric disturbances. Both cases were evaluated by physicians with little training in toxicology. Apart from abnormal liver function in case 1 and decreased power, coordination and proprioception in case 2, results of most routine medical investigations were normal. Both cases were referred for MRI brain scan and neuropsychological assessment. Abnormalities were noted on MRI but reported as being absent initially in case 1and of unknown significance in case 2. There was evidence of cognitive impairment in both and personality change in case 1 of sufficient severity to prevent both cases from returning to work and to impact on family life. There is no antidote to methyl iodide or manganese poisoning. Successful treatment requires early diagnosis and cessation of exposure, but neurotoxic syndromes are difficult to diagnose when a time lag exists between exposure and symptom onset and there is no biomarker of exposure. These syndromes may initially be confused with other neurodegenerative conditions, infectious processes, and psychiatric disorders. Clinicians lack of familiarity with the potential toxicity of environmental and industrial chemicals can lead to misdiagnosis and mismanagement, and this lack of recognition can lead to continued exposure. These cases highlight the importance of taking a detailed occupational history in patients who present with atypical neurological symptoms.

Reflections on the process of using systematic review techniques to evaluate the literature regarding the neurotoxicity of low level exposure to organophosphate pesticides

We undertook a systematic review (incorporating meta-analysis) of the literature concerning the neurotoxicity of cumulative low level occupational exposure to organophosphate pesticides, which was published online by the journal Critical Reviews in Toxicology in 2012. As far as we are aware, we were the first research team to attempt quantitative evaluation of study findings on this topic, using meta-analysis. We wish to encourage others to apply systematic review techniques in chemical risk assessment to reduce bias, increase transparency and better inform public policy. We thought it would be useful to share our experience of undertaking a systematic review in the hope of dispelling misconceptions about the complexity, time and resource issues involved along with the view that meta-analysis is meaningless when studies are not homogeneous. In this commentary paper we reflect on aspects of the process which were relatively straightforward; aspects which were more challenging; the advantages of using systematic review techniques; and the advantages and limitations of using statistical techniques such as meta-analysis in this context.

A reply to Pigatto, Ronchi & Guzzi's commentary

Pigatto, Ronchi, and Guzzi (2017) comment on a single case study which I presented in a special section of Cortex on the Neurobehavioural consequences of exposure to industrial, agricultural and environmental chemicals published in January 2016. This case study concerned a man who exhibited delayed psychiatric and cognitive symptoms following exposure to manganese at work (case 2; Mackenzie Ross, 2016). I would like to thank the authors for their interest and positive comments regarding the article and for bringing to the attention of readers the fact that a small number of animal studies and human case reports suggest that intravenous administration of calcium disodium EDTA (CA-EDTA: a chelating agent used for its metal binding effects) can reduce levels of manganese in key organs (such as the brain and liver) and has been associated with improved outcome in some human case studies. In my article I discuss how doctors did not consider a toxic cause for the symptoms reported by case 2 until more than ten years had elapsed following exposure, which is unfortunate and deprived him of the opportunity to undergo chelation therapy whichmay have benefited him if offered earlier in the course of his condition. The primary issue highlighted in my article, is that UK physicians receive little training in toxicology and lack familiarity with the potential toxicity of environmental and industrial chemicals which can lead to misdiagnosis and mismanagement. However, it is important to note that chelation treatment does not work in all cases (Dobbs, 2009; Hernandez et al., 2006; Lee, 2000) and there is no guarantee it would have worked for case 2. Indeed, urinary excretion of manganese has been detected in individuals without a significant exposure history to manganese, following the administration of chelating agents and the relationship between urinary excretion of manganese and symptom expression/progression remains unclear (Dobbs, 2009). Further research in larger groups of patients is required to establish whether Ca-EDTA treatment is effective and if so, to determine the therapeutic dose, duration and timing of treatment and to identify factors

What's your poison? Neurobehavioural consequences of exposure to industrial, agricultural and environmental chemicals

Toxicology is a multi-disciplinary science which draws on a number of disciplines to determine the adverse effects of chemicals in living organisms. There has been a huge increase in toxicological research over the last seventy years, as concerns have grown about the possible effects of exposure to the increasing number of industrial and environmental chemicals being produced every year, such as synthetic chemicals, fuels, pesticides, solvents, carbon monoxide, metals and related elements such as lead, mercury and arsenic (Klaassen, 2008). There are literally thousands of substances that possess the capacity to do harm in sufficient doses, and pollutants are now widespread in air, water, soil, food, homes, schools and workplaces. It has been estimated that there are over 100,000 toxic substances in commercial use and approximately 2,300 new chemicals developed and submitted for registration every year [Environmental Protection Agency Office of Pollution Prevention and Toxics (OPPT) 2011; European Inventory of Existing Commercial Chemical Substances, 2011]. The capacity of industry to produce chemical substances outstrips research, meaning our knowledge regarding the potential health effects of many substances is limited, giving rise to differences in opinion and controversies regarding safe exposure standards for new and existing substances. Establishing safe exposure standards is fraught with difficulty and is dependent on the outcome of interest (e.g., mortality, carcinogenicity, reproductive effects, physical ill health, neurological symptoms). In an ideal world the dose/response relationship for each potential health effect would be known, but financial constraints, concern for the welfare of animals andmethodological issuesmean not all of these outcomes are studied (Klaassen, 2008). To complicate matters further, there are substantial inter-individual differences in peoples ability