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Amyotrophic Lateral Sclerosis (ALS)

• Residential exposure associations with ALS risk, survival, and phenotype: a Michigan-based case-control study
  Background: Environmental exposures impact amyotrophic lateral sclerosis (ALS) risk and progression, a fatal and progressive neurodegenerative disease. Better characterization of these exposures is needed to decrease disease burden. Objective: To identify exposures in the residential setting that associate with ALS risk, survival, and onset segment. Methods: ALS and control participants recruited from University of Michigan completed a survey that ascertained exposure risks in the residential setting. ALS risk was assessed using logistic regression models followed by latent profile analysis to consider exposure profiles. A case-only analysis considered the contribution of the residential exposure variables via a Cox proportional hazards model for survival outcomes and multinomial logistic regression for onset segment, a polytomous outcome. Results: This study included 367 ALS and 255 control participants. Twelve residential variables were associated with ALS risk after correcting for multiple comparison testing, with storage in an attached garage of chemical products including gasoline or kerosene (odds ratio (OR) = 1.14, padjusted < 0.001), gasoline-powered equipment (OR = 1.16, padjusted < 0.001), and lawn care products (OR = 1.15, padjusted < 0.001) representing the top three risk factors sorted by padjusted. Latent profile analysis indicated that storage of these chemical products in both attached and detached garages increased ALS risk. Although residential variables were not associated with poorer ALS survival following multiple testing corrections, storing pesticides, lawn care products, and woodworking supplies in the home were associated with shorter ALS survival using nominal p values. No exposures were associated with ALS onset segment. Conclusion: Residential exposures may be important modifiable components of the ALS susceptibility and prognosis exposome.
  [Goutman, S.A. et al. (2024) ‘Residential exposure associations with ALS risk, survival, and phenotype: A Michigan-based case-control study’, Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. Available at: https://www.tandfonline.com/doi/full/10.1080/21678421.2024.2336110. ]
• Influence of pesticide exposure on farmers’ cognition: A systematic review
  

  Abstract

  Objectives:

  Pesticide application has become necessary to increase crop productivity and reduce losses. However, the use of these products can produce toxic effects. Farmers are individuals occupationally exposed to pesticides, thus subject to associated diseases as well as cognitive impairment. However, this relation is not well established in the literature, requiring further investigation. To assess the potential association between farmers’ pesticide exposure and cognitive impairment, we followed the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines, considering participants, interventions, comparators, outcomes, and study strategies.

  Materials and Methods:

  This study included articles published between 2000 and 2021 on the Scopus, Web of Science, ScienceDirect, and PubMed databases, retrieved by the terms “pesticides and cognition” and “pesticides and memory.”

  Results:

  In total, ten studies fit the established criteria and were included in the sample. All had farmers occupationally exposed to pesticides in their sample and only one study dispensed with a control group. Of the neurobehavioral tests, four studies used mini-mental state examination, six neurobehavioral core test batteries (tests recognized in the area), and the remaining, other tests. We observed that 90% of articles found an association between cognitive impairment and pesticide exposure. Overall, five studies measured the activity of cholinesterases in their sample, of which three found significant differences between groups, confirming intoxication in those exposed.

  Conclusion:

  Despite the limited number of trials, we found scientific evidence to support the existence of adverse effects of pesticides on farmers’ cognition. We recommend that future studies research similar projects, expanding knowledge on the subject.

  
  [Finhler, S. et al. (2023) ‘Influence of pesticide exposure on farmers’ cognition: A systematic review’, Journal of Neurosciences in Rural Practice, 14, pp. 574–581. doi:10.25259/jnrp_58_2023. ]
• Associations of self-reported occupational exposures and settings to ALS: a case–control study
  Background
  Environmental exposures contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS), a fatal and progressive neurological disease. Identification of these exposures is important for targeted screening and risk factor modification.

  Objective
  To identify occupational exposures that are associated with a higher risk of ALS using both survey and standard occupational classification (SOC) coding procedures, and to highlight how exposure surveys can complement SOC coding.

  Methods
  ALS participants and neurologically healthy controls recruited in Michigan completed a detailed exposure assessment on their four most recent and longest held occupations. Exposure scores were generated from the exposure survey, and occupations were assigned to SOC codes by experienced exposure scientists.

  Results
  This study included 381 ALS and 272 control participants. ALS participants reported higher duration-adjusted occupational exposure to particulate matter (OR = 1.45, 95% CI 1.19–1.78, p < 0.001), volatile organic compounds (OR = 1.22, 95% CI 1.02–1.45, p = 0.029), metals (OR = 1.48, 95% CI 1.21–1.82, p < 0.001), and combustion and diesel exhaust pollutants (OR = 1.20, 95% CI 1.01–1.43, p = 0.041) prior to ALS diagnosis, when adjusted for sex, age, and military service compared to controls. In multivariable models, only occupational exposure to metals remained significant risk (OR = 1.56, 95% CI 1.11–2.20, p = 0.011), although in an adaptive elastic net model, particulate matter (OR = 1.203), pesticides (OR = 1.015), and metals (1.334) were all selected as risk factors. Work in SOC code “Production Occupations” was associated with a higher ALS risk. SOC codes “Building and Grounds Cleaning and Maintenance Occupations”, “Construction and Extraction Occupations”, “Installation, Maintenance, and Repair Occupations”, and “Production Occupations” were all associated with a higher exposure to metals as determined using survey data.

  Discussion
  Occupational exposure to particulate matter, volatile organic compounds, metals, pesticides, and combustion and diesel exhaust and employment in “Production Occupations” was associated with an increased ALS risk in this cohort.
  [Goutman, S.A. et al. (2022) Associations of self-reported occupational exposures and settings to ALS: A case–control study, Int Arch Occup Environ Health. Available at: https://link.springer.com/article/10.1007/s00420-022-01874-4#citeas. ]

• Pesticides applied to crops and amyotrophic lateral sclerosis risk in the U.S
  Environmental exposures are implicated in the etiology of amyotrophic lateral sclerosis (ALS). Application of insecticides, herbicides, and fungicides with neurotoxic properties to crops is permitted in the U.S., however reporting of the quantities is government mandated. To identify pesticides that may be associated with ALS etiology for future study. The study geospatially estimated exposure to crop-applied pesticides as risk factors for ALS in a large de-identified medical claims database, the SYMPHONY Integrated Dataverse®. We extracted residence at diagnosis of ∼26,000 nationally distributed ALS patients, and matched non-ALS controls. We mapped county-level U.S. Geological Survey data on applications of 423 pesticides to estimate local residential exposure. We randomly broke the SYMPHONY dataset into two groups to form independent discovery and validation cohorts, then confirmed top hits using residential history information from a study of NH, VT, and OH. Pesticides with the largest positive statistically significant associations in both the discovery and the validation studies and evidence of neurotoxicity in the literature were the herbicides 2,4-D (OR 1.25 95 % CI 1.17–1.34) and glyphosate (OR 1.29 95 %CI 1.19–1.39), and the insecticides carbaryl (OR 1.32 95 %CI 1.23–1.42) and chlorpyrifos (OR 1.25 95 %CI 1.17–1.33). The geospatial analysis results support potential neurotoxic pesticide exposures as risk factors for sporadic ALS. Focused studies to assess these identified potential relationships are warranted.
  [Andrew, A., Zhou, J., Gui, J., Harrison, A., Shi, X., Li, M., Guetti, B., Nathan, R., Tischbein, M., Pioro, E.P. and Stommel, E. NeuroToxicology, 87, pp.128-135.]
• Clinical and Lifestyle Factors and Risk of Amyotrophic Lateral Sclerosis: A Population-Based Case-Control Study
  Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease of the motor neurons. The etiology of ALS remains largely unknown, particularly with reference to the potential environmental determinants. We performed a population-based case-control study in four provinces from both Northern and Southern Italy in order to assess non-genetic ALS risk factors by collecting through tailored questionnaires information about clinical and lifestyle factors. We estimated ALS risk by calculating odds ratio (OR) with its 95% confidence interval (CI) using unconditional logistic regression models adjusted for sex, age and educational attainment. We recruited 230 participants (95 cases and 135 controls). We found a possible positive association of ALS risk with trauma, particularly head trauma (OR = 2.61, 95% CI 1.19–5.72), electric shock (OR = 2.09, 95% CI 0.62–7.06), and some sports, although at a competitive level only. In addition, our results suggest an increased risk for subjects reporting use of private wells for drinking water (OR = 1.38, 95% CI 0.73–2.27) and for use of herbicides during gardening (OR = 1.95, 95% CI 0.88–2.27). Conversely, there was a suggestion of an inverse association with overall fish consumption (OR = 0.27, 95% CI 0.12–0.60), but with no dose-response relation. Consumption of some dietary supplements, namely those containing amino acids and, in the Southern Italy population, vitamins and minerals such as selenium, seemed associated with a statistically imprecise increased risk. Our results suggest a potential etiologic role a number of clinical and lifestyle factors with ALS risk. However, caution is needed due to some study limitations. These include the small sample size and the low number of exposed subjects, which affect statistical precision of risk estimates, the potential for exposure misclassification, and the uncertainties about mechanisms underpinning the possible association between these factors and disease risk.
  [Filippini, T., Fiore, M., Tesauro, M., Malagoli, C., Consonni, M., Violi, F., Arcolin, E., Iacuzio, L., Oliveri Conti, G., Cristaldi, A. and Zuccarello, P., 2020. International journal of environmental research and public health, 17(3), p.857.]
• Environmental and Occupational Risk Factors of Amyotrophic Lateral Sclerosis: A Population-Based Case-Control Study
  Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease with still unknown etiology. We aimed at investigating the association between environmental and occupational factors with ALS risk. We performed a population-based case-control study in four Italian provinces (Catania, Modena, Novara, and Reggio Emilia) by administration of tailored questionnaires to ALS cases (n = 95) and randomly selected population referents (n = 135). We estimated ALS risk by calculating the odds ratio (OR) with its 95% confidence interval (CI) using an unconditional logistic regression model. We found a positive association with disease risk for history of occupation in the agricultural sector (OR = 2.09, 95% CI 0.79–7.54), especially for longer than 10 years (OR = 2.72, 95% 1.02–7.20). Overall occupational exposure to solvents also suggested a positive association, especially for thinners (OR = 2.27, 95% CI 1.14–4.54) and paint removers (OR = 2.01, 95% CI 0.90–4.48). Both occupational and environmental exposure to electromagnetic fields show a slightly increased risk with OR = 1.69 (95% CI 0.70–4.09) and 2.41 (95% CI 1.13–5.12), respectively. Occupational but not environmental exposure to pesticides (OR = 1.22, 95% CI 0.63–2.37), particularly fungicides, and exposure to metals (OR = 4.20, 95% CI 1.88–9.38), particularly lead, mercury, and selenium, showed an imprecise but positive association. Finally, there was an indication of increased risk for living in proximity to water bodies. Despite the caution that needs to be used due to some study limitations, such as the low number of exposed subjects and the possibility of recall bias, these results suggest the potential role of some environmental and occupational factors in ALS etiology.
  [Filippini, T., Tesauro, M., Fiore, M., Malagoli, C., Consonni, M., Violi, F., Iacuzio, L., Arcolin, E., Oliveri Conti, G., Cristaldi, A. and Zuccarello, P., 2020. International Journal of Environmental Research and Public Health, 17(8), p.2882.]
• Environmental and Occupational Exposures and Amyotrophic Lateral Sclerosis in New England
  Recent data provide support for the concept that potentially modifiable exposures are responsible for sporadic amyotrophic lateral sclerosis (ALS). To evaluate environmental and occupational exposures as risk factors for sporadic ALS. We performed a case-control study of ALS among residents of New England, USA. The analysis compared questionnaire responses from 295 patients with a confirmed ALS diagnosis to those of 225 controls without neurodegenerative illness. Self-reported job- or hobby-related exposure to one or more chemicals, such as pesticides, solvents, or heavy metals, increased the risk of ALS (adjusted OR 2.51; 95% CI 1.64-3.89). Industries with a higher toxicant exposure potential (construction, manufacturing, mechanical, military, or painting) were associated with an elevated occupational risk (adjusted OR 3.95; 95% CI 2.04-8.30). We also identified increases in the risk of ALS associated with frequent participation in water sports, particularly waterskiing (adjusted OR 3.89; 95% CI 1.97-8.44). Occupation and waterskiing both retained independent statistical significance in a composite model containing age, gender, and smoking status. Our study contributes to a growing body of literature implicating occupational- and hobby-related toxicant exposures in ALS etiology. These epidemiologic study results also provide motivation for future evaluation of water-body-related risk factors.
  [Andrew, A.S., Caller, T.A., Tandan, R., Duell, E.J., Henegan, P.L., Field, N.C., Bradley, W.G. and Stommel, E.W., 2017. Neurodegenerative Diseases, 17(2-3), pp.110-116.]
• Pesticides, polychlorinated biphenyls and polycyclic aromatic hydrocarbons in cerebrospinal fluid of amyotrophic lateral sclerosis patients: a case-control study
  Neurotoxic chemicals including several pesticides have been suggested to play a role in the etiology of amyotrophic lateral sclerosis (ALS). We investigated the relation between organochlorine pesticides and their metabolites (OCPs), polychlorinated biphenyls (PCBs) and polycyclic aromatic hydrocarbons (PAHs) in the etiology of sporadic ALS, determining for the first time their levels in cerebrospinal fluid as indicator of antecedent exposure. We recruited 38 ALS patients and 38 controls referred to an Italian clinical center for ALS care, who underwent a lumbar puncture for diagnostic purposes between 1994–2013, and had 1 mL of cerebrospinal fluid available for the determination of OCPs, PCBs and PAHs. Many chemicals were undetectable in both case and control CSF samples, and we found little evidence of any increased disease risk according to higher levels of exposure. Among males >60 years, we found a slight but statistically very unstable increased ALS risk with higher levels of the congener PCB 28 and the OCP metabolite p,p’-DDE. Overall, these results do not suggest an involvement of the neurotoxic chemicals investigated in this study in disease etiology, although small numbers limited the precision of our results
  [Vinceti, M., Violi, F., Tzatzarakis, M., Mandrioli, J., Malagoli, C., Hatch, E.E., Fini, N., Fasano, A., Rakitskii, V.N., Kalantzi, O.I. and Tsatsakis, A., 2017. Environmental research, 155, pp.261-267.]
• Amyotrophic lateral sclerosis and environmental factors
  Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that affects central and peripheral motor neuron cells. Its etiology is unknown, although a relationship between genetic background and environmental factors may play a major role in triggering the neurodegeneration. In this review, we analyze the role of environmental factors in ALS: heavy metals, electromagnetic fields and electric shocks, pesticides, β-N-methylamino-L-alanine, physical activity and the controversial role of sports. The literature on the single issues is analyzed in an attempt to clarify, as clearly as possible, whether each risk factor significantly contributes to the disease pathogenesis. After summarizing conflicting observations and data, the authors provide a final synthetic statement.
  [Bozzoni, V., Pansarasa, O., Diamanti, L., Nosari, G., Cereda, C. and Ceroni, M., 2016. Functional neurology, 31(1), p.7.]
• Association of Environmental Toxins With Amyotrophic Lateral Sclerosis
  Persistent environmental pollutants may represent a modifiable risk factor involved in the gene-time-environment hypothesis in amyotrophic lateral sclerosis (ALS). To evaluate the association of occupational exposures and environmental toxins on the odds of developing ALS in Michigan. Case-control study conducted between 2011 and 2014 at a tertiary referral center for ALS. Cases were patients diagnosed as having definitive, probable, probable with laboratory support, or possible ALS by revised El Escorial criteria; controls were excluded if they were diagnosed as having ALS or another neurodegenerative condition or if they had a family history of ALS in a first- or second-degree blood relative. Participants completed a survey assessing occupational and residential exposures. Blood concentrations of 122 persistent environmental pollutants, including organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs), and brominated flame retardants (BFRs), were measured using gas chromatography–mass spectrometry. Multivariable models with self-reported occupational exposures in various exposure time windows and environmental toxin blood concentrations were separately fit by logistic regression models. Concordance between the survey data and pollutant measurements was assessed using the nonparametric Kendall τ correlation coefficient. Occupational and residential exposures to environmental toxins, and blood concentrations of 122 persistent environmental pollutants, including OCPs, PCBs, and BFRs. Participants included 156 cases (mean [SD] age, 60.5 [11.1] years; 61.5% male) and 128 controls (mean [SD] age, 60.4 [9.4] years; 57.8% male); among them, 101 cases and 110 controls had complete demographic and pollutant data. Survey data revealed that reported pesticide exposure in the cumulative exposure windows was significantly associated with ALS (odds ratio [OR] = 5.09; 95% CI, 1.85-13.99; P = .002). Military service was also associated with ALS in 2 time windows (exposure ever happened in entire occupational history: OR = 2.31; 95% CI, 1.02-5.25; P = .046; exposure ever happened 10-30 years ago: OR = 2.18; 95% CI, 1.01-4.73; P = .049). A multivariable model of measured persistent environmental pollutants in the blood, representing cumulative occupational and residential exposure, showed increased odds of ALS for 2 OCPs (pentachlorobenzene: OR = 2.57; 95% CI, 1.31-5.02; P = .006; and cis-chlordane: OR = 6.51; 95% CI, 2.05-20.73; P = .002) and 1 PCB (PCB 151: OR = 1.66; 95% CI, 1.03-2.67; P = .04. There was modest concordance between survey data and the measurements of persistent environmental pollutants in blood; significant Kendall τ correlation coefficients ranged from −0.18 (Dacthal and “use pesticides to treat home or yard”) to 0.24 (trans-nonachlor and “store lawn care products in garage”). In this study, persistent environmental pollutants measured in blood were significantly associated with ALS and may represent modifiable ALS disease risk factors.
  [Su, F.C., Goutman, S.A., Chernyak, S., Mukherjee, B., Callaghan, B.C., Batterman, S. and Feldman, E.L., 2016. JAMA neurology, 73(7), pp.803-811.]
• Organophosphate pesticide exposure and neurodegeneration
  Organophosphate pesticides (OPs) are used extensively throughout the world. The main sources of contamination for humans are dietary ingestion and occupational exposures. The major concerns related to OP exposure are delayed effects following high level exposures as well as the impact of low level exposures during the lifespan which are suggested to be a risk factor for nervous system chronic diseases. Both high and low level exposures may have a particularly high impact in population subgroups such as aged or genetically vulnerable populations. Apart from the principle action of OPs which involves inhibition of the acetylcholinesterase (AChE) enzyme, several molecular targets, such as hormones; neurotransmitters; neurotrophic factors; enzymes related to the metabolism of beta amyloid protein as well as inflammatory changes have been identified for OP compounds. Here we review the main neurological and/or cognitive deficits described and the experimental and epidemiological relationships found between pesticide exposure and Alzheimer's, Parkinson's, and Amyotrophic Lateral Sclerosis (ALS) diseases. This report also focuses on possible individual differences making groups resilient or vulnerable to these toxicants. A critical discussion of the evidence obtained from experimental models and possible sources of bias in epidemiological studies is included. In particular this review aims to discuss common targets and pathways identified which may underlie the functional deficits associated with both pesticide exposure and neurodegeneration.
  [Sánchez-Santed, F., Colomina, M.T. and Hernández, E.H., 2016. Cortex, 74, pp.417-426.]
• Amyotrophic Lateral Sclerosis and Agricultural Environments: A Systematic Review
  The aim of this study was to examine the relationship between the risk of amyotrophic lateral sclerosis (ALS) and exposure to rural environments. Studies were identified through OVID MEDLINE and EMBASE search up to September 2013 using as keywords rural residence, farmers, and pesticide exposure. Twenty-two studies were included for this meta-analysis. Summary odds ratios (ORs) were calculated using random effect model by type of exposure index, and subgroup analyses were conducted according to study design, gender, region, case ascertainment, and exposure assessment. The risk of ALS was significantly increased with pesticide exposure (OR, 1.44; 95% CI, 1.22-1.70) and with farmers (OR, 1.42; 95% CI, 1.17-1.73), but was not significant with rural residence (OR, 1.25; 95% CI, 0.84-1.87). The risk estimates for subgroup analysis between pesticide exposure and ALS indicated a significant positive association with men (OR, 1.96), and in studies using El Escorial criteria for ALS definition (OR, 1.63) and expert judgment for pesticide exposure (OR, 2.04) as well. No significant publication bias was observed. Our findings support the association of pesticide exposure and an increased risk for ALS, stressing that the use of more specific exposure information resulted in more significant associations.
  [Kang, H., Cha, E.S., Choi, G.J. and Lee, W.J., 2014. Journal of Korean medical science, 29(12), pp.1610-1617.]
• Environmental Risk Factors and Amyotrophic Lateral Sclerosis (ALS): A Case-Control Study of ALS in Michigan
  An interim report of a case-control study was conducted to explore the role of environmental factors in the development of amyotrophic lateral sclerosis (ALS). Sixty-six cases and 66 age- and gender-matched controls were recruited. Detailed information regarding residence history, occupational history, smoking, physical activity, and other factors was obtained using questionnaires. The association of ALS with potential risk factors, including smoking, physical activity and chemical exposure, was investigated using conditional logistic regression models. As compared to controls, a greater number of our randomly selected ALS patients reported exposure to fertilizers to treat private yards and gardens and occupational exposure to pesticides in the last 30 years than our randomly selected control cases. Smoking, occupational exposures to metals, dust/fibers/fumes/gas and radiation, and physical activity were not associated with ALS when comparing the randomly selected ALS patients to the control subjects. To further explore and confirm results, exposures over several time frames, including 0–10 and 10–30 years earlier, were considered, and analyses were stratified by age and gender. Pesticide and fertilizer exposure were both significantly associated with ALS in the randomly selected ALS patients. While study results need to be interpreted cautiously given the small sample size and the lack of direct exposure measures, these results suggest that environmental and particularly residential exposure factors warrant close attention in studies examining risk factors of ALS.
  [Yu, Y., Su, F.C., Callaghan, B.C., Goutman, S.A., Batterman, S.A. and Feldman, E.L., 2014. PloS one, 9(6).]
• Pesticides exposure as etiological factors of Parkinson's disease and other neurodegenerative diseases-A mechanistic approach.
  The etiology of most neurodegenerative disorders is multifactorial and consists of an interaction between environmental factors and genetic predisposition. The role of pesticide exposure in neurodegenerative disease has long been suspected, but the specific causative agents and the mechanisms underlying are not fully understood.For the main neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis there are evidences linking their etiology with long-term/low-dose exposure to pesticides such as paraquat, maneb, dieldrin, pyrethroids and organophosphates. Most of these pesticides share common features, namely the ability to induce oxidative stress, mitochondrial dysfunction, α-synuclein fibrillization and neuronal cell loss.This review aims to clarify the role of pesticides as environmental risk factors in genesis of idiopathic PD and other neurological syndromes by highlighting the most relevant epidemiological and experimental data.
  [Baltazar MT, Dinis-Oliveira RJ, de Lourdes Bastos M, et al. 2014. Toxicol Lett.S0378-4274(14)00059-9.]
• Are environmental exposures to selenium, heavy metals, and pesticides risk factors for amyotrophic lateral sclerosis?
  The etiology of sporadic amyotrophic lateral sclerosis (ALS), the most common form of this degenerative disease of the motor neurons, is still unknown, despite extensive investigation of several genetic and environmental potential risk factors. We have reviewed laboratory and epidemiological studies assessing the role of exposure to neurotoxic chemicals (metalloid selenium; heavy metals mercury, cadmium, and lead; pesticides) in ALS etiology by summarizing the results of these investigations and examining their strengths and limitations. Despite limitations in the exposure assessment methodologies typically used in human studies, we found suggestive epidemiological evidence and biologic plausibility for an association between ALS and antecedent overexposure to environmental selenium and pesticides. The relation with mercury, cadmium, and lead appears weaker.
  [Vinceti, M., Bottecchi, I., Fan, A., Finkelstein, Y. and Mandrioli, J., 2012. Reviews on environmental health, 27(1), pp.19-41.]
• Pesticide exposure and amyotrophic lateral sclerosis
  Our objectives were to summarize literature on the association of amyotrophic lateral sclerosis (ALS) with pesticides as a group and to evaluate associations of ALS with specific pesticides. We conducted a meta-analysis of published studies of ALS and pesticides as a group and investigated the association of ALS with specific pesticides, using data from the Agricultural Health Study (AHS), a cohort including 84,739 private pesticide applicators and spouses. AHS participants provided information on pesticide use at enrollment in 1993–1997. In mortality data collected through February 2010, ALS was recorded on death certificates of 41 individuals whom we compared to the remaining cohort (controls), using unconditional logistic regression adjusted for age and gender to calculate odds ratios (ORs) and 95% confidence intervals. In the meta-analysis, ALS was associated with use of pesticides as a group (1.9, 1.1–3.1). In the AHS, ALS was not associated with pesticides as a group, but was associated with use of organochlorine insecticides (OCs) (1.6, 0.8–3.5), pyrethroids (1.4, 0.6–3.4), herbicides (1.6, 0.7–3.7), and fumigants (1.8, 0.8–3.9). ORs were elevated forever use of the specific OCs aldrin (2.1, 0.8–5.1), dieldrin (2.6, 0.9–7.3), DDT (2.1, 0.9–5.0), and toxaphene (2.0, 0.8–4.9). None of these associations was statistically significant. Similar results were observed in an analysis restricted to men. In conclusion, the meta-analysis suggests that ALS risk is associated with use of pesticides as a group, and our analysis of AHS data points to OC use in particular. The latter results are novel but based on a small number of cases and require replication in other populations.
  [Kamel, F., Umbach, D.M., Bedlack, R.S., Richards, M., Watson, M., Alavanja, M.C., Blair, A., Hoppin, J.A., Schmidt, S. and Sandler, D.P., 2012. Neurotoxicology, 33(3), pp.457-462.]
• Pesticide exposure as a risk factor for amyotrophic lateral sclerosis: A meta-analysis of epidemiological studies: Pesticide exposure as a risk factor for ALS
  Exposure to pesticides and agricultural chemicals has been linked to amyotrophic lateral sclerosis (ALS) although findings have been inconsistent. A meta-analysis of studies published through May, 2011 was conducted to investigate the association of pesticide exposure and risk of ALS.Six peer-reviewed studies that met criteria were included in a meta-analysis of men involving 1,517 ALS deaths from one retrospective cohort study and 589 ALS or motor neuron disease cases from five case-control studies. A random effects model was used to calculate sex-specific pooled odds ratios (ORs).Evidence was found for an association of exposure to pesticides and risk of ALS in male cases compared to controls (OR=1.88, 95% CI: 1.36–2.61), although the chemical or class of pesticide was not specified by the majority of studies.This meta-analysis supports the relationship of exposure to pesticides and development of ALS among male cases compared to controls. The weight of evidence links pesticide exposure to ALS; however, additional prospective studies with a target exposure group are necessary to better elucidate the relationship. Future research should focus on more accurate exposure assessment and the use of job exposure matrices.
  [Malek, A.M., Barchowsky, A., Bowser, R., Youk, A. and Talbott, E.O., 2012. Environmental research, 117, pp.112-119.]
• A Case of Amyotrophic Lateral Sclerosis in a Worker Treating Pesticide Wastes
  Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease involving the motor neuron of the cerebrum, brain stem, and spinal cord. It has been suggested that various occupational or environmental agents could be a cause of ALS. We report upon a case of a person contracting ALS who experienced a long-time exposure to pesticides, implying that pesticides are probable causal agents of ALS.The patient has been experiencing shoulder pain and limitation of movement that started abruptly about three years ago. Over time, these symptoms have become aggravated despite ongoing therapies including medication. After two years, he was diagnosed with ALS through electromyography, nerve conduction velocity and many laboratory tests at a university hospital in Seoul. His social and medical history was non-specific.The patient had worked for about 15 years at a waste disposal site and mainly destroyed glass bottles containing pesticides. During this period, his respiratory tract and skin were exposed to various raw pesticides without appropriate personal protective equipment. He did this job one or two times a week and worked for two or more hours without a break.Through an investigation into the patient's working environment, significant levels of dichlorvos, one of the organophosphates, were detected. The study results revealed that the patient was exposed to considerable doses of pesticides as opposed to men spraying pesticides. Although controversial, pesticide exposures have been associated with ALS. However, we suggest that in this case the possibility that these pesticide exposures acted
  [Choy, S. and Kim, J.W., 2011. Korean Journal of Occupational and Environmental Medicine, 23(4), pp.480-487.]
• Exposure to pesticides and risk of amyotrophic lateral sclerosis: a population-based case-control study
   A few epidemiologic studies have suggested an association of agricultural work and pesticides exposure with a severe degenerative disease of the motor neurons, amyotrophic lateral sclerosis (ALS), though conflicting results have also been provided. We investigated through a populationbased case-control study the possible relation between overall occupational exposure to pesticides and ALS risk in the northern Italy municipality of Reggio Emilia. By administering a questionnaire, we investigated occupational history and leisure-time habits of the 41 ALS patients diagnosed in the 1995-2006 period, and of 82 age- and sex-matched randomly sampled population controls. More cases than controls were found to have been exposed to pesticides for at least six months (31.7% vs 13.4%, respectively), in all cases within the occupational environment. In a conditional logistic regression model, we found an excess ALS risk associated with exposure to pesticides, with a relative risk of 3.6 (95% confidence interval 1.2-10.5). Such association persisted after inclusion in the statistical analysis of potential confounders. Despite the limited statistical stability of the risk estimates, these results appear to indicate that occupational exposure to pesticides is a risk factor for ALS, suggesting the need to further investigate this issue.
  [Bonvicini, F., Marcello, N., Mandrioli, J., Pietrini, V. and Vinceti, M., 2010. Annali dell'Istituto superiore di sanita, 46, pp.284-287.]
• Exposure to Chemicals and Metals and Risk of Amyotrophic Lateral Sclerosis: A Systematic Review
  Environmental exposure to chemicals and metals may contribute to the risk of sporadic amyotrophic lateral sclerosis (ALS). Two systematic reviews of the literature on these topics performed according to the well-established MOOSE guidelines are presented. Literature cited in MEDLINE, EMBASE, CINAHL, and Cochrane databases (up to March 2007) as well as references of relevant articles were screened for case-control or cohort studies investigating the associations between sporadic ALS and exposure to chemical agents or metals. Methodology of selected studies was appraised according to Armon's classification system for ALS risk factor studies as well as a newly developed classification system for quality of exposure assessment. Seven of the 38 studies concerning exposure to chemicals and three of the 50 studies concerning exposure to metals fulfilled the validity criteria. In two independent studies meeting the validity criteria, a significant association with increased ALS risk was reported for exposure to pesticides. This systematic review demonstrated the difficulty in attaining a high level of evidence due to lack of high quality of methodological and exposure assessment components. Although pesticide exposure was identified as candidate risk factor, more well-designed studies are needed to provide a definitive answer about exogenous factors of ALS.
  [Sutedja, N.A., Veldink, J.H., Fischer, K., Kromhout, H., Heederik, D., Huisman, M.H., Wokke, J.H. and van den Berg, L.H., 2009. Amyotrophic Lateral Sclerosis, 10(5-6), pp.302-309.]
• The role of environmental mercury, lead and pesticide exposure in development of amyotrophic lateral sclerosis
  Exposure to an environmental toxicant as a risk factor in the development of amyotrophic lateral sclerosis (ALS) was first hinted at (demonstrated) in the Chamorro indigenous people of Guam. During the 1950s and 1960s these indigenous people presented an extremely high incidence of ALS which was presumed to be associated with the consumption of flying fox and cycad seeds. No other strong association between ALS and environmental toxicants has since been reported, although circumstantial epidemiological evidence has implicated exposure to heavy metals such as lead and mercury, industrial solvents and pesticides especially organophosphates and certain occupations such as playing professional soccer. Given that only ∼10% of all ALS diagnosis have a genetic basis, a gene–environmental interaction provides a plausible explanation for the other 90% of cases. This mini-review provides an overview of our current knowledge of environmental etiologies of ALS with emphasis on the effects of mercury, lead and pesticides as potential risk factors in developing ALS. Epidemiologic and experimental evidence from animal models investigating the possible association between exposure to environmental toxicant and ALS disease has proven inconclusive. Nonetheless, there are indications that there may be causal links, and a need for more research.
  [Johnson, F.O. and Atchison, W.D., 2009. Neurotoxicology, 30(5), pp.761-765.]
• A gene–environment study of the paraoxonase 1 gene and pesticides in amyotrophic lateral sclerosis
  Sporadic amyotrophic lateral sclerosis (SALS) causes progressive muscle weakness because of the loss of motor neurons. SALS has been associated with exposure to environmental toxins, including pesticides and chemical warfare agents, many of which are organophosphates. The enzyme paraoxonase 1 (PON1) detoxifies organophosphates and the efficacy of this enzyme varies with polymorphisms in the PON1 gene. To determine if an impaired ability to break down organophosphates underlies some cases of SALS, we compared the frequencies of PON1 polymorphisms in SALS patients and controls and investigated gene–environment interactions with self-reported pesticide/herbicide exposure. The PON1 coding polymorphisms L55M, Q192R and I102V, and the promoter polymorphisms −909c > g, −832g > a, −162g > a and −108c > t, were genotyped in 143 SALS patients and 143 matched controls. Statistical comparisons were carried out at allele, genotype and haplotype levels. The PON1 promoter allele −108t, which reduces PON1 expression, was strongly associated with SALS. Overall, promoter haplotypes that decrease PON1 expression were associated with SALS, whereas haplotypes that increase expression were associated with controls. Coding polymorphisms did not correlate with SALS. Gene–environment interactions were identified at the allele level for some promoter SNPs and pesticide/herbicide exposure, but not at the genotype or haplotype level. In conclusion, some PON1 promoter polymorphisms may predispose to SALS, possibly by making motor neurons more susceptible to organophosphate-containing toxins.
  [Morahan, J.M., Yu, B., Trent, R.J. and Pamphlett, R., 2007. Neurotoxicology, 28(3), pp.532-540.]
• Amyotrophic Lateral Sclerosis and Exposure to Environmental Toxins: An Australian Case-Control Study
  It has been suggested that environmental toxins could be risk factors for sporadic amyotrophic lateral sclerosis (SALS). We therefore analysed epidemiological data on 179 SALS cases and 179 age-, ethnicity- and sex-matched controls in Australia using self-reporting questionnaires. SALS was associated with solvent/chemical exposure (OR = 1.92, 95% CI: 1.26–2.93), overall herbicide/pesticide exposure (OR = 1.57, 95% CI: 1.03–2.41) and industrial herbicide/pesticide exposure (OR = 5.58, 95% CI: 2.07–15.06). Exposure to herbicides/pesticides showed a dose-response effect. All positive findings were more statistically significant in males. These findings support those from northern hemisphere studies, indicating that environmental toxins can be risk factors for SALS.
  [Morahan, J.M. and Pamphlett, R., 2006. Neuroepidemiology, 27(3), pp.130-135.]
• Analysis of factors that modify susceptibility and rate of progression in amyotrophic lateral sclerosis (ALS)
  We conducted case‐control and prospective longitudinal studies to examine risk factors and predictors of disease progression for ALS. Ninety‐five subjects with ALS and 106 healthy control subjects were enrolled. All subjects completed a risk factor questionnaire at enrollment. The ALS subjects were prospectively followed for one year to define factors that influence the rate of disease progression, measured by rate of change in percent predicted forced vital capacity (%FVC) and the ALS functional rating scale (ALSFRS) score. The association of each potential risk factor with ALS was determined using univariate logistic regression. A random slope model was used to determine the association of each risk factor with disease progression. The demographic characteristics of ALS subjects and controls at enrollment did not differ. Significant risk factors for ALS included reported exposure to lead (p = 0.02) and pesticides (p = 0.03). Disease progression was faster in the ALS subjects having bulbar onset and a shorter time period between onset of symptoms and diagnosis. Pertinent variables not associated with either causation or progression of ALS included physical activity, cigarette smoking and a history of physical trauma or other clinical disorders.
  [Muddasir Qureshi, M., Hayden, D., Urbinelli, L., Ferrante, K., Newhall, K., Myers, D., Hilgenberg, S., Smart, R., Brown, R.H. and Cudkowicz, M.E., 2006. Amyotrophic Lateral Sclerosis, 7(3), pp.173-182.]
• Increased Incidence of FMO1 Gene Single Nucleotide Polymorphisms in Sporadic Amyotrophic Lateral Sclerosis
  Flavin-containing monooxygenases (FMO) represent a gene family involved in the oxidative metabolism of a variety of xenobiotics, pesticides and drugs. A new function for FMO proteins has been recently uncovered: yeast FMO has been demonstrated to take part in maintaining the redox balance, catalysing the oxidation of reduced glutathione (GSH) to glutathione disulfide (GSSG). The GSSG/GSH balance is an important buffering system for reactive oxygen species and its involvement has been documented in ALS and other neurodegenerative disorders. Human FMO genes present different mutations, which may be related to ethnicity, altered metabolic activity and, in some cases, specific diseases. The human FMO1 gene presents 20 single nucleotide polymorphisms (SNPs) located in coding regions, intronic sequences and untranslated regions. The FMO1 gene has also recently been found underexpressed in spinal cord of ALS patients. Using SSCP and direct sequencing, we studied the allelic and genotypic frequency of two 3'UTR SNPs of the FMO1 gene in sporadic ALS patients compared to a healthy control population. We found a significantly higher frequency of these two polymorphisms, exclusive of the female population, in SALS patients compared to controls (p<0.01), suggesting that specific allelic variants of the FMO1 gene might be associated to susceptibility to develop ALS.
  [Cereda, C., Gabanti, E., Corato, M., De Silvestri, A., Alimonti, D., Cova, E., Malaspina, A. and Ceroni, M., 2006. Amyotrophic Lateral Sclerosis, 7(4), pp.233-240.]