Freya Kamel

Rotenone, Paraquat, and Parkinson’s Disease

Background Mitochondrial dysfunction and oxidative stress are pathophysiologic mechanisms implicated in experimental models and genetic forms of Parkinson’s disease (PD). Certain pesticides may affect these mechanisms, but no pesticide has been definitively associated with PD in humans. Objectives Our goal was to determine whether pesticides that cause mitochondrial dysfunction or oxidative stress are associated with PD or clinical features of parkinsonism in humans. Methods We assessed lifetime use of pesticides selected by mechanism in a case–control study nested in the Agricultural Health Study (AHS). PD was diagnosed by movement disorders specialists. Controls were a stratified random sample of all AHS participants frequency-matched to cases by age, sex, and state at approximately three controls: one case. Results In 110 PD cases and 358 controls, PD was associated with use of a group of pesticides that inhibit mitochondrial complex I [odds ratio (OR) = 1.7; 95% confidence interval (CI), 1.0–2.8] including rotenone (OR = 2.5; 95% CI, 1.3–4.7) and with use of a group of pesticides that cause oxidative stress (OR = 2.0; 95% CI, 1.2–3.6), including paraquat (OR = 2.5; 95% CI, 1.4–4.7). Conclusions PD was positively associated with two groups of pesticides defined by mechanisms implicated experimentally—those that impair mitochondrial function and those that increase oxidative stress—supporting a role for these mechanisms in PD pathophysiology.

Association of Pesticide Exposure with Neurologic Dysfunction and Disease

Poisoning by acute high-level exposure to certain pesticides has well-known neurotoxic effects, but whether chronic exposure to moderate levels of pesticides is also neurotoxic is more controversial. Most studies of moderate pesticide exposure have found increased prevalence of neurologic symptoms and changes in neurobehavioral performance, reflecting cognitive and psychomotor dysfunction. There is less evidence that moderate exposure is related to deficits in sensory or motor function or peripheral nerve conduction, but fewer studies have considered these outcomes. It is possible that the most sensitive manifestation of pesticide neurotoxicity is a general malaise lacking in specificity and related to mild cognitive dysfunction, similar to that described for Gulf War syndrome. Most studies have focused on organophosphate insecticides, but some found neuro-toxic effects from other pesticides, including fungicides, fumigants, and organochlorine and carbamate insecticides. Pesticide exposure may also be associated with increased risk of Parkinson disease; several classes of pesticides, including insecticides, herbicides, and fungicides, have been implicated. Studies of other neurodegenerative diseases are limited and inconclusive. Future studies will need to improve assessment of pesticide exposure in individuals and consider the role of genetic susceptibility. More studies of pesticides other than organophosphates are needed. Major unresolved issues include the relative importance of acute and chronic exposure, the effect of moderate exposure in the absence of poisoning, and the relationship of pesticide-related neurotoxicity to neurodegenerative disease.

Lead exposure and amyotrophic lateral sclerosis.

Background. Previous interview-based studies have suggested that exposure to neurotoxicants including metals might be related to ALS. Methods. We evaluated the relation of lead exposure to ALS, using both biological measures and interviews, in a case-control study conducted in New England from 1993 to 1996. Cases (N = 109) were recruited at two hospitals in Boston, MA. Population controls (N = 256) identified by random-digit dialing were frequency-matched to cases by age, sex, and region of residence within New England. Results. Risk of ALS was associated with self-reported occupational exposure to lead (odds ratio [OR] = 1.9; 95% confidence interval [CI] = 1.1–3.3), with a dose response for lifetime days of lead exposure. Blood and bone lead levels were measured in most cases (N = 107) and in a subset of controls (N = 41). Risk of ALS was associated with elevations in both blood and bone lead levels. ORs were 1.9 (95% CI = 1.4–2.6) for each &mgr;g/dl increase in blood lead, 3.6 (95% CI = 0.6–20.6) for each unit increase in log-transformed patella lead, and 2.3 (95% CI = 0.4–14.5) for each unit increase in log-transformed tibia lead. Conclusions. These results are consistent with previous reports and suggest a potential role for lead exposure in the etiology of ALS.

Smoking duration, intensity, and risk of Parkinson disease

Objective: To evaluate the relative importance of smoking duration vs intensity in reducing the risk of Parkinson disease (PD). Methods: The study included 305,468 participants of the NIH-AARP Diet and Health cohort, of whom 1,662 had a PD diagnosis after 1995. We estimated odds ratios (OR) and 95% confidence intervals from multivariate logistic regression models. Results: Compared with never smokers, the multivariate ORs were 0.78 for past smokers and 0.56 for current smokers. Among past smokers, a monotonic trend toward lower PD risk was observed for all indicators of more smoking. Stratified analyses indicated that smoking duration was associated with lower PD risk within fixed intensities of smoking. For example, compared with never smokers, the ORs among past smokers who smoked >20 cigarettes/day were 0.96 for 1–9 years of smoking, 0.78 for 10–19 years, 0.64 for 20–29 years, and 0.59 for 30 years or more (p for trend = 0.001). In contrast, at fixed duration, the typical number of cigarettes smoked per day in general was not related to PD risk. Close examination of smoking behaviors in early life showed that patients with PD were less likely to be smokers at each age period, but if they smoked, they smoked similar numbers of cigarettes per day as individuals without PD. Conclusions: This large study suggests that long-term smoking is more important than smoking intensity in the smoking–Parkinson disease relationship.

Risk factors for amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease. It is typically fatal within 2–5 years of symptom onset. The incidence of ALS is largely uniform across most parts of the world, but an increasing ALS incidence during the last decades has been suggested. Although recent genetic studies have substantially improved our understanding of the causes of ALS, especially familial ALS, an important role of non-genetic factors in ALS is recognized and needs further study. In this review, we briefly discuss several major genetic contributors to ALS identified to date, followed by a more focused discussion on the most commonly examined non-genetic risk factors for ALS. We first review factors related to lifestyle choices, including smoking, intake of antioxidants, physical fitness, body mass index, and physical exercise, followed by factors related to occupational and environmental exposures, including electromagnetic fields, metals, pesticides, β-methylamino-L-alanine, and viral infection. Potential links between ALS and other medical conditions, including head trauma, metabolic diseases, cancer, and inflammatory diseases, are also discussed. Finally, we outline several future directions aiming to more efficiently examine the role of non-genetic risk factors in ALS.

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

Exposure to high levels of many pesticides has both acute and long-term neurologic consequences, but little is known about the neurotoxicity of chronic exposure to moderate levels of pesticides. We analyzed cross-sectional data from 18,782 white male licensed private pesticide applicators enrolled in the Agricultural Health Study in 1993–1997. Applicators provided information on lifetime pesticide use and 23 neurologic symptoms typically associated with pesticide intoxication. An indicator of more symptoms (≥10 vs. < 10) during the year before enrollment was associated with cumulative lifetime days of insecticide use: odds ratios (95% confidence intervals) were 1.64 (1.36–1.97) for 1–50 days, 1.89 (1.58–2.25) for 51–500 days, and 2.50 (2.00–3.13) for > 500 days, compared with never users. A modest association for fumigants [> 50 days, 1.50 (1.24–1.81)] and weaker relationships for herbicides [> 500 days, 1.32 (0.99–1.75)] and fungicides [> 50 days, 1.23 (1.00–1.50)] were observed. Pesticide use within the year before enrollment was not associated with symptom count. Only associations with insecticides and fumigants persisted when all four pesticide groups were examined simultaneously. Among chemical classes of insecticides, associations were strongest for organophosphates and organochlorines. Associations with cumulative exposure persisted after excluding individuals who had a history of pesticide poisoning or had experienced an event involving high personal pesticide exposure. These results suggest that self-reported neurologic symptoms are associated with cumulative exposure to moderate levels of fumigants and organophosphate and organochlorine insecticides, regardless of recent exposure or history of poisoning.

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

Background We evaluated the relationship between diagnosed depression and pesticide exposure using information from private pesticide applicators enrolled in the Agricultural Health Study between 1993 and 1997 in Iowa and North Carolina. Methods There were 534 cases who self-reported a physician-diagnosed depression and 17,051 controls who reported never having been diagnosed with depression and did not feel depressed more than once a week in the past year. Lifetime pesticide exposure was categorized in three mutually exclusive groups: low (< 226 days, the reference group), intermediate (226–752 days), and high (> 752 days). Two additional measures represented acute high-intensity pesticide exposures: an unusually high pesticide exposure event (HPEE) and physician-diagnosed pesticide poisoning. Logistic regression analyses were performed relating pesticide exposure to depression. Results After adjusting for state, age, education, marital status, doctor visits, alcohol use, smoking, solvent exposure, not currently having crops or animals, and ever working a job off the farm, pesticide poisoning was more strongly associated with depression [odds ratio (OR) = 2.57; 95% confidence interval (CI), 1.74–3.79] than intermediate (OR = 1.07; 95% CI, 0.87–1.31) or high (OR = 1.11; 95% CI, 0.87–1.42) cumulative exposure or an HPEE (OR = 1.65; 95% CI, 1.33–2.05). In analysis of a subgroup without a history of acute poisoning, high cumulative exposure was significantly associated with depression (OR = 1.54; 95% CI, 1.16–2.04). Conclusion These findings suggest that both acute high-intensity and cumulative pesticide exposure may contribute to depression in pesticide applicators. Our study is unique in reporting that depression is also associated with chronic pesticide exposure in the absence of a physician-diagnosed poisoning.

Pesticide Use and Thyroid Disease Among Women in the Agricultural Health Study

Thyroid disease is common, and evidence of an association between organochlorine exposure and thyroid disease is increasing. The authors examined the cross-sectional association between ever use of organochlorines and risk of hypothyroidism and hyperthyroidism among female spouses (n = 16,529) in Iowa and North Carolina enrolled in the Agricultural Health Study in 1993-1997. They also assessed risk of thyroid disease in relation to ever use of herbicides, insecticides, fungicides, and fumigants. Prevalence of self-reported clinically diagnosed thyroid disease was 12.5%, and prevalence of hypothyroidism and hyperthyroidism was 6.9% and 2.1%, respectively. There was an increased odds of hypothyroidism with ever use of organochlorine insecticides (adjusted odds ratio (OR(adj)) = 1.2 (95% confidence interval (CI): 1.0, 1.6) and fungicides (OR(adj) = 1.4 (95% CI: 1.1, 1.8) but no association with ever use of herbicides, fumigants, organophosphates, pyrethroids, or carbamates. Specifically, ever use of the organochlorine chlordane (OR(adj) = 1.3 (95% CI: 0.99, 1.7), the fungicides benomyl (OR(adj) = 3.1 (95% CI: 1.9, 5.1) and maneb/mancozeb (OR(adj) = 2.2 (95% CI: 1.5, 3.3), and the herbicide paraquat (OR(adj) = 1.8 (95% CI: 1.1, 2.8) was significantly associated with hypothyroidism. Maneb/mancozeb was the only pesticide associated with both hyperthyroidism (OR(adj) = 2.3 (95% CI: 1.2, 4.4) and hypothyroidism. These data support a role of organochlorines, in addition to fungicides, in the etiology of thyroid disease among female spouses enrolled in the Agricultural Health Study.

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.

Association Between Blood Lead and the Risk of Amyotrophic Lateral Sclerosis

The authors conducted a 2003-2007 case-control study including 184 cases and 194 controls to examine the association between blood lead and the risk of amyotrophic lateral sclerosis (ALS) among US veterans and to explore the influence on this association of bone turnover and genetic factors related to lead toxicokinetics. Blood lead, plasma biomarkers of bone formation (procollagen type 1 amino-terminal peptide (PINP)) and resorption (C-terminal telopeptides of type 1 collagen (CTX)), and the K59N polymorphism in the delta-aminolevulinic acid dehydratase gene, ALAD, were measured. Odds ratios and 95% confidence intervals for the association of blood lead with ALS were estimated with unconditional logistic regression after adjustment for age and bone turnover. Blood lead levels were higher among cases compared with controls (P < 0.0001, age adjusted). A doubling of blood lead was associated with a 1.9-fold increased risk of ALS (95% confidence interval: 1.3, 2.7) after adjustment for age and CTX. Additional adjustment for PINP did not alter the results. Significant lead-ALS associations were observed in substrata of PINP and CTX levels. The K59N polymorphism in the ALAD gene did not modify the lead-ALS association (P = 0.32). These results extend earlier findings by accounting for bone turnover in confirming the association between elevated blood lead level and higher risk of ALS.