by Dr Angeline Andrew (Geisel School of Medicine at Dartmouth)
The majority of cases of motor neuron disease amyotrophic lateral sclerosis (ALS) are not explained by a familial trait or gene. Scientists suspect that certain chemicals in the environment are likely the culprit. Since many insecticides kill by over-stimulating the unprotected neurons of insects, it is not farfetched to hypothesize that certain pesticides may also harm neurons in susceptible humans.
The brain/central nervous system controls the muscles of the human body via a set of elongated cells called ‘motor neurons’. In ALS, these guiding neurons mysteriously and progressively die off leading to weakness and muscle atrophy. Sadly, in most patients respiratory failure and death usually occurs over a 3-5 year period after diagnosis. Despite extensive research efforts, there is currently no treatment to halt ALS progression, and the cause remains unclear. Identifying causal factors could help to prevent ALS and focus studies of interventions to block progression. Occupational exposure to pesticides has been implicated in ALS in several past studies: agricultural workers in Northern Italy 1964-1988; jobs with agricultural chemicals in Washington State, U.S. men 1990-1994; and U.S. professional pesticide applicators.
If working with pesticides increases ALS risk, what happens if you live in the area where they are sprayed?
With its origins in John Snow’s investigations of the Cholera epidemic of the 1850’s, scientists have used “shoe-leather epidemiology” to identify people likely exposed to an infectious agent or toxic chemical based on where they live. We took this same approach to identify the individual pesticide types associated with ALS risk.
The U.S. Geological Survey compiles annual estimates of the amount of each herbicide or fungicide, or insecticide applied to crops in each county nationwide. Our study used maps of residential locations overlaid with maps of the applied amounts of 423 pesticides to estimate pesticide exposure for each individual. We compared the amount of pesticide exposure for ALS patients to see if it was higher than the estimated amount of exposure in controls (people who do not have the disease of similar age and gender, living in the same state).
In the first phase of the project, we compared exposures of a large group of ALS patients (n=26,199) to controls. We also did a land use assessment, but did not find generically higher rates of ALS for those living near cultivated crops. This supports the hypothesis that only certain chemical pesticides have neurotoxic effects that increase risk of neurodegenerative disease. It suggests that focusing attention on overall pesticide exposure as an indicator could underestimate the contribution that exposure to some pesticides can make to ALS.
By analysing exposure to specific individual pesticides we were able to slim down the list of 423 pesticides to a shorter list of herbicides, insecticides, and fungicides that were statistically higher in ALS patients. We focused on this shorter list for the second phase of the project, which used the past residential history of ALS patients and controls to estimate pesticide exposure from a few states. Because the events that caused the neurons to begin to die-off begin years prior to a patient noticing symptoms of the disease, we obtained the addresses for 5-years prior to disease detection.
For example, past exposure to the herbicide 2,4-dicholorophenoxyacetic acid (2,4-D) used to kill broad-leafed weeds in orchards and cereal crops significantly increased the risk of getting ALS in our study. This result supports the prior finding that chemical company employees who worked with 2,4-D had a 3-fold increased risk of death from ALS compared to other company employees between 1945–1994. The chemical may damage neurons by blocking assembly of scaffolding materials in the cell, known as microtubules.
Thus, we generated a short list of herbicides, insecticides, and fungicides with geospatial and temporal links to ALS. This list includes carbaryl, chlorpyrifos, glyphosate, permethrin and paraquat. Our study is most useful for identifying those pesticides that warrant future in-depth study in controlled laboratory settings. Laboratory models of environmentally-induced disease should be used test for potential treatments that can arrest the debilitating and fatal progression of ALS.
Dr Angeline Andrew is Associate Professor at Geisel School of Medicine at Dartmouth. She uses her inter-disciplinary training in toxicology, epidemiology and statistical data analysis to assess the biological effects of environmental exposures. She is currently working closely with geospatial and clinical collaborators to identify neurodegenerative disease risk factors.
