Episode 122: Environmental Factors and Parkinson’s Disease

Dan Keller 0:02 Welcome to this episode of Substantial Matters: Life and Science of Parkinson's. I'm your host, Dan Keller, at the Parkinson's Foundation. We want all people with Parkinson's and their families to get the care and support they need. Better care starts with better research and leads to better lives. In this podcast series, we highlight the fruits of that research—the treatments and techniques that can help you live a better life now, as well as research that can bring a better tomorrow.

A common question that people ask when confronted with a diagnosis is, "How did I get this disease?" Rarely is the answer definitive, but it often leads to a recitation of a list of possible risk factors that could be at play, none of them absolute, and often just unknown. So it is with Parkinson's disease. Although several genes or genetic variants are known to be associated with a small proportion of Parkinson's cases, they do not appear to play a role for most individuals. Instead, the thing that most people around the world are exposed to is environmental pollutants, many of which can be toxic to various biological systems, including our own nervous systems.

When I spoke with Dr. Samuel Goldman of the University of California, San Francisco, he explained some of the evidence linking environmental toxins to a risk for Parkinson's, and why it's not so easy to study them. Samuel, we do hear so much about the influence of genetics in Parkinson's disease, but are environmental factors overlooked, and what specific role do you think they play?

Dr. Samuel Goldman 2:02 Well, I think we hear a lot about genetic factors because they are very discrete. We currently possess the technology to precisely measure the genetics that might potentially be involved in Parkinson's disease, and we do know that there are a handful of inherited variants that can cause Parkinson's. However, the so-called highly penetrant variants—meaning those genetic variants that, if you inherit them, almost always result in the clinical manifestation of Parkinson's disease—are extremely rare.

The less penetrant variants, such as the LRRK2 mutation, are present in only about 1% of individuals with Parkinson's disease. Even then, that specific variant is inherited with only about 30% penetrance, meaning that among the people who carry the mutation in that gene, only 30% will actually go on to develop Parkinson's disease. This clearly demonstrates that other factors are at play.

Furthermore, there are several other lines of evidence that heavily implicate environmental factors. One in particular is the study of twins. Our group conducted a massive study of twins that started back in the 1990s where we looked for Parkinson's disease across 32,000 twin pairs who had been tracked since World War Two. We identified pairs where either twin had a Parkinson's diagnosis and then looked to see if the other twin developed it as well. This is known as "concordance"—when both brothers develop the disease. When we compared the concordance rates between identical twins and non-identical, fraternal twins, we found that the likelihood of both brothers having Parkinson's was remarkably similar, regardless of whether the twins were identical or not. That serves as incredibly strong evidence that genetics are not the predominant driving factor in overall Parkinson's risk.

I guess the third major line of evidence would harken back to the discovery of a specific neurotoxin in the mid-1980s. Dr. J. William Langston recognized a cluster of intravenous drug users in Silicon Valley, all of whom acutely developed a profound parkinsonian syndrome that clinically looked identical to advanced Parkinson's disease. He identified the offending chemical to be MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). That provided a very strong clue that the environment could cause parkinsonism and possibly standard Parkinson's disease, which spurred a massive scientific search for similar compounds to MPTP in our everyday environment that might potentially be causing the disease.

Dan Keller 4:54 Fortunately, not many people run into MPTP in their daily lives. So, what sort of toxic substances in the everyday environment do you think may be contributing to this risk?

Dr. Samuel Goldman 5:07 Absolutely. It turns out that MPTP is a highly effective compound for generating animal models of Parkinson's disease because it is incredibly specific in injuring cells in the substantia nigra—specifically the dopaminergic neurons, which are the exact cells that degenerate in Parkinson's pathology. Once the mechanism of MPTP toxicity was worked out, scientists discovered that it directly injures mitochondria, the fundamental energy factories for the body and the brain.

Consequently, the search evolved in two primary directions: one was to look for compounds that were structurally similar to MPTP, and another approach was to look for compounds that were mechanistically similar to MPTP. I should also point out that MPTP wasn't the only environmental factor linked to Parkinson's back in the 1980s. We knew even before then, through epidemiological data, that individuals who lived in rural environments or who worked on farms seemed to exhibit a higher risk for Parkinson's disease. So, there was already a strong baseline suspicion surrounding certain pesticides.

Dan Keller 6:21 What about industrial solvents? They have been heavily implicated as well, spanning from dry cleaning fluids to industrial degreasers. These are substances that people might be exposed to in small amounts, but the exposure might accumulate over time.

Dr. Samuel Goldman 6:35 The observation that solvents might be increasing the risk of Parkinson's disease is a really compelling story, and it also highlights one of the major challenges with studying environmental risk factors for Parkinson's: it is incredibly difficult to accurately measure historical exposures. This difficulty is another reason why research has historically focused on genetics; it's very easy to sequence a genome, but measuring a person's environment from 30 or 40 years ago is highly complex. Most people do not know whether they were exposed to pesticides decades prior, and if they were, they rarely know the exact chemical name.

With industrial solvents, it may be even more difficult. Solvents are ubiquitous throughout our environments, and very few of us know precisely when or if we have been exposed. The link to dry cleaning and related solvents initially emerged from several clinical case reports back in the 1960s and 1970s involving individuals with parkinsonism who had been occupationally exposed to large amounts of a common cleaning and degreasing solvent called trichloroethylene, or TCE. TCE, it turns out, was heavily utilized in dry cleaning throughout the 1950s and 1960s before it was largely replaced by tetrachloroethylene, a structurally similar compound commonly known as perchloroethylene or "perc."

The narrative became significantly more serious around 2008 when a research group in Kentucky reported a distinct cluster of individuals with Parkinson's disease who had all worked at the same small manufacturing plant. They all worked directly with, or in very close proximity to, the solvent trichloroethylene. Interestingly, the workers in that manufacturing area who did not have a formal diagnosis of Parkinson's disease still exhibited subtle parkinsonian signs, such as motor slowing.

This critical observation spurred our team to evaluate the possible association with occupational TCE exposure within our twin study. We estimated which twins had been exposed to TCE occupationally and analyzed whether they faced a greater risk of developing Parkinson's. We found that those with occupational exposure to TCE had an approximate six-fold increased risk of developing Parkinson's disease. Furthermore, individuals exposed to the related dry cleaning solvent, perc, exhibited an approximate 11-fold increased risk. Since then, TCE has been shown to produce a very compelling animal model of Parkinson's that specifically targets the dopaminergic neurons in the substantia nigra and replicates key motor features reminiscent of human Parkinson's pathology.

Dan Keller 9:45 Do you think there is a direct interaction between genetic predispositions and these environmental factors? For example, could it involve the genes already identified as influencing Parkinson's risk, or perhaps genes that control drug metabolism in the liver to clear nasty chemicals out of the body?

Dr. Samuel Goldman 10:08 Yes, that is a great question. I think most researchers in the field strongly agree that even though we might debate the relative percentage impact of genes versus environment, a gene-environment interaction is responsible for the vast majority of standard Parkinson's cases. Basically, that means an individual's unique genetic makeup can make them significantly more or less susceptible to the toxic effects of a specific environmental exposure.

Historically, there hasn't been an overwhelming number of studies on these gene-environment interactions, primarily because they are incredibly difficult to design and execute. However, there have been a few notable studies looking at pesticides and specific genes—particularly genes responsible for the metabolism, absorption, and breakdown of toxicants, as well as the blood-brain barrier mechanisms that control the ability of a pesticide to infiltrate the brain.

Some of these associations are striking. One study we conducted looked at the interaction between exposure to the widely used herbicide paraquat and the deletion of a specific gene involved in our antioxidant defense systems, known as GSTT1 (glutathione S-transferase theta 1). This gene is extremely commonly deleted; about 20% of the general population lacks it entirely and cannot produce the corresponding enzyme. We discovered that individuals who were exposed to paraquat and had this GSTT1 gene deletion faced an 11-fold increased risk of Parkinson's disease. Conversely, those who only carried the genetic variant but lacked paraquat exposure, or those who were exposed to paraquat but possessed the intact gene, did not exhibit a significantly increased risk.

Dan Keller 11:52 Most of us do not and cannot know our exact genetic architecture, and even if we did, we cannot change our genes. Given that reality, what practical steps can people take right now to optimize their personal environments and reduce their risk of developing Parkinson's later in life?

Dr. Samuel Goldman 12:14 I think what we can do right now is focus on living as healthily as possible by implementing core preventive health measures. That means doing the things you should be doing for your systemic health anyway: eating a nutrient-dense diet, choosing organic fruits and vegetables whenever possible to minimize cumulative pesticide exposure, and maintaining regular, vigorous physical activity throughout your lifespan. Exercise robustly protects against cardiovascular disease and diabetes, and the data suggests it likely protects against Parkinson's disease as well. There are also a number of clinical studies demonstrating that consistent physical activity is highly effective at slowing down Parkinson's disease progression for those who have already been diagnosed.

Dan Keller 12:55 These are all fundamentally heart-healthy strategies. Neurologists often emphasize that what is good for the heart is inherently good for the head. So it sounds like exercise, a healthy diet, managing cholesterol, and increasing antioxidant consumption are highly protective. I have also heard that head trauma can increase neurodegenerative risks. It sounds like taking care of your vascular health and protecting against physical injury are vital for brain preservation.

Dr. Samuel Goldman 13:31 I think that is absolutely true. There is a remarkably consistent body of literature demonstrating an elevated risk of Parkinson's associated with head injuries; even a history of mild head trauma or concussions has been linked to an increased risk. To your point about nutrition, adherence to a Mediterranean diet has been associated in several large epidemiological studies with a reduced risk of developing Parkinson's. A heart-healthy lifestyle is absolutely a brain-healthy lifestyle.

Dan Keller 14:01 We happen to have regulatory bodies within the government, such as the Environmental Protection Agency. On a broader population health basis, is there something that the EPA or other regulatory agencies should be doing to mitigate these environmental risks?

Dr. Samuel Goldman 14:17 Absolutely. The EPA previously faced a restrictive ruling regarding the utilization of basic science research to inform human health regulations, but that has fortunately been rescinded. Now, regulators can utilize the full totality of basic science, toxicology, and epidemiological research to make informed regulatory decisions.

I believe the EPA should move forward aggressively with the restriction and regulation of certain pesticides, such as paraquat, where we possess incredibly solid data linking their usage to an increased risk of Parkinson's disease. The same standard should apply to the industrial solvent trichloroethylene. These are just a couple of prominent examples, but broadly speaking, there needs to be substantially more federal funding allocated to environmental health research so we can actively inform public policy in an intelligent, evidence-based manner.

Dan Keller 15:10 What we have discussed so far focuses primarily on primary prevention. But for individuals who have already been diagnosed with Parkinson's, do these same environmental factors and lifestyle modifications apply in terms of managing the severity or the clinical progression of the disease? I assume there isn't a massive amount of definitive research on progression interventions just yet.

Dr. Samuel Goldman 15:30 There is historically less research on interventions specifically designed to slow clinical disease progression compared to disease onset. There are a handful of observational studies suggesting that certain anti-inflammatory medications might offer a protective effect, though the evidence is not yet consistent enough to recommend them as a standard clinical intervention.

However, it makes absolute sense that patients would want to minimize ongoing exposure to substances strongly linked to Parkinson's risk. There is every reason to suspect that the toxic mechanisms driving disease onset—such as mitochondrial impairment and oxidative stress—are the exact same pathways driving ongoing neurodegeneration. Therefore, eating healthfully, avoiding toxic chemical exposures, and engaging in regular physical activity are highly likely to help slow down disease progression.

Dan Keller 16:22 What about the phenomenon of geographic or incidence clusters? In other fields of medicine, identifying clusters provides rich epidemiological ground for discovery.

Dr. Samuel Goldman 16:33 Geographic clusters simply mean that we observe a significantly higher incidence of Parkinson's disease within a specific geographic location or timeframe than would statistically be expected. True clusters provide excellent evidence of an environmental impact on disease risk because the individuals living or working in that concentrated area share common exposures.

To date, we actually haven't identified very many distinct Parkinson's clusters. There was the small manufacturing plant cluster I mentioned in Kentucky, and there have been some clusters noted in parts of Canada, but they are rare. I think the primary reason we haven't observed more clusters—aside from a historical lack of dedicated tracking—is the massive latency period between exposure and diagnosis. If a critical environmental exposure occurred 20 or 30 years ago, it becomes exceptionally difficult to recognize a cluster decades later when individuals have relocated and only then begin developing motor symptoms.

A major limitation has simply been that we haven't historically looked for them systematically. However, there is now a dedicated Parkinson's disease registry in California, and there is an ongoing effort to establish a comprehensive national registry. This will make it vastly easier to search for clusters geographically. If a group of individuals shared a residential or industrial location where there was a major environmental contamination—such as trichloroethylene in the local groundwater—we will finally be able to identify those patterns using large-scale registries. I am very optimistic that registries will provide much deeper data on environmental etiologies moving forward.

Dan Keller 18:10 I suppose if you analyze clusters not just as a geographic phenomenon but as an occupational one, you have already successfully identified agricultural workers, industrial degreasers, and dry cleaning workers. They do cluster distinctly in an occupational sense.

Dr. Samuel Goldman 18:24 Absolutely. Occupational clusters are incredibly informative, though historically, very few have been formally reported in the literature. Occupational exposures can often be orders of magnitude more intense than general environmental exposures, making the study of occupational subgroups an incredibly powerful research tool.

Dan Keller 18:44 Even within those studies, I imagine it must be exceptionally difficult to map out a clear dose-response relationship or to quantify cumulative versus acute high-intensity exposures over a person's working life.

Dr. Samuel Goldman 18:57 It is exceptionally challenging. For example, in the historical dry cleaning industry, many of the highest, most toxic exposures actually occurred among family members who lived in apartments situated directly above independent, "mom-and-pop" dry cleaning establishments. Furthermore, people who worked at small dry cleaning businesses frequently did not stay in those jobs for very long; they tended to disperse into other industries over time. Tracking a cluster among a highly mobile, dispersed workforce decades after the fact is a formidable epidemiological challenge.

Dan Keller 19:20 Right, because relying on self-reported memory or diaries to recall precise chemical exposures from 20 or 30 years prior is highly unreliable.

Dr. Samuel Goldman 19:27 Exactly, and that is precisely why we need to build and fund longitudinal life-course cohorts. We need research cohorts that are established ideally at birth, where individuals are systematically followed throughout their entire lifespans with regular, prospective exposure assessments, biometric monitoring, and detailed histories recorded in real time. That is the gold standard approach to solving these environmental questions. Of course, the challenge is that such a study takes 60 to 70 years to fully yield results.

Dan Keller 19:56 Can researchers utilize any of the massive, existing multi-generational health studies, like the Framingham Heart Study or the longitudinal health cohorts in California? Framingham has successfully followed four or five generations of families, meaning those comprehensive medical histories already exist.

Dr. Samuel Goldman 20:11 Yes, there are several outstanding cohorts that were originally established for other epidemiologic purposes, such as the Nurses' Health Study, the Framingham Heart Study, and the Honolulu-Asia Aging Study. However, because these cohorts were predominantly designed to investigate cardiovascular risk factors, strokes, and cardiac outcomes, they carry two major limitations for our purposes.

First, they are typically not large enough to study Parkinson's disease effectively. Parkinson's is a relatively rare neurological outcome compared to coronary artery disease or myocardial infarction, meaning the absolute number of Parkinson's cases within those cohorts is usually too low to achieve statistical power. Second, detailed environmental and occupational exposure histories were simply not a primary component of the data collection protocols when those studies were designed. So, while they are invaluable health resources, they often lack the granular environmental data we require.

Dan Keller 21:04 For more information on today's subject, visit our website at parkinson.org and search for "environmental factors." There you will find detailed discussions on known toxic substances, as well as our landmark publication, PD GENEration: Mapping the Future of Parkinson's Disease. The Parkinson's Foundation genetic study is actively delineating these precise gene-environment interactions, and you can learn how the foundation is supporting critical research in this domain.

There is also specialized information available that may be highly relevant to military veterans regarding potential herbicide and toxicant exposures during their service. Our podcast episode titled Preclinical Models of PD explores how laboratory scientists utilize cutting-edge models to discover the molecular, cellular, and genetic pathways driving the disease. Additionally, our Veterans Day bonus episode follows the moving story of Lou Eisenbrandt, a Vietnam veteran whose Parkinson's diagnosis was a direct result of exposure to the herbicide Agent Orange during her military service.

To listen to these episodes, visit parkinson.org/podcasts. You can find further educational material by reading the Frequently Asked Questions booklet located under the "What Causes Parkinson's" section of Chapter One at parkinson.org/library.

As always, if you need personalized guidance, our toll-free Parkinson's Foundation Helpline is available. Our bilingual information specialists are ready to answer your questions in either English or Spanish regarding environmental risks, research initiatives, or any other aspect of Parkinson's care. You can reach them directly at 1-800-4PD-INFO. To stay informed about upcoming educational webinars, local support resources, and community events, please subscribe to our email registry located at the bottom of our homepage.

If you would like to leave feedback regarding this episode or suggest future topics, please visit parkinson.org/feedback. If you found this podcast valuable, please take a moment to subscribe, rate, and review the series on Apple Podcasts or your preferred streaming platform.

At the Parkinson's Foundation, our mission is to help every person diagnosed with Parkinson's live the best possible life today. To that end, we will be back with a brand-new episode every two weeks. Until next time, for additional information and expert resources, please visit parkinson.org or call our helpline at 1-800-4PD-INFO, which is 1-800-473-4636. Thank you for listening.

Dr. Sam Goldman is Professor of Occupational & Environmental Medicine and Neurology at the University of California, San Francisco and an environmental medicine clinician and investigator at the San Francisco VA Medical Center. Prior to joining UCSF, Sam was a senior research scientist for many years at the Parkinson’s Institute in Sunnyvale, CA. He is also former co-director of the CDC-supported Western States Pediatric Environmental Health Specialty Unit. Sam attended medical school at the University of Texas Health Science Center and trained in Preventive Medicine and Environmental Health Science at the University of California Berkeley. Along with his longtime collaborator Dr. Caroline Tanner and others, he has published extensively on the epidemiology of Parkinson’s disease and other neurodegenerative diseases, with a focus on environmental risk factors. Foremost among these are pesticides, solvents and traumatic brain injury, and their interactions with genetic susceptibility factors.