INTRODUCTION

The number of people with Parkinson’s disease (PD) has more than doubled in the past 30 years [1] and, absent change, will double again by 2040 [2]. Numerous genetic causes or risk factors for the disease have been identified, but the vast majority of individuals with PD do not carry any of these mutations [3, 4]. Several environmental toxicants, especially certain pesticides [5], have also been linked to PD, and head trauma is also associated with an increased risk [6]. However, these are insufficient to explain the widespread prevalence of PD. Given the disease’s growing rates— more than can be explained by aging alone [1]— other less visible causes must be contributing to its rise. One of these may be trichloroethylene (TCE), a ubiquitous chemical that has contaminated countless sites and poses health risks to those who are (often unknowingly) exposed via their work or their environment.

The evidence linking TCE to PD to date is based on a handful of case studies [7–12], a small epidemiological study linking exposure to a 500% increased risk of PD [11], and numerous animal studies demonstrating that the chemical leads to the pathological hallmarks of PD [8, 9, 13–17]. Here we introduce the chemical, describe its association to PD and other diseases, detail its widespread use and routes of contamination, and provide circumstantial evidence for its broader role in PD through illustrative cases depicting individuals with the disease who were likely exposed to TCE through their environment or occupation. We conclude with a call for greater research on its effects on PD, protection from and remediation of contaminated sites, and banning of this century-old chemical that has caused immeasurable harm to the public’s health.

WHAT IS TRICHLOROETHYLENE?

TCE is a simple six-atom (two carbons, one hydrogen, and three chlorines) solvent that is clear, colorless, volatile, nonflammable, and environmentally persistent (Fig. 1a) [18]. It was first synthesized in the lab in 1864 (Fig. 1b), and commercial production began in the 1920s [19]. Because of its unique properties, TCE has had countless industrial, commercial, military, and medical applications. Among these are producing other chlorinated compounds (e.g., refrigerants), cleaning electronics, and degreasing engine parts for civilian and military purposes [18]. As it readily evaporates and does not shrink fabrics, TCE was used to dry clean clothes beginning in the 1930s. A closely related chemical called perchloroethylene (PCE), which has one additional chlorine atom in place of the hydrogen atom, largely supplanted TCE in dry cleaning in the 1950s. In anaerobic conditions, PCE often transforms into TCE, and their toxicity may be similar [20].

TCE is found in numerous consumer products (Table 1), including typewriter correction fluid, paint removers, and carpet cleaners [18]. Until the 1970s, it was used to decaffeinate coffee [18]. The volatile TCE was also an inhaled anesthetic until the U.S. Food and Drug Administration banned it in 1977 [19].

TCE AND PARKINSON’S DISEASE

Studies (Table 2) linking TCE exposure to PD and parkinsonism date back to at least 1969 when Huber reported parkinsonism in a 59-year-old man who worked with TCE for over 30 years [7]. Thirty years later, Guehl and colleagues documented PD in a 37-year-old woman who was exposed to the chemical while cleaning houses and again while working in the plastics industry [8]. In 2008, Gash and colleagues reported that among 30 factory workers, three developed PD after using TCE for many years to degrease and clean metal parts [9]. These three workers were stationed closest to an open TCE vat, and 14 of 27 workers who were further from the source “displayed many features of parkinsonism, including significant motor slowing” [9].

Four years later, researchers found that in twin pairs, the twin with occupational or hobby exposure to TCE had a 500% increased risk of PD (OR 6.1, 95% CI: 1.2–33; p = 0.034) compared to their unexposed twin [11]. Exposure to the closely related solvent PCE also trended toward significance with an odds ratio of 10.5 (95% CI: 0.97–113) [11]. Notably, the researchers found an interval of 10 to 40 years from the time of TCE exposure to PD diagnosis [11].

TCE and PCE likely mediate their toxicity through a common metabolite [21, 22]. Because they are lipophilic [11], both TCE and PCE readily distribute in the brain and body tissues and appear to cause mitochondrial dysfunction at high doses. This may partially explain the link to PD as dopaminergic neurons are sensitive to mitochondrial neurotoxicants such as MPTP/MPP⁺, paraquat, and rotenone [23]. Indeed, in animal studies (Table 3), TCE treatment caused selective loss of dopaminergic neurons [8, 9, 13, 15, 16]. In addition, PD-related neuropathology, such as neuroinflammation and α-synuclein phosphorylation and accumulation, was observed in the substantia nigra of rats and mice exposed to 200–1000 mg/kg TCE over chronic time periods (6 weeks to 8 months) [13, 15, 17]. While the specific metabolite or mechanism of TCE-induced neurodegeneration remains unclear, pre-clinical studies with high doses (400–1000 mg/kg) showed that mitochondrial complex I activity is dysregulated in the midbrain of rodents exposed to TCE [9, 13–15]. Mitochondrial function was further reduced in the rat striatum when TCE exposure occurred in conjunction with another PD risk factor, traumatic brain injury. The combined neurotoxic insults resulted in 50% reduction in complex I oxygen consumption [14], a more severe effect than each factor alone. This combined effect provides a key example of how TCE exposure may influence PD risk in certain populations, such as individuals who served in the military where head trauma is morecommon [24].

In addition to combined environmental factors, evidence from preclinical studies suggests that genetic risk factors may also play a role in TCE-induced neurodegeneration. For example, in a 2021 study, chronic, systemic exposure to 200 mg/kg TCE elevated the kinase activity of LRRK2 (leucine rich repeat kinase 2) in the striatum and substantia nigra of rats after 3 weeks, prior to the loss of dopaminergic neurons at 6 weeks [17]. Inherited variants of LRRK2 are linked to both familial and sporadic PD, the most common of which is the G2019S mutation, that pathogenically elevate LRRK2 kinase activity resulting in dysregulated vesicular trafficking, endolysosomal dysfunction, and oxidative stress [25]. However, despite cellular dysfunction caused by elevated LRRK2 kinase activity, individuals who inherit the LRRK2 G2019S mutation have only a roughly 50% increased risk for PD [26]. Incomplete penetrance of genetic risk factors suggests that possible gene-environment interactions could explain why only some individuals exposed to TCE develop PD and why those with a PD-related genetic predisposition may display variable risk of developing PD. Many other genetic causes of PD (e.g., Parkin, PINK1) also affect mitochondrial function, and an interaction with TCE is conceivable for carriers of mutations in these genes [27]. However, more data on gene-environment interaction between TCE, LRRK2, and other genetic risk factors associated with PD are needed.

WIDESPREAD USE, WIDESPREAD CONTAMINATION

TCE was “ubiquitous” in the 1970s [28] when annual U.S. production surpassed 600 million pounds per year, or over two pounds per person [29]. About 10 million Americans worked with the chemical or other organic solvents daily; in the U.K. an estimated 8% of workers have (Table 4) [10]. While domestic use has waned, the U.S. is still the top global exporter of TCE, and since 1990, occupational exposure to TCE has increased by 30% worldwide [30]. Exposure is widespread, and a 1994 study in Italy found TCE at relatively high concentrations in the blood and urine of three quarters of a sample of the general population [31].

Although the European Union and two U.S. states have banned TCE, it is still permitted for vapor degreasing and spot dry cleaning in the U.S. and for authorized industrial uses in the E.U. [32]. Globally, TCE consumption is projected to increase by 3% annually (Fig. 2a) [33], and China, which has the fastest growing rates of PD [1], now accounts for half the global market [34].

Workers can inhale or come in dermal contact with TCE, but millions more encounter the chemical unknowingly through outdoor air, contaminated groundwater, and indoor air pollution. In 1987, nearly 56 million pounds of TCE were released into the air in the U.S. alone (Fig. 3) [35]. TCE can also leak from storage tanks or be dumped into the ground where it contaminates up to one-third of the drinking water in the U.S. [36]. TCE has also polluted the groundwater in at least twenty different countries on five continents (Fig. 2b).

TCE contaminates countless industrial, commercial, and military sites. TCE is found in half of the 1300 most toxic “Superfund” sites that are part of a federal clean-up program, including 15 in California’s Silicon Valley where TCE was used to clean electronics [37]. The U.S. military has stopped using TCE, but numerous sites have been contaminated, including the Marine Corps base Camp Lejeune in North Carolina. For 35 years, the base— which housed a million Marines, their families, and civilians— had levels of TCE and PCE in the drinking water 280 times safety standards [38].

Beginning in 1978, another route of exposure to TCE and other volatile chemicals was recognized: vapor intrusion (Fig. 4). Researchers found that TCE, much like radon, could evaporate from contaminated soil and groundwater and enter homes, schools, and workplaces [39]. Buildings often have lower air pressure than the outdoor environment and can draw toxic fumes through cracks in the foundation, utility lines, duct work, and elevators [40, 41]. This polluted air can travel upwards to apartments and offices located above plumes, which function as underground rivers of pollutant within the groundwater. TCE has been found in the indoor air of homes, in the butter in their refrigerators (TCE and PCE are fat soluble), and in the breast milk of nursing mothers [42].

Since contaminated underground plumes can travel over a mile, individuals who live far from a contaminated site are still at risk. One plume on Long Island, New York, which was associated with an aerospace company, is over four miles long and two miles wide and has contaminated the drinking water of thousands [43]. In Shanghai, China, a village, primary schools, and homes sit atop a TCE-contaminated site where a chemical plant operated for over thirty years [44]. In Newport Beach, California, multi-million dollar homes were built above a former aerospace facility known to be contaminated with TCE and PCE [45, 46]. In Monroe County, New York, where many of the authors of this report live, over a dozen dry cleaners have contaminated the ground with TCE.

ILLUSTRATIVE CASES

Below are seven cases where TCE may have contributed to an individual’s PD. The evidence linking possible exposure to TCE in these cases is circumstantial but raises worrisome questions about the link between the chemical and the disease. The first three cases depict likely environmental exposure contributing to PD. The latter four highlight potential risks from occupational exposure. In some cases, identifying information was changed to protect privacy.