Trichloroethylene: An Invisible Cause of Parkinson’s Disease?

Abstract

The etiologies of Parkinson’s disease (PD) remain unclear. Some, such as certain genetic mutations and head trauma, are widely known or easily identified. However, these causes or risk factors do not account for the majority of cases. Other, less visible factors must be at play. Among these is a widely used industrial solvent and common environmental contaminant little recognized for its likely role in PD: trichloroethylene (TCE). TCE is a simple, six-atom molecule that can decaffeinate coffee, degrease metal parts, and dry clean clothes. The colorless chemical was first linked to parkinsonism in 1969. Since then, four case studies involving eight individuals have linked occupational exposure to TCE to PD. In addition, a small epidemiological study found that occupational or hobby exposure to the solvent was associated with a 500% increased risk of developing PD. In multiple animal studies, the chemical reproduces the pathological features of PD.
Exposure is not confined to those who work with the chemical. TCE pollutes outdoor air, taints groundwater, and contaminates indoor air. The molecule, like radon, evaporates from underlying soil and groundwater and enters homes, workplaces, or schools, often undetected. Despite widespread contamination and increasing industrial, commercial, and military use, clinical investigations of TCE and PD have been limited. Here, through a literature review and seven illustrative cases, we postulate that this ubiquitous chemical is contributing to the global rise of PD and that TCE is one of its invisible and highly preventable causes. Further research is now necessary to examine this hypothesis.

Full text

Journal of Parkinson’s Disease 13 (2023) 203–218
DOI 10.3233/JPD-225047
IOS Press
203
Hypothesis
Trichloroethylene: An Invisible Cause of
Parkinson’s Disease?
E. Ray Dorseya,b,1,∗, Maryam Zafara,1, Samantha E. Lettenbergera, Meghan E. Pawlika,
Dan Kinela,b, Myrthe Frissenc, Ruth B. Schneidera,b, Karl Kieburtza,b, Caroline M. Tannerd,
Briana R. De Mirandae, Samuel M. Goldmanfand Bastiaan R. Bloemc
aCenter for Health + Technology, University of Rochester Medical Center, Rochester, NY, USA
bDepartment of Neurology, University of Rochester Medical Center, Rochester, NY, USA
cRadboud University Medical Centre; Donders Institute for Brain, Cognition and Behaviour; Department of
Neurology; Centre of Expertise for Parkinson & Movement Disorders; Nijmegen, the Netherlands
dWeill Institute for Neurosciences, Department of Neurology, University of California-San Francisco, San
Francisco, CA, USA
eCenter for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama
at Birmingham, Birmingham, AL, USA
fDivision of Occupational and Environmental Medicine, San Francisco Veterans Affairs Health Care System,
School of Medicine, University of California–San Francisco, San Francisco, CA, USA
Accepted 31 January 2023
Published 14 March 2023
Abstract. The etiologies of Parkinson’s disease (PD) remain unclear. Some, such as certain genetic mutations and head
trauma, are widely known or easily identified. However, these causes or risk factors do not account for the majority of cases.
Other, less visible factors must be at play. Among these is a widely used industrial solvent and common environmental
contaminant little recognized for its likely role in PD: trichloroethylene (TCE). TCE is a simple, six-atom molecule that can
decaffeinate coffee, degrease metal parts, and dry clean clothes. The colorless chemical was first linked to parkinsonism in
1969. Since then, four case studies involving eight individuals have linked occupational exposure to TCE to PD. In addition, a
small epidemiological study found that occupational or hobby exposure to the solvent was associated with a 500% increased
risk of developing PD. In multiple animal studies, the chemical reproduces the pathological features of PD.
Exposure is not confined to those who work with the chemical. TCE pollutes outdoor air, taints groundwater, and contam-
inates indoor air. The molecule, like radon, evaporates from underlying soil and groundwater and enters homes, workplaces,
or schools, often undetected. Despite widespread contamination and increasing industrial, commercial, and military use,
clinical investigations of TCE and PD have been limited. Here, through a literature review and seven illustrative cases, we
postulate that this ubiquitous chemical is contributing to the global rise of PD and that TCE is one of its invisible and highly
preventable causes. Further research is now necessary to examine this hypothesis.
Keywords: Air pollution, indoor air pollution, environment, Parkinson’s disease, solvents, tetrachloroethylene, trichloroethy-
lene, water pollution, chemical water pollution
1These authors contributed equally to this work.
∗Correspondence to: Ray Dorsey, MD, University of
Rochester Medical Center, 265 Crittenden Blvd, CU 420694,
Rochester, NY 14642, USA. Tel.: +1 585 275 0663; E-mail:
ray.dorsey@chet.rochester.edu.
ISSN 1877-7171 © 2023 – The authors. Published by IOS Press. This is an Open Access article distributed under the terms
of the Creative Commons Attribution-NonCommercial License (CC BY-NC 4.0).

204 E.R. Dorsey et al. / Trichloroethylene and Parkinson’s Disease
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.
Fig. 1a. Trichloroethylene (TCE) chemical structure [84].
The evidence linking TCE to PD to date is based
on a handful of case studies [7–12], a small epidemi-
ological study linking exposure to a 500% increased
risk of PD [11], and numerous animal studies demon-
strating 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 evi-
dence 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 immeasur-
able 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 environmen-
tally persistent (Fig. 1a) [18]. It was first synthesized
in the lab in 1864 (Fig. 1b), and commercial pro-
duction began in the 1920s [19]. Because of its
unique properties, TCE has had countless indus-
trial, commercial, military, and medical applications.
Among these are producing other chlorinated com-
Fig. 1b. The history of trichloroethylene (TCE) [15, 85]. EPA, Environmental Protection Agency; FDA, Food and Drug Administration.

E.R. Dorsey et al. / Trichloroethylene and Parkinson’s Disease 205
pounds (e.g., refrigerants), cleaning electronics, and
degreasing engine parts for civilian and military pur-
poses [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 addi-
tional 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 chemi-
cal while cleaning houses and again while working in
the plastics industry [8]. In 2008, Gash and colleagues
reported that among 30 factory workers, three devel-
oped 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 neu-
rons are sensitive to mitochondrial neurotoxicants
such as MPTP/MPP+, paraquat, and rotenone [23].
Table 1
Historical usage of trichloroethylene [19, 72, 73, 85–88]
Commercial & Consumer Products
Adhesives∗
Aerosol cleaning products∗
Carpet cleaner∗
Cleaners and solvent degreasers∗
Cleaning wipes∗
Cosmetic glues
Decaffeinated coffee
Film cleaners
Glue
Gun cleaner
Fumigant
Hoof polishes
Inks
Lubricants
Mold release
Paint and paint removers∗
Pepper spray
Pesticides
Refrigerant∗
Sealants
Stain removers∗
Tap and die fluid
Toner aid
Tool cleaners
Typewriter correction fluids∗
Wood finishes∗
Industry Usage
Automotive care
Dry cleaning∗
Degreasing∗
Furniture care
Manufacturing
Computer and electronics
Disinfectants
Dyes
Fat and oil extraction
Flavor extracts (spices, hops)
Jewelry
Machinery∗
Paint and coating∗
Paper
Perfumes
Plastics
Refrigerant∗
Soaps
Medicine
Anesthesia (medical, dental, veterinary)
Surgical disinfectant
Treatment (migraines, trigeminal neuralgia)
Pharmaceutical manufacturing
∗Common current uses.
Indeed, in animal studies (Table 3), TCE treatment
caused selective loss of dopaminergic neurons [8,
9, 13, 15, 16]. In addition, PD-related neuropathol-
ogy, such as neuroinflammation and ␣-synuclein
phosphorylation and accumulation, was observed
in the substantia nigra of rats and mice exposed

206 E.R. Dorsey et al. / Trichloroethylene and Parkinson’s Disease
Table 2
Clinical studies linking trichloroethylene and parkinsonism or Parkinson’s disease [7–12]
Authors Year Ref Study Design N Findings
Huber 1969 [7] Case study 1 A 59-year-old that worked with TCE for 33 years
developed parkinsonism. The patient’s brain section
showed depigmentation and severe degenerative
changes in the substantia nigra.
Guehl et al. 1999 [8] Case study 1 A former house cleaner was exposed to TCE for
several months, beginning at age 27, in poorly
ventilated rooms. She then worked for six years in
the plastics industry in a very small, unventilated
office exposed to TCE and other volatile
compounds. Three years later, she was diagnosed
with PD at the age of 37.
Kochen et al. 2003 [12] Case series 3 Three workers chronically exposed to TCE
developed PD in the post-exposure period.
Gash et al. 2008 [9] Case series 3 Three industrial plant workers (ages 49, 76, 56)
developed PD after years of dermal and respiratory
exposure (exposure duration 25 years, 25 years, 29
years) from cleaning metal gauges in a large, open
vat of TCE. An additional 14 coworkers in this
cluster that experienced chronic respiratory
exposure to TCE exhibited parkinsonism features.
Goldman et al. 2012 [11] Case-control
study in twin pairs
discordant for PD
Both occupational and hobby exposure to PCE and
TCE among a cohort of twins was studied. TCE was
associated with a significantly increased risk of PD
(OR 6.1, 95% CI 1.2 – 33; p= 0.034) along with
PCE exposure suggestive of an increased risk (OR
10.5, 95% CI 0.97 – 133; p= 0.053).
Reis et al. 2016 [10] Case study 1 A former car repairman who worked with products
containing TCE for over 40 years was diagnosed
with PD at the age of 57.
PD, Parkinson’s disease; TCE, trichloroethylene.
to 200–1000 mg/kg TCE over chronic time peri-
ods (6 weeks to 8 months) [13, 15, 17]. While the
specific metabolite or mechanism of TCE-induced
neurodegeneration remains unclear, pre-clinical stud-
ies 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, trau-
matic 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 more
common [24].
In addition to combined environmental factors, evi-
dence 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 ele-
vated 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 dopamin-
ergic 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 traffick-
ing, 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]. Incom-
plete 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 pre-
disposition 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,

E.R. Dorsey et al. / Trichloroethylene and Parkinson’s Disease 207
Table 3
Animal studies involving trichloroethylene and Parkinson’s disease [8, 9, 13–17]
Authors Year Ref Animal Exposure Findings
Guehl et al. 1999 [8] OF1 mice 400 mg/kg TCE, 5
days/week for 4
weeks
Dopaminergic neurodegeneration in the
substantia nigra
Gash et al. 2008 [9] Fisher 344 rats 1000 mg/kg TCE, 5
days/week for 6
weeks
Mitochondrial complex I activity
inhibition in substantia nigra, increased
complex I activity in striatum,
dopaminergic neurodegeneration in
nigrostriatal tract
Liu et al. 2010 [13] Fisher 344 rats 200, 500 or
1000 mg/kg TCE, 5
days/week for 6
weeks
Dose-dependent loss of dopaminergic
neurodegeneration in the substantia
nigra, motor deficits in 1000 mg/kg
TCE-treated rats, mitochondrial complex
I inhibition in substantia nigra, elevated
oxidative stress markers, activated
microglia, and intracellular
alpha-synuclein accumulation in dorsal
motor nucleus of vagus nerve
Sauerbeck et al. 2012 [14] Fisher 344 rats 1000 mg/kg TCE,
daily for 1 or 2 weeks
with and without
traumatic brain injury
Mitochondrial impairment in striatum,
with rates of complex I dependent
oxygen consumption decreasing by 75%,
after two week exposure to TCE and
traumatic brain injury. Analysis of one
week of TCE exposure and traumatic
brain injury indicated a 50% decrease in
mitochondrial function. Motor
impairment and dopaminergic
neurodegeneration in the substantia nigra
Liu et al. 2018 [15] Male C57BL/6 mice
and postnatal day 1–3
Sprague-Dawley rat
pups
400 mg/kg/day TCE,
5 days a week for 8
months
Progressive dopaminergic
neurodegeneration, decreased dopamine
and metabolites, deficits in locomotor
activity, mitochondrial complex I
inhibition, increased accumulation of
phosphorylated a-synuclein, and
endogenous formation of toxic
metabolite (TaClo)
Keane et al. 2019 [16] A30P and wild type
mice
1000 mg/kg TCE,
twice weekly for 8
weeks
Dopaminergic neurodegeneration in the
substantia nigra
De Miranda et al. 2021 [17] Aged, male and
female Lewis rats
200 mg/kg TCE, daily
for 3 or 6 weeks
TCE activated LRRK2 kinase activity
prior to dopaminergic neurodegeneration
in the nigrostriatal tract. Elevated
oxidative stress, neuroinflammation,
endolysosomal dysfunction and
alpha-synuclein accumulation
TCE, trichloroethylene.
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]. Expo-
sure 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,

208 E.R. Dorsey et al. / Trichloroethylene and Parkinson’s Disease
Table 4
Example occupations where trichloroethylene exposure may occur
[85, 86, 90]
Aircraft maintenance workers
Automotive factory workers
Communications equipment repairers
Computer specialists
Corrosive control technicians
Distillery workers
Dry cleaners
Electronic component manufacturers
Embalmers
Food manufacturers
Insecticide manufacturers
Jet engine mechanics
Leather manufacturers
Machinery installation & assembly workers
Mechanics
Metal treatment workers
Missile technicians
Nautical equipment workers
Oil processors
Painters
Pesticide manufacturers
Pharmaceutical manufacturing factory workers
Printers
Radar technicians
Refrigerant manufacturers
Resin workers
Rubber cementers
Sewerage workers
Silk screeners
Shoe makers
Systems technicians
Taxidermists
Textile manufacturers
Textile and fabric cleaners
Tobacco denicotinizers
Waste treatment workers
Weapons specialists
Varnish workers
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 chemi-
cal 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, commer-
cial, 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 fami-
lies, 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 pres-
sure 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 drink-
ing 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 for-
mer 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 con-
tributed to an individual’s PD. The evidence linking
possible exposure to TCE in these cases is circum-
stantial but raises worrisome questions about the link
between the chemical and the disease. The first three
cases depict likely environmental exposure contribut-
ing to PD. The latter four highlight potential risks

E.R. Dorsey et al. / Trichloroethylene and Parkinson’s Disease 209
Fig. 2a. Top ten exporters and importers of trichloroethylene, 2020 [33].
Fig. 2b. Countries with published studies of sites of groundwater TCE contamination [89].
from occupational exposure. In some cases, identify-
ing information was changed to protect privacy.
Likely environmental exposure to TCE
Case 1
On May 12, 2006, Mr. Brian Grant played two min-
utes for the Phoenix Suns in a National Basketball
Association (NBA) playoff game. He did not score
a point, grab a rebound, or have an assist. However,
in the last game of his NBA career, the then 34-year-
old power forward made history—he had likely just
played an entire basketball season with PD.
Mr. Grant first noticed the symptoms of the disease
a season earlier while on the Los Angeles Lakers.
There the 6’9”, 250-pound player was puzzled to dis-
cover he could no longer jump off of his left leg as he
once could. Sometimes the leg would give out. The

210 E.R. Dorsey et al. / Trichloroethylene and Parkinson’s Disease
Fig. 3a. U.S. cities that released the most TCE into the air, 1987
[35].
Fig. 3b. U.S. cities that released the most TCE into the air, 2020
[35].
next season, he developed an intermittent tremor in
his left hand [47]. Two years later, he was diagnosed
with PD.
The roots of his PD may have been in Camp Leje-
une [48]. When Mr. Grant was three years old, his
father, then a Marine, was stationed at the base around
the time that TCE levels in the water peaked [49].
There, Mr. Grant and his family lived in a trailer park
on a dirt road. He enjoyed living on the military base,
taking a bus to pre-school, and exploring its fighter
planes. Mr. Grant also drank, bathed, and swam in
the contaminated water, unaware of its toxicity.
Mr. Grant’s PD did not become apparent until
about three decades after his family left Camp Leje-
une. No one in his large family has had PD. His
younger brother who was born on the base suffered
disabling allergies that only resolved after they moved
away. In March 2020, Mr. Grant’s father died at age
65 from esophageal cancer, which is linked to TCE
[50].
Case 2
From 1984 to 1988, a young Navy captain, Amy
Lindberg, was also stationed at Camp Lejeune in
Jacksonville, North Carolina. On hot, humid days,
Captain Lindberg swam, ran, trained, and outworked
her peers. She also drank lots of water. What Cap-
tain Lindberg did not know is that the water that
she drank, bathed, cooked, swam, and played in was
contaminated with TCE, PCE, and other toxicants.
Between active duty and the reserves, Captain
Lindberg served for 26 years, before she and her
husband retired in northern Virginia. In 2017, thirty
years after being stationed at Camp Lejeune, the
then 57-year-old Captain Lindberg developed anx-
iety, depression, and trouble thinking (“brain fog”)
and was seen by a neuropsychologist. He asked her
about her loss of smell, decreased right arm swing,
and dragging of her right leg, all of which she had
developed about two years earlier. She also had a mild
rest tremor in her right hand and long-standing con-
stipation. She soon saw a neurologist who diagnosed
her with PD, which was not present in her family.
Now 63, Captain Lindberg remains an avid runner,
boxes regularly, and works out frequently, but is dis-
abled by the disease’s non-motor features including
urinary urgency, pain, and mood changes. In 2017,
the U.S. Department of Veterans Affairs established
PD as having a “presumptive service connection” for
those who, like Captain Lindberg, served at Camp
Lejeune between 1953 and 1987 [51].
Case 3
Dr. Jesh Mittal is a 48-year-old endocrinologist
who was raised in an upstate New York commu-
nity heavily contaminated by TCE. His first home,
where he lived until age 14, was located less than
a mile from a Superfund site where TCE, PCE, or
both had contaminated 60 residential drinking wells
[52]. His second home, where he resided until start-
ing college, was also less than a mile from another
Superfund site contaminated by TCE and other sol-
vents used in vapor degreasing [53]. However, his
potential exposure did not end at home.

E.R. Dorsey et al. / Trichloroethylene and Parkinson’s Disease 211
Fig. 4. Possible modes of exposure to trichloroethylene in the environment.
The future physician attended high school adjacent
to a large computing firm where his father worked.
The soil and groundwater at the manufacturing site
were contaminated with TCE and PCE. In 1971,
seven years before his freshman year, the well at
the high school was found to have “slight contam-
ination” with TCE even after a filtration system was
installed [54]. A generation later in 2000, ground-
water monitoring found high concentrations of PCE
at the manufacturing facility [55]. Neither his homes
nor his high school were (to our knowledge) ever
checked for vapor intrusion despite their proximity
to contaminated sites.
In 2010, after a nurse noticed that his handwriting
was becoming smaller, the right-handed physician
was diagnosed with writer’s cramp. Two years later,
he developed constipation, a “twitch” in his right
hand, and dystonia in his right arm. He was sub-
sequently diagnosed with PD at age 38. He had
no family history of and no genetic marker for
PD. Two years earlier, his mother was diagnosed
with breast cancer, and three years after his PD
diagnosis, his father was diagnosed with prostate
cancer.
Likely occupational exposure to TCE
Case 4
Dr. John Smith was an 85-year-old physicist and
industry executive with a family history of PD in his
father and two paternal aunts, all of whom grew up on
a farm. At age six, the future electrical engineer and
his family moved to a farm in upstate NewYork where
the young boy would apply rotenone and DDT to
green bean plants as part of his chores. As a graduate
student, he used TCE to wash electric parts but wore
no personal protective equipment.
Upon completing his PhD, he joined National
Aeronautics and Space Administration (NASA)
where he cleaned electronics and was “swimming”
in TCE. His term at NASA was interrupted by basic
training in the army at Fort Gordon, Georgia, which
served as a testing site for Agent Orange [56]. He then
worked for a large computer manufacturing company
in East Fishkill, New York, where TCE, PCE, and
other chemicals eventually contaminated the soil and
groundwater [57].
In approximately 2010, Dr. Smith was diagnosed
with PD. His symptoms included anxiety, decreased

212 E.R. Dorsey et al. / Trichloroethylene and Parkinson’s Disease
energy, anhedonia, diminished initiative, depressed
mood, and constipation in addition to a rest tremor,
slowed movements, a stooped posture, and a soft
voice. Some of these symptoms improved with lev-
odopa, but they subsequently worsened. As part of
a physical exam in 2019, an internist found a breast
lump in Dr. Smith’s chest. The lump was cancerous.
The treatment of his breast cancer, which is associ-
ated with TCE exposure [58], required surgery and
tamoxifen.
Case 5
Mr. Ethan Jones is a 72-year-old retired teacher
who was diagnosed with PD in 2017. He also carries
a G2019S mutation in LRRK2.
In his early thirties, Mr. Jones worked for three
to four years in a small copy and print shop that
required multiple chemicals and solvents. He is
unsure whether he was exposed to TCE or PCE,
but chlorinated solvents were commonly used in the
industry in the 1970s and 1980s [59]. About 35 years
later, he noticed that he was moving slower than his
peers and was subsequently diagnosed with PD at age
68. His symptoms improved with levodopa, which he
continues to take.
Neither of his parents had PD, but his paternal
grandfather did and his nephew does. In addition to
PD, he was diagnosed with monoclonal gammopathy
of undetermined significance, a premalignant state
associated with multiple myeloma, which is associ-
ated with TCE exposure [60].
Case 6
After serving in the military, Mr. Alex Janssen
worked in the construction and automotive industry.
In these latter jobs, he worked with degreasing chem-
icals, such as TCE, for approximately seven years.
About five years after his exposure ended, he noticed
numbness on the right side of his body followed by
difficulty walking up the stairs. He later experienced a
stressful event that was followed by involuntary shak-
ing in his right arm and leg and a PD diagnosis at age
33.
The number and intensity of PD symptoms
increased significantly over the years, and he even-
tually had deep brain stimulation (DBS), which
improved his symptoms and his quality of life. Three
years later, he developed fatigue, headache, and a
facial droop. Brain imaging at age 53 revealed a stage
IV glioblastoma situated next to a DBS wire.
Case 7
In 2020, Georgians took to the polls to elect two
U.S. Senators in a closely watched election that would
determine political control of the legislative body.
The reason for the unusual election? Parkinson’s
disease. The late Senator Johnny Isakson, who was
diagnosed with PD in 2015, had stepped down due
to “health challenges” in 2019, leading to a special
election in 2020 [61].
Senator Johnny Isakson, who died in 2021 at age
76, served for fifteen years in the U.S. Senate during
which time he was a staunch advocate for veterans
and co-chaired the Congressional Caucus on Parkin-
son’s Disease [62]. In addition to his PD, Senator
Isakson had a two-centimeter renal cell carcinoma
removed from his kidney in 2019 [61], a tumor asso-
ciated with TCE exposure [63].
Nearly fifty years before his PD diagnosis, the
future Senator served in the Georgia Air National
Guard from 1966 to 1972. The military, including
the Air Force, used TCE to degrease airplanes during
this period [64], and many military bases, including
those in Georgia [65], have been contaminated with
the chemical [66].
ADDITIONAL TOXICITY OF TCE
As depicted by these cases, the adverse health
effects associated with TCE extend far beyond PD. Its
toxic effects begin shortly after conception. TCE can
cross the placenta, [67] and maternal exposure to TCE
is associated with low birth weight [68], congenital
heart disease [68], and neural tube defects [69]. At the
TCE-contaminated Marine Corps Base Camp Leje-
une, at least seven babies had anencephaly, and ten
had spina bifida [19, 70]. After birth, TCE-linked dis-
eases proliferate as the solvent is linked to conditions
affecting nearly every organ system [71] including
cancer.
According to the U.S. Environmental Protection
Agency (EPA) and World Health Organization, TCE
is carcinogenic to humans by all routes of expo-
sure [72, 73]. A meta-analysis found occupational
exposure “was associated with excess incidences
of liver cancer, kidney cancer, non-Hodgkin’s lym-
phoma, prostate cancer, and multiple myeloma, with
the strongest evidence for the first three cancers”
[74]. This is likely only a partial list. At least 78
men who lived at contaminated Camp Lejeune have
been diagnosed with breast cancer [49]. In addition,
high rates of brain and other central nervous system

E.R. Dorsey et al. / Trichloroethylene and Parkinson’s Disease 213
tumors have been reported in animal studies [19] and
in TCE-contaminated communities [75, 76].
TCE’s adverse health effects have long been
known. In 1932, Dr. Carey McCord, a physician
working for the Chrysler Corporation, wrote a letter
to the Journal of the American Medical Association
[77]. He said that activities of TCE “frequently fail
to disclose the toxic nature of this chemical and the
practical dangers that may attend its use.” He then
detailed experiments with rabbits in which repeated
skin exposure to the chemical caused death in days.
Inhalation of TCE “under conditions of trivial expo-
sure” killed the rabbits in days if not hours. Ninety
years ago, he concluded that the solvent could be “the
source of disaster for exposed workmen” [77].
CRITIQUE
The cases described demonstrate the potential role
that TCE plays in PD. However, they are far from
definitive and far from the only ones. The vignettes
highlight many of the difficulties in establishing
a strong link between the invisible TCE and PD.
Among these are the following: 1) many are unaware
of their exposure; 2) exposure, if present, was usually
unmeasured; 3) previous exposures cannot currently
be measured; 4) in many cases, exposure co-occurred
with other pollutants; 5) time between exposure and
disease is long; 6) underlying genetic risk factors,
which are often not assessed, may augment the risk
of developing PD following TCE exposure; and 7)
diagnosis of PD is often delayed or missed.
In just one of the cases above was the person—a
physicist—aware of his exposure to the toxic chem-
ical at the time it occurred, and all were unaware of
the health risks associated with the chemical. Those
who drank contaminated water or inhaled polluted air
outside or inside their workplaces, schools, or homes
generally had no idea that they were exposed. Today,
sites known to be contaminated with TCE, including
many of the most toxic ones in the U.S., have no warn-
ing signs, fences, notices, or other public notification
of the inherent dangers. As a result, it is challenging
to determine whether exposure occurred.
Moreover, if exposure did occur, retrospective
exposure assessment of TCE is difficult. Exposure is
almost never measured contemporaneously (indeed,
we are unaware of any case of PD associated with
TCE where it was). Biomarkers of historical TCE
exposure do not currently exist. The few studies [9,
20] and case reports [11, 73] available suggest that a
dose-response relationship may be present as individ-
uals who work most closely with the chemical have
a shorter lag between exposure and disease onset.
Like other environmental toxicants (e.g., smoking,
pesticides), exposure to TCE is often combined with
other exposures. Many TCE-contaminated sites are
polluted with PCE and other toxic hydrocarbons such
as benzene and carbon tetrachloride, which itself may
be associated with PD.
The effect of each individual compound has often
not been assessed, and research into the risk of expo-
sure to mixtures of toxicants is needed [78, 79].
The time between exposure and disease onset may
be decades. Individuals, if they were aware of their
exposure to the chemical, may have long since for-
gotten about it. Those who worked with the solvent or
who lived near a contaminated site may have changed
jobs or moved, making retrospective evaluation of
potential clusters challenging.
Finally, while TCE’s effects on cancer are well-
documented, its effects on PD are only recently
coming to light. Gash’s study of factory workers who
developed PD after degreasing metal parts with TCE
was published in 2008 [9]. The twin study quantifying
the high degree of association between occupational
or hobby exposure to TCE and PD is only ten years
old [11]. Many individuals who know they were
exposed to TCE and subsequently developed PD have
no reason to link the two. Today, most clinicians
are unaware of TCE’s deleterious health effects even
though they have been documented for over ninety
years [77].
FUTURE DIRECTIONS
To address the large role TCE (and other chlori-
nated solvents) may play in fueling the rise of PD,
we need to do the following:
1. Conduct more research – Given the
widespread environmental contamination
by TCE, the authors of the twin study linking
TCE to PD concluded, “the potential public
health implications are substantial” [11].
Unfortunately, that prescient warning has
largely gone unheeded. A search of TCE and
PD on PubMed yields only 15 papers in the
past decade [80]. By contrast, a search of the
genetic risk factor GBA and PD returns more
published papers in just the last two months
[81]. Among the pressing research needs are
evaluating cohorts (ideally prospectively) of

214 E.R. Dorsey et al. / Trichloroethylene and Parkinson’s Disease
individuals (likely) exposed to TCE, identi-
fying biological markers of prior exposure,
better understanding the mechanisms of injury,
and assessing gene-environment interactions
including those affecting TCE’s metabolism.
Further work is also needed to estimate the
risk of TCE exposure in conjunction with other
known neurotoxicants, such as pesticides, and
risk factors like traumatic brain injury.
2. Clean and contain contaminated sites – Hun-
dreds of thousands of sites are contaminated
across the U.S. and globally. They are found in
strip malls where dry cleaners used to operate,
on military bases where use was widespread,
in cities near old manufacturing sites (espe-
cially those near rivers or streams), and in rural
areas where landfills were created to dump haz-
ardous waste. Fortunately, contaminated sites
can be remediated, and homes, schools, and
workplaces can be protected by vapor intrusion
mitigation systems like those used for radon
[82]. Until they are cleaned, existing contami-
nated sites must be contained, limiting exposure
for humans and nature. Local, regional, and
national authorities should take responsibility in
overseeing rapid control of contaminated sites.
3. Monitor TCE levels and publicly communi-
cate risk – Most databases monitor emissions,
not current levels, and monitoring tends to be
sporadic and reactive. TCE testing in ground-
water, drinking water, soil, and in outdoor and
indoor air should be widespread, frequent, and
part of routine water quality testing. The results
should be readily and publicly available. Pol-
luted sites need to be marked as such, and the
dangers to health clearly communicated to all
parties at risk.
4. Ban trichloroethylene – In many ways, the
long-established health risks of TCE dwarf
its relationship with PD. TCE causes cancer,
increases the risk of miscarriages, contributes
to birth defects, and is associated with diseases
in nearly every organ system. The chemical is
over a century old. We do not fly airplanes from
the days of the Wright brothers or drive cars
from Henry Ford’s era; engineers have devel-
oped safer ones. Chemists can do the same for
solvents. Some companies now advertise safer
alternatives to TCE [83]. They are needed as the
use of TCE continues to rise globally.
5. Listen to our patients – Finally, we should
listen to our patients more. In medicine, we
often move from diagnosis to treatment with-
out considering the cause. The vast majority
of individuals with PD do not have a family
history of the disease or carry an identifiable
genetic risk factor. Listening to their life sto-
ries or occupational histories can help identify
TCE or other factors contributing to PD and
could help develop etiology-specific treatments.
This information can also inform their care
(e.g., cancer screening), provide guidance to
family members, co-workers, and classmates,
and advance our understanding of the poten-
tial causes of this debilitating and likely very
preventable disease.
CONCLUSION
For more than a century, TCE has threatened
workers, polluted the air we breathe—outside and
inside—and contaminated the water we drink. Global
use is waxing, not waning. Most of this has been invis-
ible, all of it is unacceptable, and none of it will stop
until we act.
ACKNOWLEDGMENTS
Thank you to those who contributed their stories,
including Mr. Brian Grant, Captain Amy Lindberg,
and several anonymous individuals.
CONFLICT OF INTEREST
Dr. Dorsey has received honoraria for speaking
at American Academy of Neurology, Ameri-
can Neurological Association, Excellus BlueCross
BlueShield, International Parkinson’s and Move-
ment Disorders Society, National Multiple Sclerosis
Society, Northwestern University, Physicians Edu-
cation Resource, LLC, PRIME Education, LLC,
Stanford University, Texas Neurological Society, and
Weill Cornell; received compensation for consult-
ing services from Abbott, Abbvie, Acadia, Acorda,
Bial-Biotech Investments, Inc., Biogen, Boehringer
Ingelheim, California Pacific Medical Center, Car-
away Therapeutics, Curasen Therapeutics, Denali
Therapeutics, Eli Lilly, Genentech/Roche, Grand
Rounds, Huntington Study Group, Informa Pharma
Consulting, Karger Publications, LifeSciences Con-
sultants, MCM Education, Mediflix, Medopad,
MedRhythms, Merck, Michael J. Fox Foundation,
NACCME, Neurocrine, NeuroDerm, NIH, Novartis,

E.R. Dorsey et al. / Trichloroethylene and Parkinson’s Disease 215
Origent Data Sciences, Otsuka, Physician’s Educa-
tion Resource, Praxis, PRIME Education, Roach,
Brown, McCarthy & Gruber, Sanofi, Seminal Health-
care, Spark, Springer Healthcare, Sunovion Pharma,
Theravance, Voyager and WebMD; research support
from Biogen, Biosensics, Burroughs Wellcome Fund,
CuraSen, Greater Rochester Health Foundation,
Huntington Study Group, Michael J. Fox Founda-
tion, National Institutes of Health, Patient-Centered
Outcomes Research Institute, Pfizer, PhotoPharmics,
Safra Foundation, and Wave Life Sciences; editorial
services for Karger Publications; stock in Included
Health, stock in Mediflix and ownership interests in
SemCap.
Dr. Schneider has received compensation for con-
sulting services from Escape Bio and Parkinson’s
Foundation; research support from Acadia Pharma-
ceuticals, Biohaven Pharmaceuticals, the Michael J.
Fox Foundation for Parkinson’s Research, National
Institutes of Health, Parkinson Study Group, and
CHDI Foundation.
Dr. Kieburtz has research support from NIH
(NINDS, NCATS) and the Michael J Fox Foundation.
He is paid to serve on DSMBs of studies for Janssen,
Lilly, and Roche/Genentech. He receives payments
from Hoover Brown LLC and Clintrex Research
Corp, and has equity interests in both. He also has
equity interests in Biohaven, Inhibikase, Modality.AI
and Safe Therapeutics LLC.
Dr. Tanner has received has received grant sup-
port from the NIH, the Michael J Fox Foundation, the
Department of Defense, the Parkinson Foundation,
the Marcus Program in Precision Medicine, Gate-
way LLC, Roche-Genentech, Biogen, Bioelectron
Technology Corporation; personal compensation
as a consultant/scientific advisory board /data &
safety monitoring board member for CNS Ratings,
Cadent, Adamas, Biogen, Neurocrine, Kyowa Kirin,
Jazz/Cavion, Lundbeck and the Australian Parkin-
son’s Mission.
Dr. De Miranda is funded by the National
Institutes for Environmental Health Sciences
(R00ES029986).
Dr. Goldman has received research support
from the Michael J. Fox Foundation, the National
Institutes of Health, the Agency for Toxic Sub-
stances and Disease Registry (ATSDR), the Health
Resources and Services Administration (HRSA), the
US Department of Defense, and the Veterans Health
Administration.
Prof. Bloem currently serves as co-Editor in Chief
for the Journal of Parkinson’s Disease but was not
involved in any way in the peer review process of this
editorial. He serves on the editorial board of Practi-
cal Neurology and Digital Biomarkers, has received
honoraria from serving on the scientific advisory
board for Abbvie, Biogen and UCB, has received
fees for speaking at conferences from AbbVie, Zam-
bon, Roche, GE Healthcare and Bial, and has received
research support from the Netherlands Organization
for Scientific Research, the Michael J Fox Foun-
dation, UCB, Not Impossible, the Hersenstichting
Nederland, the Parkinson’s Foundation, Verily Life
Sciences, Horizon 2020 and the Parkinson Vereniging
(all paid to the institute).
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