Exposure to Solvent May Increase Parkinson's Risk

November 22, 2011 — Exposure to trichloroethylene (TCE), a solvent used in manufacturing that is found in significant amounts in municipal water supplies, increases the risk of developing Parkinson's disease (PD) by more than 6-fold, according to a new study of twins.

The study also showed that 2 other solvents — perchlorethylene (PERC), and carbon tetrachloride (CCI₄) — also increased the risk for PD, but not significantly.

"We should certainly take this as a motivation to study this relationship in greater detail," said lead author Samuel M. Goldman, MD, MPH, associate professor, clinical research, the Parkinson's Institute and Clinical Center, Sunnyvale, California.

"As a society, we can regulate these compounds more intensively," said Dr. Goldman. He added that he hopes the recent Environmental Protection Agency statement calling TCE a human carcinogen will lead to stricter regulation of this solvent.

The study was published online November 14 in the Annals of Neurology.

Occupations and Hobbies

Through the National Academy of Science/National Research Council World War II Veteran Twins Registry, researchers identified 99 twin pairs (49 monozygotic, 50 dizygotic) discordant for PD. The registry is an all-male twin cohort established in the 1960s using military records.

Through interviews with subjects or proxy informants, researchers determined lifetime exposure to 6 solvents (TCE, PERC, and CCI₄ as well as n-hexane, xylene, and toluene) from occupations or hobbies.

They found a significantly increased PD risk associated with TCE and trends toward risk with PERC and CCI₄. The magnitude of association with PD for the other solvents was modest, and none approached significance, they note.

Table. Risk for Parkinson's Disease With Solvent Exposure

Solvent	Odds Ratio (95% CI)	P Value
TCE	6.1 (1.2 - 33)	.034
PERC	10.5 (0.97 - 113)	.053
CCI₄	2.3 (0.9 - 6.1)	.088

CI = confidence interval.

Although the study couldn't determine which occupations or hobbies posed the greatest risk, it identified certain tasks within these occupations that had the greatest exposure.

"We saw increased risk among people who were electricians and dry cleaners and artists who worked with certain kinds of processes," said Dr. Goldman.

For example, in the case of electricians, TCE may have been used to degrease electrical circuits, and in dry cleaning, it was commonly used as a spot remover.

As well as a dry cleaning and degreasing agent, TCE has also been used as an additive in many common household products, including adhesives, paints, and carpet cleaners. Although its use has been declining since the late 1970s, it's still a commonly used solvent in vapor degreasing of metal parts in manufacturing.

Water Supply

About 50 millions of pounds of TCE are released annually into the environment in the US. It is found in air, soil, food, and human breast milk and in up to 30% of US drinking water supplies.

"Everyone should be aware that in the US, there are requirements (for water suppliers) to provide data to customers listing compounds," said Dr. Goldman. "TCE is found in fairly substantial proportions of municipal water systems especially if these systems are using ground water; surface water has lower concentrations because it evaporates."

PERC, too, has been around for decades. Since the 1950s, it has been the leading dry cleaning solvent around the world. And although greater attention has been paid in recent years to capturing the vapors, they are still being released, and they persist in air and groundwater for at least several months.

CCI₄ was the first chlorinated solvent used in dry cleaning and was used in making refrigerants. Although consumer and fumigant uses of this solvent have been phased out, it continues to be used in industry.

How do these solvents lead to PD? Animal studies seem to show that TCE causes a pathology very similar to that seen in PD, said Dr. Goldman. "It specifically kills a particular population of neurons that secrete dopamine in the substantia nigra."

The researchers believe the actual toxic mechanism is related to mitochondria, he added. "It's toxic to mitochondria, and that leads to additional oxidative stress and for some reason it causes death of neurons exactly in the same area as where we see death of neurons in PD."

One of the strengths of the study was that it reduced recall bias by using information on job tasks gained from detailed, structured, occupational questionnaires completed by participants who were unaware of study hypotheses rather than on self-reported exposures.

Dr. Goldman emphasized the importance of replicating these study results in other populations with well-characterized exposure histories. "Although a 6-fold increased risk is extremely high, and animal models find TCE-related pathology that is very similar to what is seen in Parkinson's disease, all epidemiological research must be replicated before a definitive causal link can be established."

Intriguing Implications

Approached for a comment, Matthew B. Stern, MD, Parker Family professor of neurology, and director of the Parkinson's Disease and Movement Disorder Center, University of Pennsylvania, Philadelphia, said this was a "carefully designed study by an experienced group of epidemiologists and movement disorder specialists."

In an email to Medscape Medical News, Dr. Stern said the use of twins "minimizes the pitfalls of unrecognized genetic and environmental influences inherent in standard case-control epidemiological studies" and that recall bias was also minimized through use of task-based occupational questionnaires.

The potential implications of the findings are "intriguing to consider," said Dr. Stern. "TCE is abundant in the environment and is neurotoxic. More specifically, metabolites of TCE have been shown to inhibit mitochondrial complex 1 and potentiate dopamine cell death in a variety of experimental models. Is it possible that environmental exposure to TCE in vulnerable individuals initiates the long, slow path to neurodegeneration and is one missing link in the environmental hypothesis?"

Dr. Stern agreed that although this study has considerable public health implications, its results should be interpreted with caution. "Epidemiologic studies of PD have previously implicated exposure to industrial and agricultural chemicals, rural living, well water, certain occupations, low caffeine consumption and non smoking, yet a specific environmental cause of PD has eluded us."

Although it is a "formidable challenge" to model a toxin that may cause disease many years after exposure, "epidemiology has once again given us an important clue that will surely fuel further investigation," added Dr. Stern.

Dr. Goldman has disclosed no relevant financial relationships.

Ann Neurol. Published online November 14, 2011. Abstract