Portal latinoamericano de toxicología
Trichloroethylene and Parkinson Risk
11 February, 2010
AAN: Industrial Cleaner Again Tied to Parkinson Risk. By John Gever, Senior Editor, MedPage Today. February 07, 2010. The degreasing agent trichloroethylene (TCE) has been linked to increased rates of Parkinson’s disease among industrial workers in yet another study, this time involving a large, well-studied group of World War II veterans. Parkinson’s disease developed in individuals with occupational exposure to TCE at more than five times the rate seen in those without such exposure (odds ratio 5.5, 95% CI 1.02 to 30), reported Samuel Goldman, MD, of the Parkinson’s Institute in Sunnyvale, Calif.Goldman described the research in a phone interview with MedPage Today. It’s scheduled for presentation here in April at the American Academy of Neurology’s annual meeting.A previous study in 2008 had fingered TCE as the most likely culprit behind a cluster of Parkinson’s disease cases afflicting workers at a single industrial plant. (See then, scroll down: Trichloroethylene Implicated as Risk for Parkinsonism)
Also, Goldman said, animal studies have found that TCE is selectively toxic to nigral dopaminergic neurons, the same type of nerve cell that progressively dies off in Parkinson’s disease. He said the chemical’s activity in rodent brains is very similar to that of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a dopaminergic neurotoxin commonly used to simulate Parkinson’s disease in preclinical research.
Goldman said the new study was the first population-based analysis to link TCE to the disease.
It focused on 198 twin pairs in the National Academy of Sciences-National Research Council’s World War II Twins Cohort, which comprises some 16,000 twin pairs overall.
Members of the all-male cohort, who were born from 1917 to 1927 and served in the war, have been followed since the 1960s. Occupational histories for participants are available along with medical records from the VA healthcare system.
In those pairs chosen for the current study, records showed that one twin had developed Parkinson’s disease and the other had not. This design largely eliminates genetics as a confounding factor in the analysis.
Goldman explained that occupational histories for each participant were reviewed by a blinded industrial hygienist and a preventive medicine physician to identify likely exposures to TCE and four other industrial chemicals: xylene, toluene, carbon tetrachloride, and tetrachloroethylene.
As a single source of exposure, only TCE was significantly associated with development of Parkinson’s disease, Goldman said.
People working as aircraft mechanics, machinists, plumbers, and electricians likely had regular exposure to TCE, Goldman said. The chemical was commonly used as a "spot" cleaner to remove grease and oils from metal surfaces. It was also used for a time as a dry cleaning solvent, although tetrachloroethylene was more common for that purpose.
Goldman said no increased risk was seen with xylene or toluene, but there were near-significant trends toward increased Parkinson’s disease risk from carbon tetrachloride and tetrachloroethylene:
Carbon tetrachloride: OR 2.8 (95% CI 0.97 to 7.8)
Tetrachloroethylene: OR 9.0 (95% CI 0.78 to 103)
Twins exposed to either TCE or tetrachloroethylene were at significantly increased risk, with an odds ratio of 8.1 (95% CI 1.43 to 43) relative to individuals with no exposure to either chemical.
Goldman said the analysis also examined whether duration of exposure was associated with increased risk. He said the results were in the same pattern as for the yes-no exposure analysis, but the findings were very uncertain because of the relatively small sample size.
Occupational histories were available for only 99 of the 198 discordant twin pairs and some of the information was obtained by proxy rather than from the participant himself.
Because of the wide confidence intervals even for the yes-no exposure analysis, the findings need confirmation in a larger study, he said, noting that the best approach would be a cohort study involving people with known, long-term exposure to TCE, compared with well-chosen controls.
"The study wouldn’t have to be large," Goldman said. He estimated that 1,000 to 2,000 participants would be adequate to determine if the connection to Parkinson’s disease is real.
See previous article: Trichloroethylene Implicated as Risk for Parkinsonism. By Judith Groch, MedPage Today.January 08, 2008. Trichloroethylene is a probable risk factor for Parkinson’s disease and parkinsonism, a study here found.The finding came from a study of 31 workers at an industrial plant, including three workers with Parkinson’s disease exposed to high levels of trichloroethylene, and from animal experiments, Don M. Gash, Ph.D., of the University of Kentucky, and colleagues reported online in the Annals of Neurology.
Trichloroethylene, a degreasing agent widely used in industry and the military, is also found in drinking water, surface water, and soil as a runoff from manufacturing sites. The chemical has been identified as an environmental contaminant by the Environmental Protection Agency.
One of the three workers with Parkinson’s described 25 years of industrial exposure to trichloroethylene at a small industrial plant. He also said that two coworkers with long exposure to the chemical had also developed Parkinson’s Disease.
Along with clinical evaluations of the index patient, who had no family history of the disease, and his two coworkers (one a woman) with Parkinson’s, the researchers studied a cluster of 28 coworkers with Parkinson’s and parkinsonism.
The workers had eight to 33 years of exposure to the chemical.
Exposure resulted from both inhalation and submerging unprotected arms and forearms in a chemical vat or touching parts that had been cleaned in it.
Neurological evaluations were conducted including a general physical and neurological exam and the Unified Parkinson’s Disease Rating Scale. The investigators also measured fine motor speed and took an occupational history.
In addition, questionnaires about signs of Parkinson’s Disease, such as slowness of voluntary movement, stooped posture, and trouble with balance, were mailed to 134 former workers.
Fourteen former workers who reported three or more parkinsonian signs worked close to the trichloroethylene source. They were significantly slower (up to 250%) in fine-motor hand movements than age-matched controls.
Thirteen workers reported no symptoms. Clinical exams revealed that they worked in the same area as the symptomatic workers or farther away from the chemical vat, thus respiratory exposure was their main contact.
However, their scores on the rating scale indicated some mild features of parkinsonism. As a group, their fine-motor hand movement times were significantly slower (P<0.0001) than age-matched controls, although they were faster than the group with symptoms.
While the clinical evaluations were underway, the researchers started rat studies to determine whether trichloroethylene exposure is neurotoxic to the nigrostriatal dopamine system that degenerates in Parkinson’s Disease.
The experiments specifically analyzed Complex 1 mitochondrial neurotoxicity, as this is a mechanism in other known environmental dopaminergic neurotoxins, they said.
Neurotoxic actions of trichloroethylene showed that oral administration of trichloroethylene for six weeks brought about selective Complex 1 mitochondrial impairment in the midbrain with concomitant striatonigral fiber degeneration and loss of dopamine neurons.
Converging evidence from a number of laboratories has implicated mitochondrial Complex 1 dysfunction as a central event in the degeneration of dopamine neurons in Parkinson’s disease, the investigators said.
These results suggest that trichloroethylene joins other mitochondrial neurotoxins, MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), and some pesticides as a risk factor for parkinsonism, Dr. Gash and colleagues said.
It is important, they said, to recognize that this study was not a large scale epidemiological investigation designed to address recall, case-findings, or other sources of bias. Nevertheless, these results demonstrate a strong potential link between chronic trichloroethylene exposure and parkinsonism.
Three coworkers with chronic dermal and inhalation exposure to trichloroethylene developed Parkinson’s disease, and many coworkers with long exposure displayed features of parkinsonism, they said.
They pointed out that some trichloroethylene-exposed individuals developed frank Parkinson’s, whereas others only had mild-to-moderate parkinsonism, suggesting the possible presence of comorbid factors.
"This would be consistent with the hypothesis that the progressive loss of dopamine neurons characterizing Parkinson’s disease is due to multiple insults leading to the degeneration of the nigrostriatal dopamine system in the brain," they wrote. "We would broaden the hypothesis to include most manifestations of parkinsonism, including dyskinesia."
They added, "It will be important to follow the progression of movement disorders in this cohort over the next decade to more fully assess the long-term health risks from trichloroethylene exposure."
Goldman said the new study was the first population-based analysis to link TCE to the disease.
It focused on 198 twin pairs in the National Academy of Sciences-National Research Council’s World War II Twins Cohort, which comprises some 16,000 twin pairs overall.
Members of the all-male cohort, who were born from 1917 to 1927 and served in the war, have been followed since the 1960s. Occupational histories for participants are available along with medical records from the VA healthcare system.
In those pairs chosen for the current study, records showed that one twin had developed Parkinson’s disease and the other had not. This design largely eliminates genetics as a confounding factor in the analysis.
Goldman explained that occupational histories for each participant were reviewed by a blinded industrial hygienist and a preventive medicine physician to identify likely exposures to TCE and four other industrial chemicals: xylene, toluene, carbon tetrachloride, and tetrachloroethylene.
As a single source of exposure, only TCE was significantly associated with development of Parkinson’s disease, Goldman said.
People working as aircraft mechanics, machinists, plumbers, and electricians likely had regular exposure to TCE, Goldman said. The chemical was commonly used as a "spot" cleaner to remove grease and oils from metal surfaces. It was also used for a time as a dry cleaning solvent, although tetrachloroethylene was more common for that purpose.
Goldman said no increased risk was seen with xylene or toluene, but there were near-significant trends toward increased Parkinson’s disease risk from carbon tetrachloride and tetrachloroethylene:
Carbon tetrachloride: OR 2.8 (95% CI 0.97 to 7.8)
Tetrachloroethylene: OR 9.0 (95% CI 0.78 to 103)
Twins exposed to either TCE or tetrachloroethylene were at significantly increased risk, with an odds ratio of 8.1 (95% CI 1.43 to 43) relative to individuals with no exposure to either chemical.
Goldman said the analysis also examined whether duration of exposure was associated with increased risk. He said the results were in the same pattern as for the yes-no exposure analysis, but the findings were very uncertain because of the relatively small sample size.
Occupational histories were available for only 99 of the 198 discordant twin pairs and some of the information was obtained by proxy rather than from the participant himself.
Because of the wide confidence intervals even for the yes-no exposure analysis, the findings need confirmation in a larger study, he said, noting that the best approach would be a cohort study involving people with known, long-term exposure to TCE, compared with well-chosen controls.
"The study wouldn’t have to be large," Goldman said. He estimated that 1,000 to 2,000 participants would be adequate to determine if the connection to Parkinson’s disease is real.
See previous article: Trichloroethylene Implicated as Risk for Parkinsonism. By Judith Groch, MedPage Today.January 08, 2008. Trichloroethylene is a probable risk factor for Parkinson’s disease and parkinsonism, a study here found.The finding came from a study of 31 workers at an industrial plant, including three workers with Parkinson’s disease exposed to high levels of trichloroethylene, and from animal experiments, Don M. Gash, Ph.D., of the University of Kentucky, and colleagues reported online in the Annals of Neurology.
Trichloroethylene, a degreasing agent widely used in industry and the military, is also found in drinking water, surface water, and soil as a runoff from manufacturing sites. The chemical has been identified as an environmental contaminant by the Environmental Protection Agency.
One of the three workers with Parkinson’s described 25 years of industrial exposure to trichloroethylene at a small industrial plant. He also said that two coworkers with long exposure to the chemical had also developed Parkinson’s Disease.
Along with clinical evaluations of the index patient, who had no family history of the disease, and his two coworkers (one a woman) with Parkinson’s, the researchers studied a cluster of 28 coworkers with Parkinson’s and parkinsonism.
The workers had eight to 33 years of exposure to the chemical.
Exposure resulted from both inhalation and submerging unprotected arms and forearms in a chemical vat or touching parts that had been cleaned in it.
Neurological evaluations were conducted including a general physical and neurological exam and the Unified Parkinson’s Disease Rating Scale. The investigators also measured fine motor speed and took an occupational history.
In addition, questionnaires about signs of Parkinson’s Disease, such as slowness of voluntary movement, stooped posture, and trouble with balance, were mailed to 134 former workers.
Fourteen former workers who reported three or more parkinsonian signs worked close to the trichloroethylene source. They were significantly slower (up to 250%) in fine-motor hand movements than age-matched controls.
Thirteen workers reported no symptoms. Clinical exams revealed that they worked in the same area as the symptomatic workers or farther away from the chemical vat, thus respiratory exposure was their main contact.
However, their scores on the rating scale indicated some mild features of parkinsonism. As a group, their fine-motor hand movement times were significantly slower (P<0.0001) than age-matched controls, although they were faster than the group with symptoms.
While the clinical evaluations were underway, the researchers started rat studies to determine whether trichloroethylene exposure is neurotoxic to the nigrostriatal dopamine system that degenerates in Parkinson’s Disease.
The experiments specifically analyzed Complex 1 mitochondrial neurotoxicity, as this is a mechanism in other known environmental dopaminergic neurotoxins, they said.
Neurotoxic actions of trichloroethylene showed that oral administration of trichloroethylene for six weeks brought about selective Complex 1 mitochondrial impairment in the midbrain with concomitant striatonigral fiber degeneration and loss of dopamine neurons.
Converging evidence from a number of laboratories has implicated mitochondrial Complex 1 dysfunction as a central event in the degeneration of dopamine neurons in Parkinson’s disease, the investigators said.
These results suggest that trichloroethylene joins other mitochondrial neurotoxins, MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), and some pesticides as a risk factor for parkinsonism, Dr. Gash and colleagues said.
It is important, they said, to recognize that this study was not a large scale epidemiological investigation designed to address recall, case-findings, or other sources of bias. Nevertheless, these results demonstrate a strong potential link between chronic trichloroethylene exposure and parkinsonism.
Three coworkers with chronic dermal and inhalation exposure to trichloroethylene developed Parkinson’s disease, and many coworkers with long exposure displayed features of parkinsonism, they said.
They pointed out that some trichloroethylene-exposed individuals developed frank Parkinson’s, whereas others only had mild-to-moderate parkinsonism, suggesting the possible presence of comorbid factors.
"This would be consistent with the hypothesis that the progressive loss of dopamine neurons characterizing Parkinson’s disease is due to multiple insults leading to the degeneration of the nigrostriatal dopamine system in the brain," they wrote. "We would broaden the hypothesis to include most manifestations of parkinsonism, including dyskinesia."
They added, "It will be important to follow the progression of movement disorders in this cohort over the next decade to more fully assess the long-term health risks from trichloroethylene exposure."