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Relationship Between Rotenone Use in Fisheries Management and Parkinson's Disease

Introduction

The Fish Management Chemicals Subcommittee Task Force on Fishery Chemicals of the American Fisheries Society believes that the reported findings of a relationship between Parkinson's disease and rotenone in an Emory University study (Betarbet et al. 2000) do not suggest a need for additional precautions with respect to current uses of rotenone. Neither studies conducted for the U.S. Environmental Protection Agency nor the use of rotenone for many decades have indicated any associations with Parkinson's disease. Unfortunately, the report is certain to generate unfounded fears, caused by the inaccurate and incomplete reporting of the study and its implications. In fact, Betarbet et al. (2000) concluded that their findings do not show that exposure to rotenone has caused Parkinson's disease. They stated further that "rotenone seems to have little toxicity when administered orally".

Parkinson's Disease

Parkinson's disease results in a lost function of the brain cells that produce dopamine, used to transmit signals in the brain. Symptoms of the disease usually include limb tremors and occasional rigidity. The causes of Parkinson's disease are diverse and complex. Some cases can be attributed to genetic factors, and several mutations have lead to familial Parkinson's disease (Giasson and Lee 2000).

Summary of Emory University Study

Emory University (Atlanta, Georgia) conducted a study that demonstrated that rotenone produced Parkinson's-like anatomical, neurochemical, and behavioral symptoms in laboratory rats when administered chronically and intravenously (Betarbet et al. 2000). In this study, 25 rats were continuously exposed for 5 weeks to 2 to 3 mg rotenone (dissolved in dimethyl sulfoxide [DMSO] and polyethylene glycol [PEG]) per kg body weight per day. The exposure was accomplished by injecting the mixture directly into the right jugular vein of the rats using an osmotic pump. Twelve of the 25 rats developed lesions characteristic of Parkinson's disease. Structures similar to Lewy bodies (microscopic protein deposits) in the neurons of the substantia nigra in the brain (characteristic of Parkinson's disease) were produced in several of the rotenone-exposed rats.

Method of Exposure Limits the Usefulness of Emory University Study to Establish Relationship Between Rotenone Use in Fisheries Management and Parkinson's Disease

The manner that rotenone was administered to the laboratory rats was highly unnatural. Not only was it administered by continuous jugular vein infusion, it was mixed with DMSO and PEG. DMSO enhances tissue penetration of many chemicals (Dr. Peter Kurtz, M.D., California Department of Food and Agriculture, personal communication) The normal exposure to rotenone in humans from its use in fisheries management would be ingestion, inhalation or through the skin. Direct injection is the fastest way to deliver chemicals to the body, as evidenced in intravenous application of medicines. Continuous intravenous injection, as done in this study, also leads to continuously high levels of the chemical in the bloodstream. Normal ingestion, inhalation, and dermal exposures significantly slow down the introduction of chemicals into the bloodstream. Administering any chemical directly into living tissues can have grave consequences. For example, sodium chloride (table salt) administered to developing chick embryos causes birth defects (Dr. P. Kurtz, M.D., California Department of Food and Agriculture, personal communication). However, this model has no practical predictive value for humans ingesting salt. Similarly, penicillin injected into the brain of cats induces seizures, but this does not suggest that ingestion will cause similar effects in humans.

Likewise, the method of exposure in the Emory University study cannot be used as a model for any form of rotenone exposure in fisheries management. Rotenone exposure in the environment is extremely limited. Rotenone is very unstable in the environment (half-life measured in days), is oxidized (neutralized) through enzymatic action in the gut of mammals and birds, is metabolized to very polar (water soluble) compounds in the body, and these compounds are excreted by the liver and kidney (Finlayson et al. 2000). Because of the rapid metabolism and clearance in mammals and birds, it is not likely that rotenone could reach the site of action in the substantia nigra in the brain where the dopamine is formed. Rotenone is toxic to fish because it is taken up rapidly across the gills and gets directly into the bloodstream, thus, bypassing the gut. Rotenone is considered safe for the environment because it loses all its toxicity in a few days. In fact, it is significant that the Emory University investigators could not administer rotenone in any other manner except intravenously and get delivery of rotenone to the brain; otherwise, rotenone would have been neutralized in the gut and liver.

Exposure to applicators applying rotenone in fisheries management is further minimized through the use of protective equipment such as air-purifying respirators, protective clothing (coveralls, gloves), and eye protection (splash goggles or face shields) that are required on the product labels (Finlayson et al. 2000). Specific information on proper handling procedures and protective equipment are found on rotenone labels.

The results from a chronic feeding study with rats using rotenone found no Parkinson's- like anatomical or behavioral symptoms (Marking 1988). In this 24-month chronic feeding study, rotenone was orally administered to 320 rats in doses up to 75 mg/kg per day. All surviving animals were sacrificed and tissues and organs of all test animals were examined macroscopically and microscopically. The brain was sectioned, and microscopic examinations of the basal ganglia, frontal cortex, occipital cortex, thalamus, and cerebellum were completed. No changes were observed in the brain of these rotenone-exposed rats. It is significant that these rats were exposed to up 30 times more rotenone (2.5 versus 75 mg/kg/day) for 21 times longer (5 versus 104 weeks) than the rats used in the Emory University study. However, these rats were exposed to rotenone by ingestion, the route people would be exposed to rotenone.

What is the Value of the Emory University Study?

Several researchers in Parkinson's disease (including J. Langston, Director of the Parkinson's Institute) have stated that the study is not direct evidence that rotenone causes Parkinson's disease. The U.S. Environmental Protection Agency has known for some time of the effects of rotenone on the nervous system when injected directly into animals. In 1993, the U.S. Environmental Protection Agency published the Worker Protection Standard Handbook that listed all the known effects of pesticides and necessary steps for treating pesticide poisoning (Pesticide Regulation Notice 93-7). In the Biologicals section of the handbook the following statement is made, "When rotenone has been injected into animals, tremors, vomiting, incoordination, convulsions, and respiratory arrest have been observed. These effects have not been reported in occupationally exposed humans." Thus, the effects of rotenone injected directly into animals was known before the study done at Emory University. The true value of the study is in developing a model of Parkinson's disease so researchers will have a better method to study the cellular defects associated with Parkinson's disease, not in discovering the cause(s) of Parkinson's disease.

References

Betarbet, R., T. Sherer, G. MacKenzie, M. Garcia-Osuna, A. Panov, and J. Greenamyre. 2000. Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nature Neuroscience 3:12 1301-1306.

Finlayson B., R. Schnick, R. Cailteux, L. Demong, W. Horton, W. McClay, C. Thompson, and G. Tichacek. 2000. Rotenone use in fisheries management: administrative and technical guidelines. American Fisheries Society, Bethesda, Maryland.

Gaisson, B., and V. Lee. 2000. A new link between pesticides and Parkinson's disease. Nature Neuroscience 3:12 1227-1228.

Marking, L. 1988. Oral toxicity of rotenone to mammals. U.S. Fish and Wildlife Service, Investigations in Fish Control 94. 5 pp.


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