The National Institute for Occupational Safety and Health (NIOSH) received a request from the United States Fish and Wildlife Service (FWS) to determine if there is a relationship between acoustic neuroma and fish hatchery work. The request was triggered by a report from an FWS employee who suspected the possibility of such an association. Investigators used data provided by the personnel office of the FWS to calculate the incidence of acoustic neuroma among fish hatchery workers, and then to compare it with national rates.
Four confirmed cases of acoustic neuroma were found among former fish hatchery workers. The overall incidence was estimated to be 15.41 per 100,000 personyears. This rate is more than 15 times higher than the rate among the general population. Even so, the small number of cases, as well as other factors, preclude the NIOSH from concluding that there is a definite cause-and-effect relationship. Further study is warranted.
Acoustic neuroma--also called neurinoma, neurilemoma, and schwannoma--is a benign tumor of the myelinforming Schwann cells that cover the VIIIth cranial nerve. It is the most common tumor of the cerebellopontine angle. Acoustic neuromas represent 5 to 8% of all diagnosed primary brain tumors. [1,2] Since the incidence of all primary brain tumors is 11.8 per 100,000 person-years, the incidence of acoustic neuroma is estimated to be between 0.59 and 0.94 per 100,000 person-years.  The literature reveals that its annual incidence is approximately 1 per 100,000 (range: 0.78 to 1.27 per 100,000). [4,6]
Acoustic neuromas generally develop during the fourth to sixth decades of life. They are equally distributed between men and women. Although most occur spontaneously, about 5% occur in patients who have neurofibromatosis 2 (central neurofibromatosis). [1,2] More than 90% of patients with neurofibromatosis 2 have bilateral acoustic neuromas. [1,2] Other than neurofibromatosis 2, only noise has been proposed as a risk factor for acoustic neuroma; this possibility is suggested by the findings of one population-based study. 
The usual presenting symptom of acoustic neuroma is a unilateral sensorineural hearing loss. Other common symptoms are tinnitus, vertigo, and unsteadiness. The diagnosis can be made by brainstem auditory evoked potentials and by gadolinium-enhanced magnetic resonance imaging (MRI). Surgical removal is the primary form of treatment.
This case series highlights the difficulties of determining the etiology of occupational neoplasms, including acoustic neuroma. The purpose of reporting this cluster is to make clinicians aware of the possible link between acoustic neuroma and workplace exposures, as well as to heighten sensitivity to the relationship between occupational exposures and other neoplasms. It is the responsibility of the clinician to include an occupational history in the general medical history and to take it into account when performing the physical examination.
The National Institute for Occupational Safety and Health (NIOSH) received a request from the United States Fish and Wildlife Service (FWS) to determine if there is a relationship between acoustic neuroma and fish hatchery work. The request was triggered by a report from an FWS employee who suspected the possibility of such an association.
As part of the Department of the Interior, the FWS endeavors to conserve, protect, and enhance fish and wildlife and their habitats for the continuing benefit of the American people. The FWS's major responsibilities are to care for migratory birds, endangered species, certain marine mammals, and freshwater and spawning fish. The FWS's operates 511 wildlife refuges, 72 hatcheries, nine fish health centers, and five fish technology centers across the U.S.
Investigators used data provided by the personnel office of the FWS to calculate the incidence of acoustic neuroma among fish hatchery workers, and then compared it with national rates.
The FWS is a small organization, and, according to the employee who triggered the investigation, most of the staff biologists know each other. This employee provided a list of those current and former employees who, to his personal knowledge, had developed brain tumors. The list was compiled during 1996 and 1997. NIOSH investigators contacted these persons, or their survivors, by telephone to determine if their medical history was consistent with a diagnosis of acoustic neuroma. Four current or former fish hatchery workers did have such a history, and their medical records were obtained to confirm the diagnosis. All cases of acoustic neuroma had been diagnosed by MRI or computed tomography (CT).
Investigators also visited three fish hatcheries and a fish health center in the Pacific Northwest to better understand past and current exposure to chemical, physical, and biological hazards.
Based on the number of full-time equivalent employees reported by the FWS personnel office, investigators determined that the FWS employees accounted for 154,290 person-years worked during the 22-year period from 1976 through 1997; the annual average was 7,013 person-years. (Computerized records of this information were not available prior to 1976.) The work force at the FWS is relatively stable; turnover has been low, and there have been no significant expansions or downsizing. Therefore, the estimated total person-time worked since 1961, the date that the first case began employment (or "exposure"), was 259,485 person-years. Fish hatchery workers accounted for approximately 10% of the employees at FWS, or 25,949 person-years.
The list provided by the employee who initiated the investigation contained the names of 14 current or former FWS employees who had developed brain tumors. One current employee and three retirees--all of whom had worked in fish hatcheries--had a history consistent with acoustic neuroma, and these diagnoses were confirmed by a review of their medical records (see case histories below). Seven others on the list did not have a history consistent with acoustic neuroma--that is, they had either a malignant tumor, aneurysm, meningioma, or metastatic disease to the brain. The remaining three persons could not be reached.
Case 1. Case 1 began work as a fish biologist for the FWS in 1966. Except for one 3-year assignment to a regional office, he had worked in cold-water hatcheries until he retired in 1994. In 1981, he sought medical treatment for tinnitus, dizziness, and a progressive rightsided hearing loss. His CT scan was consistent with an acoustic neuroma in the right cerebellopontine angle. The tumor was surgically removed. He had no personal or family history of neurofibromatosis 2.
Case 2. Case 2 is the employee who requested the investigation. His father had been a career fish biologist, and he had lived on hatcheries as a child and often assisted his father with his duties. Case 2 began work on his own as a fish biologist for the FWS in 1978. He worked at both warm- and cold-water hatcheries until 1985, when he transferred to a fish health center to work as a pathologist. In 1984, he began to notice difficulty hearing with his left ear. A CT scan was negative. Still, his hearing loss progressed, and another CT was performed in 1986, at which time an acoustic neuroma was detected in the left cerebellopontine angle. The lesion was surgically removed. He had no personal or family history of neurofibromatosis 2.
Case 3. Case 3 spent the summers of 1961 and 1962 working for the FWS in cold-water hatcheries. In 1963, he began full-time employment as a fish biologist in a cold-water hatchery, where he stayed for about 1 year. He then moved to an office job, where he completed his career in 1994. He began to have difficulty hearing and tinnitus in the left ear in 1982. His hearing loss progressed to the point that he could no longer hear on the telephone, and he sought treatment in February of 1989. His audiogram revealed a severe sensorineural hearing loss; his speech reception threshold was 40 dB, and his speech discrimination in the left ear was 30%. CT revealed a lesion in the left cerebellopontine angle and a widening of the internal auditory canal that was consistent with acoustic neuroma. The tumor was surgically removed. He had no personal or family history of neurofibromatosis 2.
Case 4. Case 4 began work as a fish biologist for the FWS in 1963. After spending his entire career in cold-water fish hatcheries, he retired in 1995. In 1991, he sought treatment for a 5- to 6-year history of progressive right-sided hearing loss. Audiologic testing revealed a severe sensorineural hearing loss; his speech reception threshold was 30 dB, and his speech discrimination in the right ear was 44%. MRI revealed an acoustic neuroma, which was surgically removed. He had no personal or family history of neurofibromatosis 2.
Based on these four confirmed cases, the incidence of acoustic neuroma among former fish hatchery workers is estimated at 15.41 per 100,000 person-years, a rate that is more than 15 times higher than the rate among the general population. [4-6] If there are other unreported cases, this rate would, of course, be higher.
Health events often occur in a cluster, which scientists define as an unusual concentration of cases in a specific area or time. Multiple cases among workers of a different age or gender group than is usual might constitute an occupational cluster. Sometimes these cluster events have a common cause, but often their occurrence is merely coincidental. Rare diseases such as acoustic neuroma can occasionally cluster in a way that is statistically unlikely but still not related to exposure.  In instances where the number of cases is small, it can be difficult to ascertain a common cause, especially when there are no apparent tumor-causing exposures.
This paper reports an apparent cluster of acoustic neuromas among fish hatchery workers in which the incidence was much higher than that seen in the general population. The magnitude of the excess, however, must be interpreted cautiously because of the potential for detection bias. The prevalence of undiagnosed acoustic neuroma at autopsy is 0.8 to 0.9%. [9,10] As noted earlier, the annual incidence of symptomatic, diagnosed acoustic neuroma is approximately 1 per 100,000. It is conceivable that FWS employees might have been alerted to a possible connection between acoustic neuroma and workplace exposure and mentioned this to their physicians. If so, they would have been more likely to have their acoustic neuroma diagnosed. This possibility is unlikely, however, because the index case was diagnosed some time after one of the other cases had been detected. Moreover, the employee who initiated the investigation did not compile his list of employees with brain tumors until 1996 and 1997, several years after the last of the four cases had been diagnosed. Interviews with the four cases indicated that they were not aware of any other such cases in the FWS or that there was any personal communication between the cases at the time of diagnosis. In addition, medical record reviews and interviews indicate that all cases were already symptomatic at the time of diagnosis.
An important issue to consider when evaluating the possibility of an occupational cause of a tumor is the latency period. Latency periods vary by tumor type, but typically are 15 to 20 years. The shortest such latency period among occupational exposures appears to be that of acute myelogenous leukemia following exposure to benzene, which averages 10 years.  At the other end of the range, it can take mesothelioma as long as 30 years to develop after exposure to asbestos. 
In this study, the interval between the start of employment at a fish hatchery and a diagnosis of acoustic neuroma ranged from 8 to 28 years (mean: 20). It should be kept in mind that the employee who had the shortest latency period had lived on hatcheries as a child and often assisted his father with his duties as a career fish biologist. Therefore, his exposure exceeded his length of employment by many years.
Possible causes. The use of chemicals in the hatchery environment is extensive. These chemicals include internal therapeutics, anesthetics, disinfectants, herbicides, and fish toxicants. Among the internal therapeutic agents are oxytetracycline, chloramphenicol, and several sulfa drugs. Anesthetics include tricaine methanesulfonate (MS-222) and quinaldine. Disinfectants include formalin, malachite green, benzalkonium chloride, chlorine, iodine, and potassium permanganate. Herbicides and pesticides include 2,4-dichlorophenoxyacetic acid, 2,4,5-trichlorophenoxyacetic acid, sodium arsenite, warfarin, and carbaryl. Many other substances have been or are being used in FWS, state, and private hatcheries.
Forty years ago, only a very few of these substances had been approved and registered by the Food and Drug Administration. Although protocols for the treatment of various fish diseases did exist, it was possible to deviate from these protocols on an as-needed basis. This practice came under the scrutiny of the FDA in the mid-1960s. As a result, the FDA's Bureau of Veterinary Medicine notified the Bureau of Sport Fisheries and Wildlife that all chemicals used at federal, state, and private hatcheries must be cleared and registered for specific uses against designated species under defined conditions. The FWS then polled all federal hatcheries, as well as 14 state units, to determine which chemicals required top priority for clearance. The initial list included 95 substances: 23 herbicides, 18 internal treatments for fish disease, 16 external treatments and disinfectants, 13 pest controls for species other than fish, eight fish controls, seven fish transport aids, seven anesthetics, and three dyes.  These substances were entered into the approval process, and the list was updated periodically. But by 1982, only 15 of these compounds had received FDA or Environmental Protection Agency approval for aquatic or fishery use. 
Malachite green. Interviews with the four FWS employees with acoustic neuroma, as well as with several long-term employees at three salmon hatcheries in the Pacific Northwest, revealed a concem that adverse health effects might have been caused by malachite green. Malachite green was banned from use in hatcheries in the mid-1980s, except as an investigational new drug for use in endangered species. Prior to then, there had been extensive use of malachite green, and workers had worn no personal protective equipment when handling it.
Malachite green is a triphenylmethane dye used in aquaculture for the treatment of fungal and parasitic infections in fish and their eggs. It is structurally similar to gentian violet, a carcinogenic triphenylmethane dye.  It is reduced to some extent in the body to leucomalachite green, which has a longer half-life. Malachite green is mutagenic in Salmonella typhimurium TA98 in the presence of an exogenous metabolizing system, but is not in several other strains.  It is markedly cytotoxic, inducing cell transformation and lipid peroxidation in mammalian cells.  The results of carcinogenicity assays have been equivocal, but the dye does appear to act as a tumor promoter.  Malachite green was nominated as a priority chemical for carcinogenicity testing by the National Toxicology Program in 1993, based on the potential for significant worker and consumer exposure, evidence of tumor promotion in rodent livers, and a suspicion of carcinogenicity based on its chemical structure.  Testing data are not yet available.
Data gathering. This investigation provides an example of how difficult it can be to identify occupational neoplasms. One problem is the difficulty of identifying other cases, which is necessary to conduct epidemiologic studies. We considered obtaining information from health insurance records, but the task was not practicable: FWS employees are scattered throughout the U.S., and their healthcare is provided by approximately 350 different health plans. Furthermore, these plans are required to keep claims data for only 3 years, which is not a long enough period to identify a sufficient number of cases of a condition as rare as acoustic neuroma.
We also considered obtaining data from tumor registries, but not all states have them. Even among those that do, data collection is not uniform. For example, only 24 state registries collect information on benign tumors. Of equal concern is the lack of information about a patient's occupation and industry, despite the federal government's efforts to encourage the inclusion of this information. The National Program of Cancer Registries (NPCR), established in 1992, calls for funded states to establish statewide, population-based registries and obtain uniform data elements in compliance with standards for completeness, timeliness, and quality. Although the NPCR requires the reporting of each patient's usual occupation and industry if this information is recorded in the clinical record, this information is often missing.
Usual occupation and industry. Usual occupation and industry refers to any given person's longest-held occupation and the industry in which he or she worked. Because the latency of neoplasms is so long, epidemiologists prefer to consider a person's usual occupation and industry rather than his or her current or latest occupation and industry. The coding of occupations and industries by healthcare professionals should be in accordance with the system used by the U.S. Census Bureau, which groups thousands of job titles into approximately 500 occupations and 200 industries.  It is important that physicians document this information in medical records, not only as part of the medical history, but so that it is there for state registries to abstract. The NPCR does not require the reporting of noninvasive tumors such as acoustic neuroma.
The Acoustic Neuroma Association (ANA), headquartered in Atlanta, not only provides support for patients, but acts as an information source for healthcare professionals, promotes research, and educates the public on symptoms, thus facilitating early diagnosis.  In 1989, the ANA established the Acoustic Neuroma Registry. Cases are reported voluntarily by surgeons (to obtain reporting forms, contact the registry at P.O. Box 12402, Atlanta, GA 30355; phone: (404) 237-8023). Unfortunately, no information regarding work history is collected either from ANA members or by the registry. The establishment of a comprehensive system of collecting information on occupation and industry in both the registry and membership would enable researchers to conduct epidemiologic studies to evaluate possible associations between work-related exposures and acoustic neuroma.
The author would like to acknowledge Kenneth C. Rozas, Chief of Occupational Safety and Health, U.S. Fish and Wildlife Service; James L. Lee, Management and Personnel Analyst, U.S. Fish and Wildlife Service; and Rosalie Schnick, National Aquaculture NADA Coordinator, for their invaluable assistance in this investigation.
From the National Institute for Occupational Safety and Health, Epidemiology Program Office, Centers for Disease Control and Prevention, Cincinnati.
Reprint requests: Elena H. Page, MD, Epidemic Intelligence Service, Centers for Disease Control and Prevention, 4676 Columbia Pkwy., MSR-lO, Cincinnati, OH 45226-1998. Phone: (513) 458-7144; fax: (513) 458-7105; e-mail: firstname.lastname@example.org
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