Dr. John Harshbarger - Overview of Fish Tumor History and Epidemology

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Presentations Session I: Historical Overview Dr. John Harshbarger - Overview of Fish Tumor History and Epidemology Dr. Harshbarger opened his presentation by clarifying the following terms: tumor, neoplasm,
Presentations Session I: Historical Overview Dr. John Harshbarger - Overview of Fish Tumor History and Epidemology Dr. Harshbarger opened his presentation by clarifying the following terms: tumor, neoplasm, toxin, and hyperplasia. Tumor and neoplasm are interchangeable in current medical usage. A tumor or neoplasm, is a heritably altered (mutated), relatively independent (autonomous), relatively atypical (dysplastic) growth of tissue of no use and often detrimental to the host. In other words a neoplasm is a population of abnormal cells that continue to proliferate after mutation is no longer present. Tumors that are growing by simple expansion are often benign while tumors that are invading and destroying host tissue are cancers. Since cancers can arise in benign tumors one should not become complacent about benign tumors. Causes of the heritable abnormality include certain chemicals, ionizing radiation, ultraviolet radiation, and certain viruses. There is no minimum threshold level for the oncogenic mutagen. Toxin is derived from the Latin word toxicum meaning poison. Poison kills cells via the production of free radicals that interfere with intracellular mechanisms: thus, toxin causes the cessation of cellular-proliferation in contrast to neoplastic transformation, which enhances cellular proliferation. Toxins have a minimum threshold. Hyperplasia is the unscheduled proliferation of normal cells and is often accompanied by organ hypertrophy. Examples include: 1) Kidney donors have compensatory hyperplasia and hypertrophy of the retained kidney; 2) Overeaters have nutritional hyperplasia of adipose tissue to store the excess calories; 3) Hypertension induces functional hyperplasia and hypertrophy of cardiac muscle; 4) Sunburn releases toxic free radicals leading to regenerative hyperplasia to replace the dead skin cells; 5) Iodine deficiency biofeedback causes endocrine hyperplasia of the thyroid tissue with goiter formation. Following the clarification of these terms, Dr. Harshbarger briefly outlined the history of the role of carcinogens in tumors and milestones in the use of fish environmental sentinels. 1775: Sir Percival Potts reported that boys used as chimney sweeps developed scrotal cancer. 1850: Fish neoplasms first documented in North America. 1900: The carcinogenicity of coal tar (chimney soot) was experimentally confirmed. 1930: Benzo(a)pyrene was the first pure carcinogen isolated from coal tar. 1940: Skin papillomas were discovered on brown bullheads in industrially polluted Delaware and Schuylkill Rivers in Philadelphia. 1956: Evidence that a herpesvirus can cause cancer was discovered in northern leopard frogs. 1957: Oral papillomas were found on the lips of white croakers feeding at a California sewage outfall while white croakers feeding in relatively pristine water were tumor free. 9 1962: The carcinogenicity of aflatoxin, a common, potent human carcinogen produced by fungi, was discovered when hatchery rainbow trout developed panzootic liver cancer following the global introduction of mold contaminated pelleted trout chow. 1963: White suckers in a polluted waterway had oral papilloma and liver cancer. 1964: Zebrafish were exposed to diethylnitrosamine in the first experimental carcinogen study with small fish. 1965: The Registry of Tumors in Lower Animals was started. 1970: The 1940 s report of skin cancer was confirmed and liver cancer was discovered in brown bullhead catfish sampled every 10 miles in the Delaware River between Trenton, NJ and Philadelphia, PA. 1972: Neoplasms reported in several fish species in the polluted Fox River west of Chicago compared to almost none in the same species from pristine Canadian lakes. 1977: Liver cancer reported in English sole in a polluted tributary of Puget Sound. 1978: Tomcod liver cancer discovered in lower Hudson River, NY heavily polluted by PCB s and PAH s. 1979: Paul Baumann found skin and liver cancer in brown bullheads at a coking plant outfall in the Black River, Ohio. 1981: Neoplasms reported in fish species from the Buffalo River, Buffalo NY. 1981: Liver cancer reported in sauger and walleye from Torch Lake MI contaminated by copper mine tailings and chemicals used to extract copper. 1982: CNN ran a series of reports on fish tumors associated with chemicals dumped into Torch Lake (Michigan), the coking plant on the Black River and the lower Hudson R. There was a huge unexpected worldwide response. 1983: Congressional hearing held in concern of fish cancer prevalence where human cancer was also high. 1985: Winter flounder liver cancer reported from Deer Island sewage outfall, Boston Harbor. 1985: Skin painting of extracts of sediment from Black River, OH and Buffalo River, NY produced cancer on brown bullheads and mice. 1987: Bowfin liver cancer reported from Detroit River, MI. 1987: White perch liver tumors reported from Chesapeake Bay. 1988: Oyster toadfish pancreas and liver cancer reported from York River, VA near a refinery. 1988: Oral papillomas and liver neoplasms in white sucker reported from polluted sites on Lake Ontario 1990: Mummichog liver cancer reported from creosote polluted Elizabeth River, VA. 1991: Experimental trophic transfer of carcinogens to winter flounder fed contaminated blue musssels 1991: Brown bullhead liver cancer reported in Cuyahoga River, Cleveland, OH. 1995: Brown bullhead liver cancer in Black River, OH drops sharply after coking plant closes and PAH s plummet. 1995: Oral papilloma reported in white sucker from St Lawrence River, PQ Canada 1998: Lake whitefish liver cancer reported in St Lawrence River, PQ Canada. 2001: Brown bullhead liver and skin cancer reported in the Potomac River, and Anacostia River 10 This incomplete list shows the importance of fish liver and skin neoplasms as sentinels for environmental carcinogens. Dr. Harshbarger discussed epizootic tumors in other organ systems as well including the hematopoietic system, pigment and nerve cell neoplasm, excretory system, etc., according to the predominate species and site of their occurrences. The number of epizootic fish, amphibian, reptile, and mollusk neoplasms has increased steadily from a combined total of 18 in 1954 to 145 in Several examples were given linking pollutants and chemical contaminants to tumors and deformities in fish species associated with affected environments. These included mid-western frogs with polydactyly (Fig 1) and sea lampreys in the Great Lakes and tributaries with teratoid anomalies (Fig 2). In Orange County, California, oral papillomas in white suckers near the sewage outfall (Fig 3) declined to zero following the renovation of the sewage facilities. Dr. Harshbarger was an expert witness at a trial concerning Millstone nuclear power plant in Connecticut and its involvement in the massive discharge of carcinogenic compounds into the surrounding aquatic ecosystem. Nuclear power plant operators add huge volumes of chemical oxygen scavengers such as hydrazine to the cooling water to prevent internal corrosion. The principle compounds used are carcinogenic and associated with carcinogenic contaminants; therefore, the large number of nuclear power plants around the great lakes are a likely source of environmental carcinogens and fish in the vicinity of the discharges should be monitored for liver cancer. Dr. Harshbarger was asked by the IJC to put together a report relating contaminants and fish tumor occurrence. It was his suggestion that all sources of point source pollution should be documented and the chemicals that were being put into the environment should be noted. Bioassays of fish containing tumors and deformities could be carried out to determine if the chemical causing these deformities could be linked to point source pollution. He then concluded by stating: the companies or persons responsible for putting these harmful pollutants into the environment should be responsible for their actions, and if they were not, penalties should be administered. Selected data from that report are included here. 11 Dr. John Harshbarger s Power Point Presentation Figure 1: Frog With Polydactyly Figure 2: Histopath of a Teratoid Anomaly Found in Sea Lampreys Figure 3: Oral Papillomas on a White Sucker Toward a Transboundary Monitoring Network: A Continual Binational Exploration Vol. 2 Proceedings of a Workshop Convened by the International Joint Commission, U.S.A. and Canada And Relata Assembled During the Editing Process Bruce L. Bandurski, Peter T. Haug, and Andrew L. Hamilton Editors June Relevance of Fish Cancer to Human Cancer Common Basis Many human cancers are believed to be due to altered activity of 20 or so host growth factor genes or oncogenes. Data has been published for similar oncogenes in fish and in various invertebrates down to the primitive level of sponges. Thus, many types of cancer appear to have a common basis throughout phylogeny. Common Metabolism Most carcinogens act indirectly, that is, they are not carcinogenic themselves, but when they are metabolized for excretion, usually by the liver, reactive, proximate, carcinogenic intermediate compounds are created. Fish utilize metabolic pathways similar to mammals in the process. Common Results Experimentally, mammalian carcinogens are also carcinogenic for fish and the liver is the primary target organ for most chemicals in both cases. 14 Carcinogen Bioassay Pure test material can be microinjected directly into Mt. Shasta strain rainbow trout ova at a rate of 200 ova/hr/person. This combines a well-known sensitive fish having a 20-year record of carcinogenecitity studies with the most sensitive stage (embryo). It uses the least amount of chemical in a closed route of exposure for maximum safety and minimum by-product for disposal. In lieu of injection, ova can be bathed in the test chemical for 15 minutes. Liver tumors begin appearing in three months and 12 months is the usual post exposure period. Also, the ova bathing exposure can be utilized with small fish species that appear especially suitable for carcinogen bioassay. Medaka appears to be the best small fish species for bioassay, but several others are also promising, including guppy, rivulus, platyfish/swordtail hybrid, zebra danio, topminnow and Amazon molly. Small fish have the advantage that a sagittail section of the entire fish will fit on a single micro slide for expeditious examination of all tissues. A second advantage is that liver tumors begin appearing in seven weeks; therefore, six months is a suitable post treatment period. Advantages of Fish Bioassay (1) Miniscule amount of test chemical for safer handling and disposal. (2) High sensitivity, equivalent or better than rodents and significantly, this based on a single short exposure. (3) Six months to one-year experimental period versus two years for rodents. (4) All or none response. No tumor in controls, as often happens in rodent experiments requiring statistical evaluation to significant difference. (5) Cost: Approximately $20,000/test versus $500,000 to $1,500,000 for rodents. (6) No sentimental lobby groups protesting cruelty to fish. (7) Useful to test carcinogenicity of chemical mixtures in concentrated effluent, sediment extracts and extracts of smokestack filtrate. Can also be used to bioassay bile extracts of wild fish and liver equivalents of wild invertebrates for carcinogenic reactive metabolic intermediates. (8) Fish are real world organisms, i.e., they are part of the natural ecology rather than being inbred laboratory animals. 15 Conclusions One necessary step to clean up the environment is to eliminate the input of noxious chemicals. Eventually, as shown by declining DDT levels in the Great Lakes, microbial and other types of degradation will gradually reduce residues. The only way to stop input of noxious chemicals into the environment is to register every outfall and smokestack, test the output regularly for noxious chemicals, penalize owners for non-compliance and make owners fully responsible for resulting detrimental effects. It is proposed that chronic fish bioassays of effluent are an efficacious method to detect carcinogens and teratogens in outfall effluent concentrates and in smokestack filtrates. Rodent bioassays of effluent are too costly and time consuming for broad chronic carcinogenic screening, but positive results of fish bioassay could be funneled to rodent tests for corroboration if fish results were challenged (so far rodents have been little used for bioassays of chemical mixtures). In addition to testing effluent, the chronic fish bioassay is useful in: (1) testing bile from wild fish or extracts from liver equivalents of wild invertebrates to determine presence of carcinogens in water ways and (2) testing new or untested existing chemicals to prevent or eliminate exposures to unsuspected carcinogens in common usage. 16 Dr. John Gannon Fish Tumor Listing/ Delisting Criteria Dr. Gannon began his presentation by discussing how the problems facing the health of fish species arose and what needs to be done to restore fish health. The appearance of fish tumors and other deformities are believed to have appeared with the onset of the industrial revolution. In order to restore fish health, sources of pollution must be eliminated and aquatic habitats must be restored through human intervention (i.e. dredging and excavation) and/or natural recovery. Dr. Gannon followed the fish health issues by outlining the history of the binational management policy. In 1972, the Great Lakes Water Quality Agreement (GLWQA) was developed in order to decrease phosphorus concentrations in the hope of preventing eutrophication. The GLWQA was revised in 1978 to include toxic substances. Areas containing toxic substances were separated into two classifications: Class A severely polluted and Class B moderately polluted. A protocol was designed in 1987, which included the designation of Areas of Concern and the development of Remedial Action Plans in order to restore these areas. In 1988, listing and delisting criteria were developed in order to restore the 43 Areas of Concern (currently there are 42 Areas of Concern Collingwood Harbor in Canada has been delisted). These criteria are known as beneficial-use impairments and are related to both human activity and ecosystem impacts. There are currently 14 beneficial-use impairments: 1) Restrictions on drinking water consumption, or taste and odor problems 2) Beach closings 3) Degradation of aesthetics 4) Added costs to agriculture of industry 5) Restrictions on fish and wildlife consumption 6) Tainting of fish and wildlife flavor 7) Restrictions on dredging 8) Eutrophication or undesirable algae 9) Degradation of phytoplankton and zooplankton populations 10) Degradation of benthos 11) Degradation of fish and wildlife populations 12) Loss of fish and wildlife habitat 13) Bird or animal deformities or reproduction problems 14) Fish tumors or other deformities Dr. Gannon went into detail discussing the beneficial-use impairment: fish tumors or other deformities. When bullhead liver tumors exceed 2% or 3.5% in suckers, it is listed as a beneficial-use impairment, and when rates drop below these levels it is delisted. Dr. Gannon proposed the question, does this value need to be updated to reflect current trends or new scientific evidence? Dr. Gannon concluded his presentation by proposing challenges and opportunities that need to be addressed as they relate to the science linkage and science-management linkage. Science linkage - Cause and effect links between fish tumors and environmental contaminants - Population and ecosystem response to remediation (i.e. changes in biodiversity) - Habitat creation, restoration, and protection of soft sediments or soft engineering of hard substrate (alternatives to rock or steel rip-rap) Science-Management linkage - Monitoring, assessment and evaluation component - Guidance on Area of Concern fish tumor abnormality studies based on case studies in the Black River and other areas - Refine listing/delisting criteria for fish tumors 18 Dr. John Gannon's Power Point Presentation The Fish Tumor Listing / Delisting Criterion Its History and Prognosis for the Future in Linking Science and Management in the Great Lakes Areas of Concern By Dr. John Gannon Great Lakes Regional Office International Joint Commission Windsor, Ontario Fish Health Problems: Just One Expression of the Loss of Ecosystem Integrity 19 How Did We Get Into This Mess? How Do We Get Out of This Mess? - Eliminate Sources of Pollution - Remediate and Restore Habitat Through * Human Intervention * Natural Recovery History of Binational Resource Management Policy Response 1972 Great Lakes Water Quality Agreement (GLWQA): Focus on Eutrophication of Phosphorus Control GLWQA: emphasis on Toxic Substances - Class A Areas of Concern (Severely polluted) - Class B Areas of Concern (Moderately polluted) 1987 GLWQA Revision by Protocol - 42 Areas of Concern - The How Clean is Clean? Debate -Evolution of Listing/De-listing Criteria 2001 Recognition of Area of Recovery 20 14 Beneficial Use Impairments - Restrictions on drinking water consumption, or taste and odor problems - Beach closings - Degradation of aesthetics - Added cost to agriculture or industry - Restrictions on fish and wildlife consumption - Tainting of fish and wildlife flavor - Restrictions on Dredging - Eutrophication or undesirable algae - Degradation of phytoplankton and zooplankton populations - Degradation of benthos - Degradation of fish and wildlife populations - Loss of fish and wildlife habitat - Bird or animal deformities or reproduction problems - Fish tumors or other deformities Fish Tumors or Other Deformities Listing Criteria When the incidence of neoplastic or pre-neoplastic liver tumors exceeds 2% in bullheads or 3.5% in suckers. De-Listing Criteria When the incidence of neoplastic or pre-neoplastic liver tumors in bottomdwelling fishes does not exceed 2% in bullheads or 3.5% in suckers. 21 22 Dr. Paul Baumann - History Lessons: Two Decades of Field Data and Its Ability to Assess Changes in Fish Pathology in the Black River Since tumor prevalence is a good measure of whether an ecosystem is improving or not, there is a need to match historic data with more recent data to establish trends. While historic databases have much valuable information, there are also inconsistencies in what data were often recorded, and these need to be recognized. When analyzing bullheads from ages 3 (age of maturation) and up, several assumptions were often made: 1. Tumor rates are independent of age, or variation is stable across sample years and sample sites. 2. Hepatic and biliary tumors have the same trends or causes. 3. Presence and absence of the most advanced lesions (cancers or at least neoplasms) is the best measure for liver pathology. Studies associated with the Black River, Ohio have shown that these assumptions may be incorrect. A comparison between age 3 and age 4 fish in a 1992 study showed that age 4 fish possessed higher rates of hepatocellular and cholangiocellular carcinomas and higher rates of hepatocellular neoplasms, indicating that the tumor rates are dependent on age. Also the ratio of neoplasms to cancers is about equal in age 3 and 4 fish for hepatocellular (liver) tumors, but not for cholangiocellular (bile duct) tumors. Thus these types of tumors have different patterns and may have different causes. A comparison between fish containing various types of lesions may cause information to be lost on trends and causes. For example: fish A has hepatic cancer, biliary cancer, and hepatic neoplasms, fish B only has biliary cancer, and fish C has hepatic neoplasms, biliary neoplasms, and hepatic altered foci. In many data sets, fish A and fish B would be classified equally as having cancer, and fish C would be classified as having a neoplasm. Obviously this represents only a fraction of the information available. A series of
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