Contents Executive Summary i Introduction 1 What Are Cyanobacteria? 4 Human Health and the International Policy Context 6 Infection of the Food Web and Global Epidemiology 7 Water Guidelines for the Prevention of Disease 14 Oklahoma’s Approach to Protecting Human Health 17 Oklahoma State and National Epidemiology 19 Conclusion 23 : Executive Summary BLUE-GREEN ALGAL TOXINS ON THE SOURCE OF ALZHEIMER’S, ALS-PDC, AND CANCERS IN OKLAHOMA SUBMITTED BY THE NATIONAL CFIDS FOUNDATION WITH THE NANCY TAYLOR FOUNDATION FOR CHRONIC DISEASES Prepared by Dana T. Cesar, Ph.D. Because of the evolutionary function of blue-green algae (BGA) to biodegrade matter, effluents into Oklahoma’s water system encourage algal blooms that produce toxins that target the nervous system, the brain and the liver. Toxins are lethal or debilitating, even in small amounts. Vulnerable populations, like children, the elderly, or those with lowered immune systems are particularly susceptible to diseases caused by algal toxins. i BMAA (beta-methylamino-alanine) is a often superficially investigated. The state has particular threat to human health as nearly no official state water standards where every genera of blue-green algae produce the cyanotoxins are concerned. Water quality neurotoxin which researchers believe is the authorities lack training and support in testing cause of many common diseases such as for and filtering toxins. Consequences to Alzheimer’s, Parkinson’s, and ALS, or Lou human health are unclear as there is no Gerhig’s Disease, as well as many cancers. infrastructure for tracking HAB-related illness. Although BGA—also known as cyanobacteria—live in fresh, brackish or salt Because the United States has not yet set water as well as in soil, the nearly exclusive guidelines for “any of the cyanotoxins,” state finding of BGA in freshwater is especially and local authorities are left to determine their concerning to drinking, bathing, recreational own standards, as per the Clean Water Act of and irrigational water quality in Oklahoma. 1972. Further, the Safe Drinking Water Act Because the bacteria can become airborne or amendment of 1996 requires states to protect aerosolized through irrigation or recreational “drinking water and its sources: rivers, lakes, activities, it can be inhaled. reservoirs, springs, and ground water wells.”1 Oklahoma’s abundant shoreline, coupled with In light of the evolutionary endurance of the the state’s industrial farming of chicken, beef bacteria, a current outbreak of harmful algal and pork, renders the state particularly blooms, and an impending water shortage, vulnerable to algal toxins, as illustrated by the this Green Paper calls on authorities to September 2009 federal case, State of generate focused and coordinated discussion Oklahoma v. Tyson Foods, Inc, et al. At the for immediate state action in mobilizing judicial level, this case points out the resources at “war-time speed” for the correlation between poultry production and protection of the public against cyanobacterial cyanobacterial outbreaks in the Illinois River toxin exposure. Watershed and Lake Tenkiller. Further, media report that Lake Thunderbird and Grand Lake have been plagued by algal blooms since the mid-1980s. Lake Elmer near Kingfisher experienced a bloom in summer 2009 that left the lake devoid of wildlife. Statewide, other blooms persist and go unreported as there are no official mechanisms for predicting, preventing, or reporting blooms. The dramatic effects of blooms— such as fish kills or unpalatable water—are 1 Environmental Protection Agency. Safe Drinking Water Act website. Retrieved 9/14/09 from http://www.epa.gov/OGWDW/sdwa/basicinformation.html ii : A Green Paper BLUE-GREEN ALGAL TOXINS ON THE SOURCE OF ALZHEIMER’S, ALS-PDC, AND CANCERS IN OKLAHOMA SUBMITTED BY THE NATIONAL CFIDS FOUNDATION WITH THE NANCY TAYLOR FOUNDATION FOR CHRONIC DISEASES Prepared by Dana T. Cesar, Ph.D. Introduction In early September 1985, the Norman Transcript released a series of news reports regarding concerns of a University of Oklahoma algologist, Dr. Lois Pfiester, that the foul odors and tastes of drinking and bathing water from Lake Thunderbird may be explained by toxins excreted from a dramatic expansion of algae blooms in the lake. Although city officials assured Norman, Del City and Midwest City residents the water was “100 percent safe,” Pfiester sampled the water and found four types of algae—microcystis, anabeana, aphanizomenon and Lyngbya—with cell counts between 200,000 to 300,000 per millimeter of water. The same news story reported a small cluster of emergency room visits to Norman Regional Hospital for “cases of gastrointestinal disorders, including diarrhea.”1 1 Linam, Steve Ray. “Lake algae worrisome to officials.” Norman Transcript, 9/6/85, p. 1 Pfiester’s work with Lake Thunderbird was cited the following day in the Tulsa World as it reported “funny” tasting city water that was explained by “a breakdown in equipment at the A.B. Jewel Water Treatment Plant at 21st Street and 193rd East Avenue” which affected the south, southeast and east sections of Tulsa. However, City-County Health Department official, Tom Drake, attributed the problem to an algal bloom at the “Oologah Reservoir in Rogers and Nowata counties.” One Tulsa resident stated that his dog refused the water and the paper reported an increase in the sale of bottled water.2 In subsequent news stories that summer, Pfiester was reported to have met with the Norman City Council to inform them of the “correlation between toxin byproducts from blue-green algae and health problems.” Children were particularly vulnerable to the health threats caused by the algae.3 She commented on the death of cattle and fish caused by the toxins and stated, “‘If it’s toxic enough to kill a cow, I think human beings should be concerned.’”4 Water samples were sent to expert Dr. Wayne Carmichael at Wright State University, which came back inconclusive as to toxin content.5 Regardless, Pfiester later urged officials to restrict nutrient input into the lake, stating that “one observer counted boaters dumping 30 portable toilets into the lake during a one-hour period this spring. Swimmers and leaking septic tanks also add to the problem” as algae feed on the phosphorous and nitrates of such pollutants. Pfiester, for whom a dinoflagellate was named for her groundbreaking work with algae, was quoted as saying she preferred her roles as “teacher, researcher and mother” over political agitator. Image taken from: Ramsdel, J.S. et al, (eds). Harmful Algal Research and Response: A National Environmental However, she wasn’t Science Strategy 2005–2015, p. 18. Ecological Society of America: Washington, D.C. “going to lie about Lake Thunderbird . . . a true problem exists, and a lot of people in this community are resistive to facing up to it.”6 2 Pratter, Mark. “Tulsa’s Water Tastes Funny, Safe to Drink.” Tulsa World, 9/7/85, p. 1. 3 Linam, Steve Ray. “Water tests proposal eyed.” The Norman Transcript, 9/25/85, p. 2 4 Wall, Judith. “Botanist links health problems with algae in Norman’s water.” OU Update, section: Profile, not dated, p. 3 & 4 5 Linam, Steve Ray. “Testing fails to confirm water toxins.” Norman Transcript, 10/18/85, p. 1 6 Wall, Judith. “Botanist links health problems with algae in Norman’s water.” OU Update, section: Profile, not dated, p. 3 & 4 2 Lois Ann Pfiester died in 1992 at the age of 56 with a diagnosis of general autoimmune dysfunction. Her postdoctoral student, Peter Timpano, with whom she closely worked between 1983 and 1986 on an NSF study of algae dinoflagellates, died in 1987 of liver cancer at the age of 38.7 It is both appropriate and notable that Pfiesteria was specifically mentioned as an immediate threat to human health and the fishing industry in 602 Title VI—Harmful Algal Blooms & Hypoxia Research and Control Act of 1998, as it is probable that both Pfiester and Timpano died from exposure to the various algae they studied. The “marine algae, dinoflagellates” is said to be “the most important toxin producers” in its devastation of marine waters. However, “in the freshwater environment, toxins have almost exclusively been identified from Cyanobacteria.”8 The nearly exclusive finding of cyanobacteria in freshwater is highly significant to drinking, bathing, recreational and irrigational water quality in Oklahoma, especially in light of the state’s approximately 11,611 miles of shoreline, “78,578 miles of rivers and streams [and] 1,120 square miles of water area in lakes and ponds.”9 7 Taylor, Thomas N. (ed). December 1987. Plant Science Bulletin. Volume 33 No. 4 Retrieved online at http://www.botany.org/plantsciencebulletin/psb-1987-33-4.php 8 Chorus, I. and Salas, H.J. 1997. “Health Impacts of Freshwater Algae: Draft for Guidelines for Recreational Water and Bathing Beach Quality.” Paper presented at the III Regional AIDIS congress for North America and the Caribbean, San Juan, Puerto Rico, 7 – 12 June. p. 1 – 2. 9 Oklahoma Water Resources Board. “Oklahoma Water Facts.” Retrieved online at http://www.owrb.ok.gov/util/waterfact.php 3 What Are Cyanobacteria? Cyanobacteria, the second oldest life form on earth, have played a pivotal role in the evolutionary history of the planet. The bacteria evolved 2,500 million years ago with the ability to produce oxygen, making life on earth possible.10 Due to its evolutionary function to degrade dead matter, cyanobacteria are responsible for producing raw crude from prehistoric waste. It has also been found effective at biodegrading industrial agricultural waste, human and animal waste, chemical waste including fertilizers, water run-off from urban centers, and oil spills.11 THE INTERACTIVE PHYSICAL, CHEMICAL AND BIOTIC VARIABLES CONTROLLING CYANOHAB EXPANSION ACROSS THE FRESHWATER-MARINE INTERFACE Above image taken from: Paerl, H.W. and Fulton III, R.S. 2006. Ecology of Harmful Algae. Ecological Studies, Vol. 189, p. 98, Springer-Verlag Bwerlin Heidelberg. A recent and rapid increase in phosphorous and nitrogen-rich pollutants into the water system are feeding cyanobacteria, enabling them to populate and form mats with the potential to “expand over an area equivalent to a football field within an hour. . . [Australian Environmental Protection 10 Paerl H.W. & Fulton, R.S. III. 2006. “Ecology of Harmful Cynobacteria” in Ecological Studies. Vol 189, chapter 8, p. 95. Graneli Edna & Turner, Jefferson T. (eds). 11 Raghukumar, C., Vipparty, V., David, J.J., Chandramohan, D. 2001. “Degradation of crude oil by Marine Cyanobacteria.” Applied Microbiology and Biotechnology. Vol. 57, pp. 433-436.; Eve Riser-Roberts. 1998. Remediation of Petroleum Contaminated Soils: Biological, Physical, and Chemical Processes. Lewis Publishers, Boca Raton, FL. 4 Agency 2003].”12 Certain taxa of the bacteria have been “known to cover thousands of square kilometers of the Earth’s oceans” and are “observable by satellite from earth orbit.”13 Global warming further encourages the duration, scope and density of bacterial “blooms” and the bacteria is spread by boats and ships’ ballast water. Also known as blue-green algae, cyanobacteria can live in fresh, brackish or salt water as well as in soil. The bacteria can become airborne or aerosolized through irrigation or recreational activities and so can be inhaled. Detailed records of the harmful effects of cyanobacteria date to the 19th century, although researchers suggest that even early aboriginal people had knowledge of the poisonous effects of algae to humans, livestock, fish and pets. Paleontologists have reported “cyanotoxin-related mass mortality event[s]” near lakes containing oil shale pits between the Middle Eocene and Pleistocene eras when fossilized remains of cyanobacteria, deer, forest elephant, rhinoceros, ox, lion, horse, turtle, bat and bird skeletons were found to have died in autumn when algal blooms are frequently at their peak.14 The commercial value of cyanobacterial compounds has complicated the study of effects on human health and the larger ecosystem. The blue-green pond scum has been used in traditional Chinese medicine for centuries as an anti-fungal and antibacterial and continues to be sold in health food stores as a food supplement.15 It has recently been genetically modified as a treatment for malaria. Researchers have identified cyanobacteria as an alternative energy source and so are genetically modifying the organism so that more hydrogen compound may be harvested.16 For example, Dr. Daniel Crunkleton, Director of the Alternative Energy Institute at the University of Tulsa, is working on the development of algae-based transportation fuel with support from San Diego-based Sapphire Energy.17 Nevertheless, microbiologists, ethnobotonists, organic chemists, veterinarians, neurologists, ecologists, oncologists and others are incrementally closing the gap between anecdotal or strongly correlative links, and empirical evidence of lethal or debilitating effects of the various compounds produced by algae. 12 Hudnell, K.H., Dortch, Q. and Zenick, H. 2008. “An Overview of the Interagency, International Symposium on Cyanobacterial Harmful Algal Blooms (ISOC-HAB): Advancing the Scientific Understanding of Freshwater Harmful Algal Blooms.” In Hudnell, Kenneth H. (ed.) 2008. Cyanobacterial Harmful Algal Blooms: State of the Science and Research Needs. p. 6 New York: Springer.; 13 Cox et al April 5, 2005 “Diverse taxa of cyanobacteria produce B-N-methylamino-L-alanine, a neurotoxic amino acid.” Proceedings of the National Academy of Sciences. Vol. 102, no. 14, pp. 5074–5078. 14 Stewart, I., Seawright, A.A., Shaw, G.R. 2008. “Cyanobacterial Poisoning in Livestock, Wild Mammals and Birds—An Overview.” Chapter 28, p. 615 - 618, in Hudnell, Kenneth H., 2008. Cyanobacterial Harmful Algal Blooms: State of the Science and Research Needs. Spring: New York. 15 Patterson, Gregory and Carmeli, Shmuel. 1992. “Biological Effects of Tolitoxin (6-hydroxy-7-)-methyl-scytophycin b), a potent bioactive metabolite from cyanobacteria.” Archives of Microbiology. Vol. 157, pp. 406 – 410. Springer-Verlag. 16 Economist. 4/9/2005. “The Scum of the Earth.” Vol. 375, issue 8421, p 68 – 69; See also Amyris Biotechnologies at http://www.amyrisbiotech.com/, that used a grant from the Bill & Melinda Gates Foundation in 2004 to develop a cost-effective medicine for malaria using a genetically modified form of cyanobacteria. See the following links for more information about the company. http://cleantech.com/news/1806/amyris-pulls-in-70m-for-unique- biofuel; http://barrier-busting.com/2008/09/biofuels-balancing-equations/. See also a talk by John Doerr who briefly refers to “bugs,” which are cyanobacteria. http://www.ted.com/index.php/talks/john_doerr_sees_salvation_and_profit_in_greentech.html; From http://www.councilforresponsiblegenetics.org/GeneWatch/GeneWatchPage.aspx?pageId=45; See also Rosenwald, M.S., "J. Craig Venter's Next Little Thing," Washington Post, Monday, February 27, 2006; D01. 17 Tulsa Engineer: Monthly Bulletin of the Engineer’s Society of Tulsa, Inc. Biography section, February 23, 2009, Issue # 75. 5 Human Health and the International Policy Context In light of the serious health threats posed by freshwater algae, many in the scientific community have expressed dismay at the lack of fiscal support and an organized, “proactive” governmental response on the part of the United States.18 However, some researchers maintain that a corner was turned in the policy arena when, in 1998, the EPA included “freshwater cyanobacteria and their toxins on the first Candidate Contaminant List (CCL). . . . for two reasons, namely that (1) they are not necessarily associated with fecal contamination, and therefore will not be adequately controlled by provisions of either the Surface Water Treatment Rule or the Enhanced Surface Water Treatment Rule, and (2) they may not be adequately removed from drinking water by conventional water treatment techniques.”19 Human health and well being in Oklahoma is further framed within a sluggish international policy context that includes the “first comprehensive international conference” on freshwater algae in August 1995 and the development of safe cyanotoxin levels by the World Health Organization (WHO) in 1999.20 In light of the evolutionary endurance of the bacteria, a current outbreak of harmful algal blooms, and an impending water shortage,21policies must be generated at the state level that are particular to Oklahoma’s waterways and socio-economic contexts. Lester Brown encourages haste in confronting contemporary environmental threats, in that nothing less but mobilizing resources at “war-time speed” can reverse a cycle of environmental decline.22 Immediately implemented state- level policies are urgently required to proactively protect the state’s water cycle and food web from infection by cyanobacteria. Also see http://www.orgs.utulsa.edu/altenergy/Site/Biofuels.html. See also Klein, Autumn, Silverman, Phillie, and Wasti, Ali. November 2008. “ Solarigene: A Platform for Biofuels and Commodities.” Presentation posted to: www.hbs.edu/units/tom/conferences/docs/Solarigene.ppt 18 As stated by Yoo, et al, “One can only speculate as to why the United States has remained reactive rather than proactive on the issue of cyanobacterial toxins . . . it is unlikely that natural toxins would ever receive the same attention, ether by the public or the media, as do man-made contaminants or pollutants. As described in the literature on risk communication there are a number of ‘outrage factors’ that contribute to the public’s perceptions about a particular risk. These include whether the risk of Cyanobacterial toxins are generally less newsworthy than industrial chemicals because they are natural and not as morally relevant or dreaded.’” Quoted in Chorus, Ingrid and Sala, Henry J. “Health Impact of Freshwater Algae: Draft for Guidelines for Recreational Water and Bathing Beach Quality.” Paper presented to III Regional AIDIS Congress for North American and the Caribbean, San Juan, Puerto Rick, 7-12 June, 1997. 19 Hoehn, R.C. and Long, B.W. Not dated. “Toxic cyanobacteria (Blue-green algae): An Emerging Concern.” Paper presentation, not specified. p. 1 & 2, 20 Chorus, I. and Bartram, J. 1999. Toxic Cyaobacteria in Water: A guide to their public health consequences, monitoring and management. St. Edmundsbury Press: London. Retrieved online at http://www.who.int/water_sanitation_health/resourcesquality/toxicyanbact/en/ 21 Both marine and freshwaters are experiencing an increase in the instances of blooms as per HARNESS. 2005. Harmful Algal Research and Response: A National Environmental Science Strategy 2005 – 2015. Ramsdell, J.S., Anderson, D.M. and Gilbert, P.M. (eds). Ecological Society of America, Washing, DC, 96pp. Retrieved online at http://www.whoi.edu/redtide/nationalplan/2005nationalplan.html. See also Lopez, C.B., Jewett, E.B., Dortch, Q., Walton, B.T., Hudnell, H.K. 2008. Scientific Assessment of Freshwater Harmful Algal Blooms. pp. 21 & 30. Interagency Working Group on Harmful Algal Blooms, Hypoxia, and Human Health of the Joint Subcommittee on Ocean Science and Technology. Washington, DC. Demand for water in the Oklahoma City metropolitan area is expected to increase 2% each year, according to the City of Oklahoma City 2007 Consumer Confidence Report. By 2021, water will be pumped from Sardis Lake and a second pipeline will be installed to transport water from Atoka Lake in order to meet growing demand. See also Smith, Rodney T. June 2009. Water Strategist: Analysis of Water Marketing, Finance, Legislation and Litigation. pp. 21 – 22. According to Lester Brown, the nonreplenishable Ogallala water aquifer is dropping 100 meters every year. (See footnote 23 for reference). 22 “Massive change is inevitable. Will the change come because we move quickly to restructure the economy or because we fail to act and civilization begins to unravel? Saving civilization will take a massive mobilization, and at wartime speed.” Brown, Lester. December 3, 2008. “Book Bytes: A Wartime Mobilization.” Retrieved online at http://www.earthpolicy.org/index.php?/book_bytes/2008/pb3ch13_ss1 6 Infection of the Food Web And Global Epidemiology In general, cyanobacteria are environmentally adaptive and evolutionarily opportunistic. Because of the algae’s unique cellular structure, they are capable of living symbiotically within their host, bioaccumulating within infected species. In this way, the bacteria are capable of co-opting and mutating cell structures and even changing the evolutionary trajectory of host species.23 Most importantly for human health, cyanotoxins, which are produced within algal cell walls and released after cell death, present grave immunological challenges. So far, scientists have identified a few dozen genera of blue-green algae, all of which produce potent toxins that target the nervous system, the brain and the liver.24 Most cyanotoxins cannot be metabolized but are capable of surviving digestion where they are transported or carried unimpaired to block or promote proteins and/or sodium channels important to human health.25 International agencies identify two toxins in particular—microcystins and saxitoxins—as necessitating focused attention because their molecular structure and particular composition of amino acids render them easily absorbed into the human system. Because of the “molecular switches” of their toxins, they are considered “the most hazardous algal metabolites.”26 23 Because cyanobacteria possess mitochondria, they are capable of establishing themselves symbiotically within other species. Such symbiosis has allowed cyanobacteria to provide plants with the ability to obtain energy from the sun by giving them chlorophyll, to provide amino acids as “sunscreens” for ultraviolet protection from the sun, and to share with their hosts toxic compounds, like b-methylamino-L-alanine (BMAA), as a defense against predators, as outlined in: Usher, Kayley M., Bergman, Birgitta, Raven, John A. August 2007. Annual Review of Ecology, Evolution, and Systematics. 38:255-73. 24 Lipopolysaccharides, which will not be addressed in this paper, also pose threats to human health. as per Hudnell, Kenneth H., 2008. Cyanobacterial Harmful Algal Blooms: State of the Science and Research Needs. See also Chapter 3, Section 1.3 in Chorus, Ingrid and Bartram, Jamie. 1999. Toxic Cyanobacteria in Water: A Guide to Their Public Health Consequences, Monitoring and Management. Retrieved online at (http://www.who.int/water_sanitation_health/resourcesquality/toxcyanchap1.pdf) (see also Chapter 3, Table 3.5 for a list of blue-green algal species. ) http://www.who.int/water_sanitation_health/resourcesquality/toxcyanchap3.pdf) 25 Dietrich, D.R, Fischer, A. Hoeger, S..J. 2008. “Toxin Mixture in Cyanobacterial Blooms—a Critical Comparison of Reality with Current Procedures Employed in Human Health Risk Assessment.” Chapter 39, p. 886 in Hudnell, Kenneth H., 2008. Cyanobacterial Harmful Algal Blooms: State of the Science and Research Needs. Spring: New York.; Chorus, Ingrid and Bartram, Jamie. 1999. Toxic Cyanobacteria in Water: A Guide to Their Public Health Consequences, Monitoring and Management. Chapter 3, Sections 3.1 & 3.1.1 Retrieved online at http://www.who.int/water_sanitation_health/resourcesquality/toxcyanchap3.pdf) 26 Chorus, Ingrid and Salas, Henry J. “Health Impacts of Freshwater Algae: Draft for guidelines for Recreational Water and Bathing Beach Quality” paper delivered at the III Regional AIDIS Congress for North America and the Caribbean San Juan, Puerto Rico, 7-12 June 1997; Dietrich, Daniel; Fischer, Michael and Hoeger, SJ. 2008. “Toxin Mixture in Cyanobacterial Blooms.” p. 886, Chapter 39; Falconer, I.R. 2008. “Health Effects Associated with Controlled exposures to Cyanobacterial Toxins.” Chapter 17, p. 607 in Hudnell, Kenneth H. (ed). Cyanobacterial Harmful Algal Blooms: State of the Science and Research Needs. Springer: New York.; Chorus, Ingrid and Bartram, Jamie. 1999. Toxic cyanobacteria in water: A guide to their public health consequences, monitoring and management. Chapter 3 St. Edmundsbury Press: London. Retrieved online at http://www.who.int/water_sanitation_health/resourcesquality/toxcyanchap3.pdf 7 GENERAL FEATURES OF THE CYANOTOXINS (Note that beta-methylamino-alanine (BMAA) is not included in this table, but can be found in each toxin group.) Toxin Group Primary Target Cyanobacterial Organ in Mammals Genera2 Cyclic Peptides Microcystins Liver Microcystis, Anabaena, Planktothrix (Oscillatoria), Nostoc, Hapalosiphon, Anabaenopsis Nodularin Liver Nodularia Alkaloids Anatoxin-a Nerve Synapse Anabaena, Planktothrix (Oscillatoria), Aphanizomenon Anatoxin-a(S) Nerve Synapse Anabaena Aplysiatoxins Skin Lyngbya, Schizothrix, Planktothrix (Oscillatoria) Cylindrospermopsins Liver3 Cylindrospermopsis, Aphanizomenon, Umezakia Lyngbyatoxin-a Skin, gastro-intestinal tract Lyngba Saxitoxins Nerve axons Anabaena, Aphanizomenon, Lyngbya, Cylindrospermopsis Lipopolysaccharides (LPS) Potential irritant; affects any All exposed tissue 1 Many structural variants may be known for each toxin group. 2 Not produced by all species of the particular genus. 3 Whole cells of toxic species elicit widespread tissue damage, including damage to kidney and lymphoid tissue. Table, above, taken from Chorus, Ingrid and Bartram, Jamie. 1999. Toxic cyanobacteria in water: A Guide to Their Public Health Consequences, Monitoring and Management. p. 57, Chapter 3, St Edmundsbury Press: London. MICROCYSTIN. Microcystin is a water-soluble cyclic peptide and as such is unable to “penetrate lipid membranes of animal, plant and bacterial cells. Therefore, to elicit their toxic effect, uptake into cells occurs through membrane transporters which otherwise carry essential biochemicals or nutrients.” The metabolic pathway or transporter for microcystin is “the bile acid carrier, which is found in liver cells.” This essentially “restricts the target organ range in mammals largely to the liver.” However, “adverse affects” have also been found in “the small intestine and kidney.” Although the “tumor promoting activity of microcytins is well documented, . . . microcytins alone are not carcinogenic.”27 Individuals who are genetically predisposed or who have lowered immune defenses, 27 Chorus, I. and Salas, H.J. 1997. “Health Impacts of Freshwater Algae: Draft for Guidelines for Recreational Water and Bathing Beach Quality.” p. 5, Paper Presented to the III Regional AIDIS congress for North America and the Caribbean, San Juan, Puerto Rico, 7 – 12 June.; Dietrich, D.R, Fischer, A. Hoeger, S..J. 2008. “Toxin Mixture in Cyanobacterial Blooms—a Critical Comparison of Reality with Current Procedures Employed in Human Health Risk Assessment.” Chapter 39, p. 886 in Hudnell, Kenneth H., 2008. Cyanobacterial Harmful Algal Blooms: State of the Science and Research Needs. Spring: New York.; Falconer, I.R. 2008. “Health Effects Associated with Controlled Exposure to Cyanobacterial Toxins.” Chapter 27, p. 607, in Hudnell, Kenneth H. (ed.) Cyanobacterial Harmful Algal Blooms: State of the Science and Research Needs. Springer: New York. 8