Toxic and Obesogenic Effects of Tributyltin Oxide more

Toxic and Obesogenic Effects of Tributyltin Oxide Kelly Moltzen Environmental Health December 16, 2010 Professor Andrew Burgie Moltzen Tributyltin is a pesticide with a variety of industrial uses. However, it is also a known toxin with endocrine-disrupting properties and other adverse health and environmental effects. Some steps have been taken in the United States and internationally to lessen the potential for contamination with tributyltin, but the toxin is still present in the environment, and more of an effort could be made to minimize exposure. Background Tributyltin (TBT) is part of the family of chemicals known as organotins, and has a variety of uses as a pesticide, including as a fungicide, disinfectant, algicide, microbiocide, and microbiostat (Sanders, 2008). Some examples of use include as a fungicide on food crops, as an antifungal agent and preservative in wood treatments and building materials, industrial water cooling systems, paper, leather and textile mills, and in paints and stains. In particular, it has been largely added as an antifouling agent in paint for ships and other marine equipment in order to prevent encrustations from attaching to the hull. As the outermost paint layer wears off the ship, new TBT is released in the paint, providing continuous protection from undesirable organisms for up to 4-5 years before it becomes hydrolyzed in seawater (Benson, 1999). TBT¶s organic nature results in it being rapidly absorbed by organic materials such as bacteria and algae or adsorbed onto suspended particles in water (Benson, 1999). Pesticides such as TBT are toxic to living organisms, and so not only affect the undesirable organisms which they are designed to kill, but all other living organisms as well. This means toxicity to marine life, farm animals and plants, and humans who are exposed through handling the chemical without adequate protection. Furthermore, because it is readily taken up by organic materials, it 1 Moltzen persists in the food chain and bioaccumulates so that any person or animal that eats something contaminated with TBT will be ingesting the toxin. One compound in particular, tributyltin oxide (TBTO), tends to bioaccumulate primarily in the liver and kidneys of organisms, possibly via a protein-binding mechanism. It has been found in tissues of marine organisms such as zooplankton, grazing invertebrates, as well as higher organisms such as fish, water birds, and mammals where it accumulates (Antizar-Ladislao, 2008). Metabolism in lower organisms such as fish and mollusks is slower than in mammals, and so there is a greater capacity for bioaccumulation (Benson, 1999). The mechanism of degradation is influenced by a variety of factors, such as biological activity, UV radiation, and temperature. In freshwaters, half-life estimates for TBT range from around 6 weeks to 5 months, but in sediments where degradation is primarily anaerobic, degradation is estimated to take decades (Antizar-Ladislao, 2008). Fortunately for humans, metabolism of TBT is rapid (metabolites have been found in blood 3 hours after TBTO administration), because TBT becomes progressively less toxic as it degrades (Benson, 1999; Antizar-Ladislao, 2008). TBTO bioaccumulates in the liver and kidneys before the chemical and its metabolites are eliminated principally via bile (Benson, 1999). The substance can be absorbed into the human body by ingestion (most likely route of entry), inhalation, or through the skin, and has been shown to cause a number of health effects. Toxic effects are exerted on the immune and endocrine systems, due to the chemical¶s capacity for depressing immune functions dependent on the thymus (Benson, 1999; Antizar-Ladislao, 2008). 2 Moltzen Based on past research studies done on TBT with laboratory animals, a lowest observed adverse effect level (LOAEL) for immunotoxicity was established at 2.1 mg/kg body weight per day, and the no observed adverse effect level (NOAEL) was established at 0.19 mg/kg body weight per day. The LOAEL for immunosuppression is 0.25 mg/kg body weight per day, and the NOAEL is 0.025 mg/kg body weight per day, with a guidance value for oral exposure at 0.0003 mg/kg body weight per day after accounting for extrapolation from a laboratory animal species to humans (Benson, 1999). Rat studies have also found TBTO to be linked to incidence of tumors in some endocrine tissues, however a guidance value to estimate cancer risk does not currently exist (Benson, 1999). Other health impacts of TBTO include skin and eye irritation, increased liver weight, and increased mortality in rats at high doses. The effect level for mortality was at identified as 0.7 mg/kg body weight per day (Benson, 1999). Major environmental sources of organotins include contaminated seafood, agricultural products, drinking water and leaching from plastics (Grum et al, 2009). Metabolism Hormones in the body such as leptin and ghrelin, and hormone receptors such as proliferator-activated receptors K and H (PPAR K, H) naturally regulate food intake, metabolic efficiency, and energy storage. However, chemicals present in the environment called endocrine disrupting chemicals (EDCs) offset this natural balance, mimicking the effects of natural lipophilic hormones in the body. Organotins such as tributyltin are one type of persistent organic pollutant classified as EDCs, as they have been shown to have endocrine-disrupting properties in both vertebrates and invertebrates (Grun and Blumberg, 2006). 3 Moltzen In aquatic invertebrates, particularly marine gastropods, even at low concentrations these compounds induce irreversible sexual abnormality, or ³imposex,´ in females (Nakanishi, 2007). While there are many reports describing the toxicity of organotins, the critical target molecules and biological mechanism by which EDCs function is still unclear. In human ovarian granulosa cells, these compounds suppress aromatase activity, which converts androgen to estrogen at the nanomolar level. Meanwhile, in human choriocarcinoma cells, these compounds enhance estrogen biosynthesis (Nakanishi, 2007). Several hypotheses propose that EDCs have the ability to act as environmental ³obesogens,´ or obesity-causing chemicals. One of these hypotheses is that these chemicals can lead to a perturbation of thyroid function, which is an indicator of basal metabolism (Hatch et al, 2010). A number of EDCs, such as phthalates, bisphenol A, and polybrominated diphenyl ethers, are suspected thyroid disruptors and may reduce circulating thyroid levels. Small reductions in thyroid level have been found to be associated with significant increases in body mass index, according to a large cross-sectional study in Denmark (Knudsen et al, 2005). Another environmental obesogen hypothesis shows that EDCs such as tributyltin and triphenyltin act as ligands to, and activate, the nuclear receptor transcription factors known as retinoid X receptor (RXRE, RXRF, and RXRK) and peroxisome proliferator-activated receptor K (PPAR K) (Grun and Blumberg, 2006). PPAR K is a recognized ³thrifty gene´ for its ability to promote energy storage in fat cells, or adipocytes. It is involved in lipid homeostasis and adipogenesis, and its activation increases the expression of genes that promote storage of fatty 4 Moltzen acids and represses genes that induce fat breakdown (Grun and Blumberg, 2006). This can lead directly to the differentiation of cells into adipocytes, and can predispose and/or sensitize exposed individuals to obesity. The ability of these chemicals to cause obesity and consequent medical disorders may be seen more concretely in individuals who consume a high calorie, high fat Western diet ± a fact that should not be overlooked in the U.S. where over one third of the population suffers from obesity (Flegal et al, 2010), and where direct health costs attributable to obesity put a huge burden on the economy: an estimated $75 billion in 2003 (CDC, 2004). Overweight and obesity are known to increase risk for a number of serious medical conditions such as type 2 diabetes, hyperinsulinemia, insulin resistance, coronary heart disease, high blood pressure, stroke, gout, liver disease, asthma and pulmonary problems, gall bladder disease, kidney disease, reproductive problems, osteoarthritis and some forms of cancer (Newbold et al, 2008). Furthermore, it has become apparent that xenobiotic chemicals, particularly those with hormone-like activity, can have a significant impact on cell differentiation of the developing fetus (Grun and Blumberg, 2006; Newbold et al, 2008). Therefore, not only do EDCs impact adult and child risk for obesity, but maternal stores of xenobiotics have the potential to influence obesity risk of the fetus while the child is still in the womb. In addition, TBTO can be transferred across the blood±brain barrier and from the placenta to the fetus (Benson, 1999). In newborn mice, developmental exposure to TBTO results in lipid accumulation in adipose tissues and hepatic steatosis (Zuo et al, 2010). Both human and mouse stem cells exposed to TBT were found to differentiate into adipocytes (Kirchner et al, 2010). 5 Moltzen Legislation Steps have been taken globally to try and regulate TBT. In the 1980s, the use of organotin-based antifouling paints in small boats was prohibited by some countries such as France, followed by similar regulations in most other European countries, North America, the United Kingdom, Australia, New Zealand, and Hong Kong. An international prohibition of TBTbased paints started in 2003 and went into total effect in January 2008 for members of the International Maritime Organization (IMO) (Antizar-Ladislao, 2008; Sanders, 2008). However, this prohibition does not impact countries that are not part of the IMO, and TBT is likely to continue to be produced and used for various purposes, particularly by developing countries and non-IMO countries (Antizar-Ladislao, 2008). Over the past decade, Korea, Canada and the European community banned or severely restricted TBT from use in antifouling paint formulations because of the dangers it poses to the marine environment. Canada and Europe have also banned TBT from use as a pesticide, while still allowing its use as a material preservative, wood preservative, and slimicide. Japan has specifically banned TBTO from all uses (UNEP, 2010). Because regulatory actions banning or severely restricting TBTO as a pesticide have been received from at least two different regions of the world, it is listed in Annex III of the Rotterdam Convention on Prior Informed Consent Procedure for Certain Hazardous Chemicals and Pesticides in International Trade. This means that all parties have been sent a ³decision guidance document´ requesting that they decide on whether or not to allow future import of the 6 Moltzen chemical for use as a pesticide (its use as an industrial chemical is not included in Annex III). Unfortunately, the U.S. still has not ratified the Rotterdam Convention, which entered into force in 2004 and as of May 2010 has 134 parties signed on (UNEP, 2010). While it has not yet ratified the Convention, the U.S. has passed some anti-TBT legislation. In 1988, it enacted the Organotin Antifouling Paint Control Act, which banned the use of organotin antifouling paint on vessels 25 meters or less in length and restricted the allowable leaching rate of organotin chemicals used on organotin-containing vessels (U.S. Fish and Wildlife Service, no date). The Occupational Safety and Health Administration and the National Institute for Occupational Safety and Health have established workplace exposure limits of 0.1 mg / m3, and the Food and Drug Administration has set limits for the use of tin as an additive for food (Antizar-Ladislao, 2008). Distribution, sale, and use of TBT as a pesticide are controlled by the U.S. Environmental Protection Agency (EPA) under the Federal Insecticide, Fungicide and Rodenticide Act, and in 2008, the EPA conducted a critical review of uses of TBT and deemed certain industrial uses to be ineligible for re-registration. In the U.S., the last TBTbased antifouling hull paint registration was cancelled in 2005 (Sanders, 2008). TBTO has been used in a number of settings where it has the potential to make its way into the food supply. On farms, it is used to disinfect housing for livestock, veterinary clinics, animal laboratories, and breeding facilities. It is also used on farm vehicles and other equipment (Sanders, 2008). While there are some regulations specifying that animals should be removed from the premises before and two days after treatment, the disinfectant is not rinsed or removed 7 Moltzen from most treated surfaces, so there is still a high likelihood it is contaminating farm animals and other edible products. Per the EPA: No dietary residue data are available to assess potential exposures resulting from any of these uses. The Agency does not ordinarily require residue data for antimicrobial pesticides that are used in animal premises, but because TBT residues are not physically removed from surfaces, animals, or eggs in treated areas, and because TBT is very persistent in the environment and is bioaccumulative, the Agency believes that it is possible for residues to remain in and on animals, eggs, and animal premises long after a treatment has occurred, and to concentrate in animals via incidental or dermal exposure. Consequently, there is a potential for human dietary exposure associated with the livestock premises uses. These potential exposures cannot be quantified without residue data. Residues in drinking water: Discharges of treated cooling water, disposal of excess TBT solution from farm premises treatments, and leaching of TBT from treated exterior building materials and irrigation tubing may have potential to impact drinking water sources. A quantitative drinking water assessment has not been conducted as an appropriate method for assessing exposure data is lacking. (Sanders, 2008) The EPA understood that most of the discharge from water tower cooling systems was directed to municipal water treatment facilities, and therefore decided in 2008 that use of TBT for cooling towers is unacceptable and was not deemed eligible for re-registration with the EPA (Sanders, 2008). In a similar manner, other practices that could contaminate natural waters such as use for wood preservatives, immersion treatments on farming premises, oil field and petrochemical injection systems, and irrigation tubing for non-agricultural applications were also deemed ineligible for re-registration. The use of TBT in egg handling facilities and vehicles (hatcheries, egg rooms, incubators, egg trucks, etc.) when eggs are present is also now prohibited 8 Moltzen because of the possibility that residues applied to egg shells could transfer to hatched chicks (Sanders, 2008). Tributyltin (TBT) compounds are recognized by the U.S. EPA as well as internationally as toxic chemicals with endocrine-disrupting properties, and some countries have taken steps to ban its use from use in certain industries (UNEP, 2010; Sanders, 2008). However, while the EPA and other governmental organizations have specified safe handling practices and labeling regulations which must be followed for this class of chemicals, use of TBT is still allowed in some industries and persists in the environment such as through storage in sediments. Further, new restrictions will not immediately remove TBT from the environment (Antizar-Ladislao, 2008). There are many more precautionary steps that governments could be taking to protect public health from this toxic, bioaccumulating, endocrine-disrupting and obesogenic pesticide, such as by banning its use from all farming premises and from all practices which could contaminate the water supply. 9 Moltzen References Antizar-Ladislao B. (2008). Environmental levels, toxicity and human exposure to tributyltin (TBT)-contaminated marine environment: a review. Environment International 34(2):292-308. Benson, Robert. (1999). Tributyltin Oxide. Concise International Chemical Assessment Document 14. World Health Organization; Geneva. Available at: http://www.who.int/ipcs/publications/cicad/en/cicad14.pdf CDC. (2004). Obesity Costs States Billions in Medical Expenses. Available at: http://web.archive.org/web/20080308094559/http://www.cdc.gov/od/oc/media/pressrel/r0 40121.htm Flegal KM, Carroll MD, Ogden CL, and Curtin LR. (2010). Prevalence and Trends in Obesity Among US Adults, 1999-2008. Journal of the American Medical Association, 303(3):235-241. Hatch EE, Nelson JW, Stahlhut RW, Webster TF. (2010). Association of endocrine disruptors and obesity: perspectives from epidemiological studies. International Journal of Andrology, 33(2): 324±332. Kirchner, S, Kieu T, Chow C, Casey S, Blumberg B. (2010). Prenatal Exposure to the Environmental Obesogen Tributyltin Predisposes Multipotent Stem Cells to Become Adipocytes. Molecular Endocrinology; 24(3):526±539. Knudsen N, Laurberg P, Rasmussen LB, Bülow I, Perrild H, Ovesen L & Jørgensen T. (2005). Small differences in thyroid function may be important for body mass index and the occurrence of obesity in the population. Journal of Clinical Endocrinology and Metabolism 90(7): 4019±4024. Nakanishi T. (2007). Potential Toxicity of Organotin Compounds via Nuclear Receptor Signaling in Mammals. Journal of Health Science, 53(1):1-9. Newbold RR, Padilla-Banks E, Jefferson WN, Heindel JJ. (2008). Effects of endocrine disruptors on obesity. International Journal of Andrology, 31(2): 201±208. Sanders FT. (2008). Reregistration Eligibility Decision for the Tributyltin Compounds: Bis(tributyltin) oxide, Tributyltin benzoate, and Tributyltin maleate (Case 2620). United States Environmental Protection Agency. Available at: http://www.epa.gov/oppsrrd1/REDs/tbt-compounds-red.pdf UNEP. (2010). Consolidated List of Products whose Consumption and/ or Sale have been Banned, Withdrawn, Severely Restricted or Not Approved by Governments. Contribution by the United Nations Environmental Programme covering Pesticides and Industrial Chemicals. Available at: 10 Moltzen http://www.chem.unep.ch/Legal/ECOSOC/UNEP%20Consolidated%20List%2010%20 May%202010.pdf U.S. Fish and Wildlife Service. (no date). Digest of Federal Resource Laws of Interest to the U.S. Fish and Wildlife Service. Organotin Antifouling Paint Control. Available at: http://www.fws.gov/laws/lawsdigest/organon.html Zuo Z, Chen S, Wu T, Zhang J, Su Y, Chen Y, Wang C. (2010). Tributyltin Causes Obesity and Hepatic Steatosis in Male Mice. Environmental Toxicology. Accessed October 18, 2010. Available at: http://life.xmu.edu.cn/eco/research/UploadFiles_9059/200912/2009121520543085.pdf 11