<p>Pharmaceuticals and Endocrine Disrupting Compounds </p><p>What are pharmaceuticals, endocrine disrupting compounds, and personal care products? Pharmaceuticals are defined as substances used for the diagnosis, treatment, alteration, or prevention of disease, health condition, structure, or function of the human body (Daughton and Ternes, 1999). Pharmaceuticals include both prescription medications and over-the-counter drugs including analgesics and anti-inflammatories, such as aspirin, acetaminophen, and ibuprofen; antioplastics; antiseptics; antibiotics; beta-blockers; psychiatric drugs; and diagnostic agents, such as contrast media used in imaging. This definition can be extended to veterinary drugs, as well as illicit drugs. Endocrine disrupting compounds (EDCs) are substances that directly or indirectly affect the body’s ability to regulate homeostasis, growth, and reproduction. Endocrine disrupting compounds may influence the synthesis, transport, or metabolism of hormones in the body. Endocrine disrupting compounds may be medical substances like ethinyl estradiol, the active ingredient used in hormonal birth control, but also include metals, pesticides, plasticizers, toxins such as polychlorinated biphenyls (PCBs), and naturally occurring phytoestrogens from plants like soy. The broader category of pharmaceuticals and personal care products (PPCPs) comprise all the drugs available by prescription or over-the-counter, EDCs, illicit drugs, and consumer products such as fragrances, insect repellants, shampoos, toothpaste, and sun- screen (Daughton, 2004a). </p><p>How do pharmaceuticals and personal care products enter the environment? Pharmaceuticals and personal care products enter the environment in a number of ways. Wastewater treatment infrastructure and discharge, land application of biosolids, landfill leachate, agriculture, and pest control all contribute or convey PPCPs to the environment. The primary pathway of PPCPs to the environment is through the use of PPCPs by individuals. Many human (and veterinary) pharmaceuticals are only partially metabolized and are excreted unchanged in urine and feces (Daughton, 2004a). Wastewater treatment plants are not designed to remove PPCPs and the efficiency of removal is largely unknown (Daughton and Ternes, 1999). Most pharmaceuticals resist microbial degradation, and wastewater treatment plant microbiota are assaulted with new pharmaceuticals every year. Pharmaceuticals may either adsorb to colloidal material and become part of the aqueous effluent or attach to solids and partition to the solid fraction. Liquid effluent may be discharged to a receiving waterbody or injected to groundwater, putting both surface water and aquifers at risk. Underground leakage of septic systems or the sewage infrastructure may allow PPCPs to escape to the environment. Overflow, bypass, upsets, and system failures at wastewater treatment facilities may allow waste to enter receiving waterbodies. Pharmaceuticals that have attached to solid particles may enter the environment when sludge (biosolids) is land applied. </p><p>1 Research, manufacturing, and the sale of PPCPs may also lead to environmental contamination. Pharmaceuticals in any stage of clinical testing but not Federal Drug Administration (FDA)-approved for dispensing are subject to release into the environment (Daughton and Ternes, 1999). Manufacturing and research facilities, pharmacies, physicians, and humanitarian drug surplus release treated and untreated pharmaceutical waste and byproducts to wastewater treatment plants. Additionally, illicit drug operations may dispose of drugs in ways that allow them to enter the environment. Evidence suggests that large quantities of prescription and over-the-counter drugs are never consumed and are disposed of through the sewage treatment system or in landfills (Daughton and Ternes, 1999). Unused or expired PPCPs may be disposed of through sewage treatment systems such as septic tanks, municipal wastewater treatment plants, straight-piping of untreated sewage from homes to surface receiving waters, and the release of treated and untreated hospital wastes to municipal wastewater treatment facilities (Daughton, 2004a). Failing landfills may allow contaminated leachate to enter the environment (Daughton and Ternes, 1999). Pharmaceuticals are used heavily in agriculture. Confined animal feeding operations (CAFOs) often utilize antibiotics for infection control and for enhanced growth and hormones are used to control reproductive cycles and speed growth. Like humans, animals do not completely metabolize pharmaceuticals, and their waste contains measurable levels of pharmaceutical parent and daughter compounds. The land application of manure may contaminate soil resources (Daughton, 2004a). Manure-laden runoff introduces pharmaceuticals to receiving waterbodies, as does leaking manure storage facilities. Improper disposal of euthanized or medicated carcasses can also allow pharmaceuticals to enter the environment. Aquaculture also uses many antibiotics and other anti-infectives and anesthetics (Daughton and Ternes, 1999). The close proximity of aquaculture facilities, medicated feed, and waste and natural aquatic ecosystems increases the probability that pharmaceuticals will enter the environment. Some pharmaceuticals are purposefully applied to the environment as pest control. Warfarin (an anticoagulant) is used as rodenticide, 4-aminopyridine (an experimental multiple sclerosis drug) is used as an avicide, azacholesterol and antilipidemics (cholesterol reducing drugs) are used as avian and rodent reproductive inhibitors, acetaminophen (an analgesic) is used as brown tree snake control, caffeine is used as coqui frog control, and antibiotics are used to control pathogens in orchards (Daughton, 2004a). In general, the final fate of PPCPs is the aquatic ecosystem, either from direct discharges of contaminated wastewater or from runoff from land application of PPCP contaminated solids (Daughton, 2004a). Once in the environment, some PPCPs undergo changes, including degradation from exposure to ultraviolet light, mineralization, and even uptake by plants. Surface water can become contaminated with PPCPs, especially if the source is a receiving waterbody for wastewater effluent. Groundwater injection of wastewater effluent puts aquifers at risk as well (Daughton, 2004b). Both surface and ground water contamination may taint drinking water supplies.</p><p>2 How much PPCPs are in the environment? The use of PPCPs is on par in terms of quantity with agrichemicals (Daughton and Ternes, 1999). This prevalent use of PPCPs makes them ubiquitous in the environment – they can be found in the rivers, lakes, and coastal waters of any place humans live or even visit (Daughton and Ternes, 1999). Pharmaceuticals and personal care products have been detected in wastewater effluents, surface waters, groundwater, and drinking water supplies around the world (Westerhoff et al., 2005). About 100 PPCPs have been detected in European and U.S. surface waters in the parts per trillion (ppt) to parts per billion (ppb) range (Hemminger, 2005). The United States Geological Survey (USGS) conducted a study of pharmaceuticals, hormones, and other organic wastewater contaminants in 139 U.S. streams in1999 and 2000 (Buxton and Kolpin, 2002). They analyzed stream water for 95 different organic compounds routinely found in residential, industrial, and agrichemical wastewaters. They found human and veterinary drugs, including antibiotics and natural and synthetic hormones, detergent metabolites, plasticizers, insecticides, and fire retardants in waters downstream of animal production facilities and heavily urbanized areas. Eighty-two contaminants were detected at least once and one or more organic wastewater contaminants were detected in 80 percent of the streams sampled (Kolpin et al., 2002). Mixtures of contaminants were common – 75 percent of the sampled streams had more than one, 50 percent had seven or more, and 34 percent had ten or more contaminants present. In March 2008, the Associated Press released the results of an investigation into pharmaceutical contamination of U.S. drinking water supplies: at least 41 million Americans are exposed to drugs such as pain relievers, antibiotics, anti-convulsants, mood stabilizers, and sex hormones (Associated Press, 2008). The AP National Investigative Team reviewed hundreds of scientific reports; analyzed federal drinking water databases; visited environmental study sites and treatment plants; surveyed the nation’s largest 50 cities, a dozen major water providers, and small water providers in all 50 states; and interviewed more than 230 officials, academics, and scientists. Besides identifying pharmaceuticals in drinking water supplies, the team also determined that 34 of the major water providers do not conduct any testing for these substances, and that those communities that do test do not share the results with the public. As detection methods are developed and improved these numbers will most likely only rise, especially since thousands of distinct PPCPs are available commercially, and thousands of tons per year are used (Daughton, 2004a). </p><p>Are PPCPs in drinking water and the environment a concern? The effects of PPCPs on humans through drinking water contamination and aquatic organisms and wildlife exposed through the environment are just beginning to be documented. Traditionally, PPCPs were seldom viewed as potential environmental pollutants (Daughton and Ternes, 1999). They are detected in very low levels in the environment and in drinking water supplies – in the parts per million or parts per billion ranges. There is little risk for acute toxicity in humans at these concentrations (Daughton, 2004a), there is a body of emerging science that suggest that these very low exposures can affect humans at the cellular level (Goodman, 2008). Some diseases, such </p><p>3 as cancer, can be triggered by low level exposures of certain substances like estrogen. But even at very low levels, PPCPs are highly bioreactive by design: they are intended to have a physiological or psychological response on the body. Yet, for many pharmaceuticals, the specific modes of action and interaction with other substances are not fully understood (Daughton, 2004a). And while the concentrations remain low, effects may build up over a long period of time. The same is true for wildlife and fish exposed to combinations of PPCPs in the environment. When the specific modes of action are unknown for the target species, the effects on non-target species, such as amphibians or fish, are completely unpredictable (Daughton, 2004a). This, combined with unintended side effects, makes designing eco- toxicity research experiments almost impossible. In fact, eco-toxicity data are available for less than one percent of human pharmaceuticals, according to estimates published in the Journal of Regulatory Toxicology and Pharmacology in April of 2004 (Hemminger, 2005). Additionally, many PPCPs are persistent and bioaccumulative, but for even those that are not, persistence in the ecosystem is not critical since PPCPs are continually introduced to the environment, resulting in perpetual exposure for wildlife (Daughton and Ternes, 1999). These concentrations may remain low and effects may accumulate slowly, allowing for major changes to go unnoticed to the point of irreversibility, or the changes that do occur are attributed to natural ecologic succession rather than human influence. Humans may also be negatively affected by PPCPs that contaminate (including bioaccumulate) animals and animal products we eat, such as fish. Historically, the primary interests in risk assessment have been acute toxicity and carcinogenesis. However, PPCPs may impact exposed organisms in more subtle ways. For example, EDCs may cause or contribute to the feminization of fish. A study in a 1994 issue of Chemistry and Ecology linked male carp and trout that were producing vitellogenin, an egg protein usually only found in females, to exposure of sewage effluent containing the active ingredient in birth control pills (Hemminger, 2005). Another concern is the neurobehavioral changes that may accompany chronic exposure (Daughton, 2004a). Some neurobehavioral changes may stem from the exposure to pharmaceuticals used to modify human behavior. Other neurobehavioral changes may be a result of exposure to pharmaceuticals that affect non-target organisms in unexpected ways. Behavioral changes are more difficult to quantify than toxicity in wildlife and can be more subtle, but have the potential to have significant effects on a population through multigenerational exposure (Daughton and Ternes, 1999). Antibiotic resistance is another concern. Stream surveys have indicated the presence of native bacteria that are resistant to a wide variety of antibiotics used by humans as well as in domesticated animals (Daughton and Ternes, 1999). </p><p>What is being done to reduce the presence of PPCPs in the environment? There are three primary ways that have the potential to reduce the presence of PPCPs in the environment, and therefore drinking water: source reduction, diversion from wastestream, and improved wastewater treatment. The reduction of pharmaceutical manufacture and use is highly unlikely. Pharmaceutical and personal care products are </p><p>4 designed to improve the quality of life, and many times, preserve life. In a time of increased pharmaceutical use, it is unlikely that this trend would be reduced. Diversion of PPCPs from the wastestream is an attractive mode of PPCP reduction from the environment. Drug take-back programs for expired pharmaceuticals are already in place in parts of Europe (Hemminger, 2005) and in regions of the United States (Goodman, 2008). These programs typically work in one of two ways. Consumers are either given the ability, usually through prepaid mailers, to return drugs to a way station for collection and disposal or they drop drugs off at a collection center. The success of these programs hinges on public participation as well as proper disposal of the collected products. Improved wastewater treatment is another option. Wastewater treatment technologies are continually evolving. Increased retention times within treatment plants, and treatment methods such as chlorination, ozonation, and biological treatment have the potential to increase the removal of some PPCPs from wastewater (Hemminger, 2005). Even so, the retained contaminants and byproducts must be dealt with. However, it is a huge endeavor for wastewater treatment plants to keep pace with the number and variety of new PPCPs that flood the market each year. It is important to note that there are no federal limits for PPCP discharges to the environment in the U.S., nor are there drinking water standards for public or private drinking water supplies, including bottled water. As such, municipalities are not obligated to test drinking water sources or recreational waters for PPCP contamination. If they do test their waters they are not required to release results to the public. The U.S. also lacks environmental risk assessments for new PPCPs. However, the European Union has made significant progress in this area: in 1999, the European Medicines Agency (EMEA) began drafting guidance that outlines an environmental risk assessment procedure to accompany the applications of any new drugs for use in Europe (Hemminger, 2005). The risk assessment procedure covers active drugs and their metabolites, and potentially their excipients, the inert substance in which the drug is delivered, if they are similar to chemicals with known adverse environmental effects. If risks are found, the EMEA recommends that the manufacturer take precautionary measures to limit the environmental impact of their product, specifically labeling to educate consumers about the best method of disposal of unused or expired pharmaceuticals. It is the hope that this process will also generate new eco-toxicity data for use around the world. </p><p>References Associated Press. 2008. Prescription drugs found in drinking water across U.S. www.cnn.com/2008/HEALTH/03/10/pharma.water1. Last visited 4 April 4, 2008. Buxton, H. and D.W. Kolpin. 2002. Pharmaceuticals, Hormones, and Other Organic Wastewater Contaminants in U.S. Streams. Fact Sheet FS-027-02. United States Geological Survey. Toxic Substances Hydrology Program. Reston, Virginia. Daughton, C. 2004a. PPCPs as Environmental Pollutants. U.S. Environmental Protection Agency. Office of Research and Development. Las Vegas, Nevada.</p><p>5 Daughton, C.G. 2004b. Groundwater recharge and chemical contaminants: challenges in communication the connections and collisions of two disparate worlds. Ground Water Monitoring and Remediation. 24(2):127-138. Daughton, C.G. and T.A. Ternes. 1999. Special report: pharmaceuticals and personal care products in the environment: agents of subtle change? Environmental Health Perspectives. 107. Supp. 6. Goodman, A. 2008. Sedatives and sex hormones in our water supply. Democracy Now! www.alternet.org/water/80505/?page=1. Last visited 4 April 2008. Hemminger, P. 2005. Damning the flow of drugs into drinking water. Environmental Health Perspectives. 113(10). Kolpin, D.W., E.T. Furlong, M.T. Meyer, E.M. Thurman, S.D. Zaugg, L.B. Barber, H.T. Buxton. 2002. Pharmaceuticals, hormones, and other organic wastewater contaminants in U.S. streams, 1999-2000: a national reconnaissance. Environmental Science and Technology. 36(6). Westerhoff, P., Y. Yoon, S. Snyder, E. Wert. 2005. Fate of endocrine-disrupter, pharmaceutical, and personal care product chemicals during simulated drinking water treatment processes. Environmental Science and Technology. 39(17). </p><p>More resources AusIndustry. Year unknown. Pharmaceuticals Partnership Program (P3). www.ausindustry.gov.au/content/azindex.cfm?Keyword=Pharmaceuticals %20Partnerships%20Program%20%20(P3). Last visited 4 April 2008. United States Geological Survey. 2002. Pharmaceuticals, Hormones, and Other Organic Wastewater Contaminants in U.S. Streams Fact Sheet. http://toxics.usgs.gov/pubs/FS- 027-02/. Last visited 4 April 2008. Waterkeeper Alliance. 2006. Persistent, Bioaccumulative, and Toxic Pollutants Fact Sheet. Irvington, New York.</p><p>6</p>