Chemicals from the practice of healthcare: Challenges and unknowns posed by residues in the environment

The practice of health care often relies heavily on the use of a bewildering array of chemicals for diagnostics, therapy, prophylaxis, and lifestyle or cosmetic modification. Excretion, bathing, manufacturing, and disposal of pharmaceuticals and personal care products (PPCPs) serve as conduits to the environment for complex mixtures of parent chemicals and transformation products, primarily via sewage and domestic refuse. As members of a much larger universe of natural products and other anthropogenic chemicals that already pervade the environment, PPCPs enter the environment primarily from multitudes of individually miniscule sources. Each source by itself contributes relatively insignificant quantities, but the combined inputs can yield measurable levels in waters and other environmental compartments, with the general exception of air. Scenarios abound for chronic, low-level ambient exposure of wildlife, microbiota, and humans, but special situations can lead to higher level, acute exposures. Whatever the existing risks, they can span a wide spectrum of modalities and can be difficult to decipher because of the complexities posed by simultaneous exposures to numerous chemical stressors—perhaps each present below any individual level known to perturb biological processes—and some leading to difficult-to-detect or delayed-onset subtle effects. The study of PPCPs in the environment (PiE) has proved challenging over the course of the last 15 to 20 years of international research. Significantly, the ultimate aims of PiE research are sometimes unclear. Overall priorities need to be established to achieve outcomes that still remain to be articulated. While the published scientific literature has grown to thousands of papers targeted primarily at deciphering the shape, scale, intensity, and spatiotemporal aspects of the environmental footprint, exposure envelope, and potential for biological effects of PPCPs, many aspects of PiE remain obscure. Given the possible reality of continually diminishing resources for research, a concerted effort is needed to identify those select aspects capable of removing the most uncertainty in assessing whatever risks might be posed by PiE, target those aspects having the highest potential to broadly benefit human health and the environment, and better coordinate and focus future research. The study of PiE is notable in that it requires expertise spanning a remarkably diverse spectrum of disciplines—ranging from hydrology, civil engineering, and chemistry, to pharmacology, toxicology, medicine, and even social psychology and risk communication. Study of PiE has captured the attention of not just scientists, but also policy makers, legislators, regulators, environmental agencies, health-care communities, public, press, and the pharmaceutical, pharmacy, and health insurance industries. It has also slowly morphed into the much larger issue of the so-called but loosely defined “emerging contaminants”—a catch-all term for contaminants whose presence or significance was previously unknown, unrecognized, or underappreciated [1]. Why does PiE persist as a topic of interest for so many? A major reason is that despite the accelerating pace of published investigations, new questions continue to be generated while some major ones remain unanswered. Moreover, the fact that PPCPs (a term coined 10 years ago [2]) occur in waters serves to illustrate the intimate connections between the activities and behaviors of humans and the environment—a continual reminder of the hydraulic connectivity between sewage and “natural” waters. They remind each of us that we are integral parts of the water cycle. Their seeming ubiquity in waters, especially potable waters, serves as a constant (and sometimes emotional) reminder that these waters originated at least in part from the excretions of others—from feces, urine, and sweat [3]. This factor certainly looms large with the life cycle of PPCPs and can play a critical role in the public acceptance of water reuse. Pharmaceuticals and personal care products comprise thousands of distinct chemical entities and tens of thousands of commercially formulated products, possessing an immense range of physicochemical and physiological properties. For drugs, each active pharmaceutical ingredient (API) can be assigned to one of many therapeutic groups, such as those of the tiered Anatomic Therapeutic Chemical (ATC) classification system or the analogous system for veterinary medicines (e.g., see discussion in Table 5 of Ruhoy and Daughton [4]). Because of the extreme diversity of PPCPs (especially their wide range of biochemical activities), generalizations applied across the entire spectrum (or even within defined classes) are prone to misrepresentation and numerous exceptions. Even broad classes sharing the same therapeutic modalities (e.g., lipid regulators [ATC C10] or antidepressants [ATC N06A]) can act via a wide variety of biochemical routes. Despite these categories of therapeutic action, actual mechanisms of action are frequently unknown and individual APIs can be promiscuous in their biochemical actions. Among the reference citations in the U.S. Environmental Protection Agency's (U.S. EPA) bibliographic database on PPCPs (www.epa.gov/ppcp/lit.html), publications with a focus on personal care products comprise a much smaller portion (about 10% of the total) than do APIs. The major personal care product groups that have been investigated are the synthetic musks, triclosan and triclocarban, ultraviolet filters and sunscreens, parabens, and siloxanes, in decreasing order of prevalence in the literature. Phthalates, bisphenol A, and nonylphenols are involved with higher numbers of publications but their usage in personal care is minor compared with other commercial uses. In general, the active agents in the thousands of commercial formulations of personal care products are produced and consumed in much larger quantities than APIs but their biological potencies are also much lower. Nearly all aspects of APIs in the environment have parallels for both human and animal pharmaceuticals; indeed, many APIs have dual uses. The relative importance, however, of these aspects among human and animal applications can differ greatly because of the dominance of (and special needs imposed by) confined animal feeding operations in the overall use of APIs targeted for animals, where antibiotics and the endogenous and synthetic steroids play dominant roles. The focus of roughly 10% of the articles inventoried in the U.S. EPA bibliographic database on PPCPs is veterinary and aquaculture usage. Perspectives on the roles of veterinary medicines as environmental contaminants have been covered in a number of excellent reviews, including those published in Crane et al. [5]. Environmental scientists and health-care professionals face nearly endless challenges with PPCPs. But which of these challenges leads to valuable near-and long-term outcomes that protect and improve human health and ecological function? We must also determine where PPCPs fall within the growing list of overarching environmental issues in a world of diminishing resources and continually emerging new concerns. The issues and concerns surrounding PiE involve the interface between humans and the environment—where the everyday individual actions, activities, and behaviors of multitudes of people combine and intersect with the environment via dynamic transfer and recycling of countless different chemicals, most of which were designed to impart biological effects. Targeting of research will require integration of knowledge regarding the presence, fate, and effects of PPCPs in the environment with what is known about the countless sources and origins of their release as a direct result of the management and administration of health care. A key insight into this challenge is that a wide spectrum of actions targeted at reducing the transfer of PPCPs to the environment holds the potential for reciprocally improving the quality and costs of health care [6]. Treating the environment and health care as an integral system could greatly clarify where and how to invest resources to achieve optimal outcomes, as improvements in either can lead to collateral improvements in the other. Using prioritization tools such as multi-criteria decision analysis coupled with value of information, and examining the continuum of steps spanning the risk paradigm—beginning with sources and origins and ending with biological effects and risk management—could be used to establish relative priorities; for examples of this process, see Kiker et al. [7] and Linkov et al. [8]. Nearly every stakeholder involved with PiE serves not only as an interested party, but also as an actual contributor to some aspect of the overall problem, as well as a potential beneficiary from solutions. Each stakeholder also can play an active role as problem solver; the physician can alter prescribing habits, the consumer can make more prudent purchases and properly dispose of leftover drugs, and the insurer can encourage dispensing of prudent quantities. To identify the relative importance of each modification needed to improve a system as large and complex as health care requires establishing clear priorities, which in turn must be based on quality data. Of the 7,000 or so references currently captured in the U.S. EPA bibliographic database on PPCPs (over 85% of which are articles from journals or books but largely omitting the non-English literature), over 90% have been published only since 1999 (Supporting Information, Fig. S1; http://dx.doi.org/10.1897/09–138.S1). The international extent of the topic is evident from the numbers of publications that feature a particular country in the abstract or title. Over 1,600 articles mention 10 different countries (Australia, Britain, Canada, China, Europe, Germany, Italy, Japan, Spain, and Sweden) and Europe, and over 600 mention the United States. Of 150 academic dissertations, 60% are from outside the United States. Of the seven most highly cited papers on PiE, five originated in Europe and two from the United States. While this certainly shows an ongoing escalation in publishing activity, it does not tell us if these works have targeted the most pressing needs, if they are being actively used to inform decision making, or whether they are resulting in useful outcomes for society. Moreover, if one were to assume an extremely conservative cost of merely US$10,000 to $100,000 per paper, the last 10 years of research targeted toward PPCPs may have consumed minimum resources roughly upwards of US$600 million. Such a substantial investment prompts the question of whether these resources could have had more productive outcomes or greater impact if they had been invested elsewhere in the field of PPCPs or, perhaps more significantly, even elsewhere in environmental sciences at large. Perhaps not surprisingly, the impressive wealth of data published on the topic of PiE has generated a host of new questions, which, paradoxically, can serve to breed yet more uncertainty. At the same time, however, the new knowledge gained for PPCPs is often directly relevant to other types of chemical contaminants, serving to leverage resources throughout the environmental sciences arena. Two overarching concerns for PiE have centered on human health risk and ecological integrity, especially aquatic effects from the perpetual entry of residues via sewage (pseudo-persistence). The ultimate destination for PiE research might be evident only in the larger context involving a truly holistic examination of PiE and the complete life cycles of PPCPs. Can health-care systems and the manufacturing and distribution of PPCPs be designed and optimized to leave a minimal environmental footprint? The argument has been made that in taking actions to reduce and ultimately minimize an ill-defined hazard (namely, the release of PPCPs to the environment) by reinventing health-care administration and delivery of health care, improvements in therapeutic outcomes might follow naturally, together with reductions in the costs associated with medical care [6]. The best outcomes regarding release to the environment might emerge from optimizing the way in which health care and personal care are administered, distributed, prescribed, dispensed, and employed and how PPCPs are designed and produced. Reactive approaches using end-of-chain controls are not as efficient or effective as proactive solutions that optimize source reduction or pollution prevention. By focusing on less sustainable end-of-pipe solutions, such as improved ways to dispose of unwanted medications or more efficient treatment of wastewaters, approaches with even better outcomes might escape consideration. As one example, consider that the imprudent usage of PPCPs coupled with the extent of leftover medications can be viewed as direct measures of the inefficiencies and wastefulness that can occur along the entire life cycle of PPCPs. Leftover medications represent much more than just chemical wastes needing disposal. They represent wasted health-care resources, inflated and unnecessary consumer expense, and missed opportunities for achieving optimal therapeutic outcomes [6]. By focusing on controlling the many causes leading to the accumulation of unwanted medications, not only would the need for disposal be reduced, but excretion and discharge of residues of PPCPs might also be incidentally reduced as a result of optimized usage. Such holistic approaches require the involvement of specialists from fields that may not have foreseen ever playing active roles in the PiE issue. In the early 1920s, Henry Ford conceived of a new strategy for inventory maintenance designed to improve return on investment. Called “just-in-time,” this new paradigm redefined on-hand inventory as essentially being the equivalent of waste. Optimal performance meant perfect balance between demand and on-hand supply. If a just-in-time perspective were applied to health care, medication waste could be viewed not just as additional chemical contaminant burden for the environment, but more importantly as a prime metric of inefficient, nonoptimal administration of health care. Redesign of health care using the just-in-time perspective and the knowledge and expertise of medical practitioners, health-care administrators, pharmaceutical manufacturers, and environmental scientists could lead to a holistic system of balanced and optimally targeted delivery of medical care. Such a system could yield improved therapeutic outcomes, lowered costs, and reduced environmental impact. The effectiveness of efforts directed at pollution prevention or source reduction increase as the targeted steps reside closer to the source or origin of the chemical. Tracing the ultimate origin back to chemical design, advancements in eco-design could prove to have significant outcomes not only in reducing environmental impact, but also in improving health-care outcomes ([6, 9]; http://www.mistra.org/download/18.1fe8f33123572b59ab800011033/A+Healthy+Future.pdf). In the near term, consideration could be given to the design of pilot projects designed around stewardship actions in health care. Healthcare organizations having control over all aspects of medical care might serve as excellent testing grounds for pilot projects; in the United States, one example for testing new approaches could be the nation's largest integrated healthcare system—the Veterans Health Administration. Despite the thousands of publications devoted to the many facets of PiE, unanswered questions persist and continue to proliferate. Many of these questions, however, are also germane to some of the major issues that permeate environmental science as a whole rather than being critical to solving specific problems associated solely with PiE. Significantly, despite the wealth of published data, little has yet proved of use in actual implementation of system redesigns that are more sustainable or even for informing regulatory deliberations regarding PiE. A major weakness in the application of environmental science to PiE has been the failure to frame the issue in a much larger context—using a “systems” approach that involves experts from fields other than primarily just analytical chemistry and environmental engineering. A comprehensive, international strategy for tackling PiE using a harmonized approach integrated across a spectrum of disciplines could also involve social psychologists and risk communicators, physicians, pharmacologists, pharmacists, drug designers, and health insurers. Once the PiE issue is successfully framed in a larger, holistic context having meaning to a broader audience, and collaborations are established among those from across disparate disciplines, more productive outcomes could possibly emerge. The requisite framing must show how health care and personal care can lead directly to environmental contamination. But more importantly, clear communication would be essential for how measures directed at redesigning their administration to minimize the PiE footprint can in turn improve the affordability and desired outcomes from the consumer use of PPCPs. Required actions could become clearer and more readily embraced when considering the patient and the environment as an interconnected whole. Although voluminous published and gray literatures exist for PiE, a large number of gaps remain that could be investigated [10]. Science is never short on questions. More important to address first, however, is what exactly do we wish to accomplish with more research? What outcomes are we seeking? How would the uncertainty associated with assessing risk be most efficiently minimized? Closer collaboration between researchers and risk assessors would be highly beneficial. Most importantly, however, the concerns, challenges, and solutions regarding PiE need to be framed and examined in the expanded context of the larger systems used for the care of human and animal health. In the table (Supporting Information, Table S1; http://dx.doi.org/10.1897/09–138.S2), some notable gaps and unresolved questions are compiled, and examples are provided to illustrate a range of issues that might be considered for further attention and discussion. The following these questions and concerns. that might at to a problem can have and sometimes The of world might from and it is certainly in the new “systems” But the that is to was less than years ago by as of the in can never do merely one or outcomes can result from a action was captured by what where the ultimate can differ from what was But the to the environmental was more than 150 years that pervade all of can be in or any of of or other by or or other the surrounding by the same the to other and the given the whole examples of to PiE are provided in Table decision analysis and value of could serve as the for PiE A number of on face value to concerted Many have been in publications and A need is to on what is already published which could a wealth of data not yet examined and certainly never compiled, and into useful and This is largely because and of data are not in science as much as the of new data. But given the uncertainty as to the extent these published have been that much of the published literature in general has never even been the value of publishing clear outcomes in must be This prompts the more general questions of how the impact of publishing can be and how do we encourage the and of this examination of the U.S. EPA bibliographic database on PPCPs that publishing on the topic of PiE in around which roughly as many articles as in The publications devoted to the topic of PiE, however, to in the of the significant works from and at the U.S. of the years by et al. The topic to more than a publications per in The two of more publications than in all of 1999 in the of over have either been published or are in A literature not in greatly the that an ever greater of these publications will not as can a individual to being with the literature as a in individual aspects of the topic is and this can advancements in the of The of greatly the risk of of and in not focusing new where the highest gaps might additional aspects of literature are (Supporting Information, Table of the published to that the of data to focus on environmental and and on for wastes and At the other of the spectrum significant have little of the major ones are (Supporting Information, Table important aspect of environmental or is the of of contaminant The with which PPCPs in environmental have is This potential weakness leads to a number of questions (Supporting Information, Table to analytical us to into the of chemical with greater and While this chemical might be to and serves to further the universe of chemical at the same it greater challenges for risk This is especially with to one of the problems exposure to chemical each present at individual While is to be the most of action at the of mechanisms of action be especially since mechanisms of action can with exposure levels and can across will greater challenges for and diminishing an known universe of potential chemical will challenge the or of on a At the other in the sometimes or the potential for for by acute exposures and just of humans and from leftover medications, but also of via previously source and exposure and even or mechanisms of Can improved of risk for PPCPs for the of exposure or What additional knowledge is to the and of such as the of and by or residues of such as (and possibly in from domestic animals, or to the acute of APIs to environment the of and air. It also where we and even where residues of countless chemicals are applied to or from the and to other where can be [3]. for acute exposures (e.g., from levels of APIs on the application or via the and human with excretions from these issues are germane for therapeutic using highly or to APIs for little an importance of data from therapeutic or commercial or usage needing consideration are other critical involved with the life cycles of such as (e.g., the extent to which an is as feces, urine, or delivery patient of and the need for usage leading to and an for A major problem with of low-level ecological exposure is the challenge of the of what might to be an in a from the of as ambient The problem of effects to exposure is further (Supporting Information, Table this problem also regulatory based on of hazard for individual Moreover, even if can be the must be if effects impart at the level of the gaps and research needs can be along the continuum of the risk spanning the range from chemical sources to biological effects and [10]. to the topic of drug the surrounding sources and origins are important (Supporting Information, Table As with any field of present is a risk that and can become as is needed to the of especially when might be used to inform decision regarding PiE may be based more on than and might benefit from more (Supporting Information, Table A involves the key importance in establishing and the context in which PPCPs exist in the environment as potential for biological Their in the larger universe of chemical is essential to so that the public can a more and perspective of chemical exposure in general and that optimally regulatory can be resources for research must be directed to the most significant of environmental Of the of the relative importance of PPCPs can only be by considering all including of such as and among many This an that yet be at least be continually in the of discussion and to in the to risk in a truly holistic In the time, we can at the least the issue of PiE in the environment as an a for improving the and of the By involving the many in health care, sustainable systems can be designed that could yield in health-care resources, improved patient outcomes, and combined of human health and ecological Fig. publications relevant to PPCPs. at Table questions, and framing a regarding PiE. at The is not for the or of any by the than be directed to the for the

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