Pharmaceuticals and Personal Care Products in the Environment: Scientific and Regulatory Issues
Illicit Drugs in Municipal Sewage
|Proposed New Non-Intrusive Tool to Heighten Public Awareness of Societal Use of Illicit/Abused Drugs and Their Potential for Ecological Consequences|
|[also note: Post-Publication Commentary: http://www.epa.gov/nerlesd1/chemistry/pharma/book-post.htm]|
Christian G. Daughton
Chief, Environmental Chemistry Branch, ESD/NERL, Office of Research and Development, Environmental Protection Agency, Las Vegas, NV 89119, USA; e-mail: firstname.lastname@example.org; 702-798-2207; fax 702-798-2142.
Even though a body of data on the environmental occurrence of medicinal, government-approved ("ethical") pharmaceuticals has been growing over the last two decades (the focus of this book), nearly nothing is known about the disposition of illicit (illegal) drugs in the environment. Whether illicit drugs are similarly discharged to and survive in the environment (as discussed for medicinal drugs in the previous chapters of this book), and if so, whether they have adverse effects on native biota, is completely unknown. Regardless, with the newly acquired ability of environmental chemists to monitor for medicinal drugs in environmental samples, science is now afforded the rare opportunity to simultaneously advance the understanding of a pollution process (i.e., the inadvertent discharge of illicit drugs to the environment via their purposeful use) and to also have the ability to impact public discourse and social policy on a highly controversial subject -- namely, the pervasive manufacture, trade, and use of illegal drugs and abused controlled substances.
The idea proposed in this chapter provides a rare bridge between the environmental and social sciences. The central aspect to the proposal centers on the use of non-intrusive drug monitoring at sewage treatment facilities and the use of the resulting non-incriminating data to determine collective drug usage parameters at the community level as well as to provide exposure data for the aquatic realm. This is the first feasible approach to obtaining real-time data that truly reflects communitywide usage of drugs -- while concurrently assuring the inviolable confidentiality of every individual. At the same time, this approach yields environmental data for a class of potential pollutants never before considered as such.
This proposal, which merely capitalizes on science's existing technical capabilities in analytical chemistry, is ground-breaking in its parallel objectives of (i) advancing our understanding of the intimate, immediate, and inseparable connection between humans and their environment (through personal use of chemicals), and (ii) furthering a national debate regarding the use/abuse of illicit and recreational drugs; any national discussion on the purported adverse effects of illicit drugs on a wide spectrum of societal concerns and issues should be helped with the availability of hard data regarding usage. In this sense, the capability outlined here is unique in its purpose of linking social discourse with the furthering of our understanding of environmental processes (such as fate and effects of pollutants). Implementation of this proposal on either limited local levels, nationwide, or internationally could provide a radically innovative approach and totally new dimension to the decades-old quest of understanding the overall issue of illicit drug use as well as informing the public on the perceived widespread use and the many purported consequences of illicit/recreational drugs.
Human actions and activities can impact the environment in many ways -- deforestation and the potential for global warming being but two obvious examples. Through the interconnectedness of humans and their environment, these impacts can in turn affect our daily lives. Another possible aspect of our society that might harbor the potential for impacting both the environment and the lives of ourselves and others is the purported widespread and continually escalating use of illicit drugs and the misuse/abuse of certain medicinal pharmaceuticals. Drugs comprise a myriad of chemical and therapeutic classes, all of which are specifically designed to elicit potent pharmacological effects (mediated through hundreds or possibly thousands of unique biochemical receptors or targets), as well as numerous toxicological side effects (e.g., adverse effects). A greatly underappreciated aspect of environmental pollution is that the personal, individual use of these substances can lead to both their direct (purposeful) and indirect (inadvertent) discharge (as well as that of any associated bioactive metabolites) to the environment via excreta (through untreated sewage and sewage treatment systems) and by illegal disposal.
Illicit drugs are considered a world-wide concern, harboring the potential for profoundly affecting societies in a myriad of ways. They can have profound economic and political ramifications in locales where they are manufactured or transported -- by weakening of government authorities and fostering corruption, eventually leading to political instability. They also elicit intense debate over moral issues. These problems, coupled with the problems attendant to smuggling into consumer countries, can pose concerns with respect to national security. Potential ecological aspects of manufacturing, disposal, and usage also cannot be ignored.
In spite of an awareness of the general problem, the actual types and quantities of illicit drugs used across the U.S. are ill-defined, and numerous new illicit drugs appear annually. The quantities discharged to sewage systems are totally unknown. The relative contributions from individual ingestion versus disposal by clandestine drug labs are also unknown. Clandestine manufacturing and use of illicit drugs, and abuse of controlled substances, constitute a potentially large and highly dispersed source of a chemically diverse (both natural and synthetic), bioactive group of pollutants (both the economic drug and bioactive metabolites, as well as synthesis by-products), differing in many respects from the conventional (priority) pollutants.
Overviews of the types of illicit drugs used in the U.S. are available from the White House Office of National Drug Control Policy (ONDCP) (at: http://www.whitehousedrugpolicy.gov/), from the National Institute of Drug Abuse (NIDA) (at: http://www.nida.nih.gov/NIDAHome1.html), from the Drug Enforcement Administration (at: http://www.usdoj.gov/dea/concern/concern.htm), and from "Streetdrug. org". The major common classes of abused drugs include stimulants, hallucinogens, opioids, depressants, inhalants, and steroids; these are augmented by several other classes of lesser importance. Terminology of psychoactive recreational and prescription drugs by generic, street, and trade names is available at: Office of National Drug Control Policy (Street Terms: Drugs and the Drug Trade), http://www.whitehousedrugpolicy.gov/streetterms and http://www.behavenet.com/capsules/treatments/drugs/drug.htm. Certain illicit drugs are used not just recreationally, but also for self-prescribed medical purposes.
Sensitive chemical analysis methodologies to identify and quantify medically prescribed and over-the-counter drugs in community sewage treatment plant influents and effluents have been successfully employed (see review: Daughton and Ternes ; also other chapters in this book). Expanding this approach to illicit drugs could accomplish a variety of additional objectives not relevant to medicinal drugs. Objective data that reflect overall illicit drug manufacturing, disposal, and consumption on a communitywide basis could be gained without the risk of implicating or incriminating individuals.
The community-scale surveillance tool proposed in this chapter has multiple objectives. The idea centers on the technological ability to sample community sewage treatment systems (preferably influents, where concentrations are highest) and to analyze for trace chemicals - in this case illicit drugs. This idea has never before been considered and is an outgrowth of the recent review and overviews of Daughton and Ternes (1) and Daughton (2). It more fully develops the question briefly first posed in those articles as to the significance of illicit (recreational, street) drugs in the environment. Never before has the opportunity presented itself for gaining a window into the collective personal chemical-use activities of a community - without implicating or incriminating the individual. The proposed "surveillance" approach could serve as an unobtrusive, non-invasive means of assessing collective communitywide manufacturer, use/abuse, and disposal of illicit drugs (both types and quantities) and controlled substances while assuring the anonymity and privacy of the individual. As to which of these three major sources is the major contributor to overall loading of a particular drug in sewage would be a function of each individual locale.
Drugs are known to enter the environment via several routes, the most significant one with respect to the work proposed here being domestic sewage. Simply stated, any chemical ingested by humans has the potential to be excreted via the feces and urine -- usually passing directly into sewage treatment systems and septic systems and sometimes simply being directly "straight-piped" (without treatment) into surface waters. Direct disposal of unused/unwanted drugs and synthesis by-products to domestic sewage is another source. The amounts that are discharged to the environment via excreta are a function of pharmacokinetics (absorption, distribution, metabolism, and excretion -- the last two of which are also influenced by transformation by gut microbiota), biodegradation or biotransformation (including conversion of conjugates back to the parent drug) during conveyance of sewage to treatment plants, and amounts removed during physicochemical/biological treatment (these additional removals do not occur with direct discharge of untreated sewage).
Quantification data acquired for drugs identified in STW influents would be used to compute an average consumption rate normalized across the population serviced by the sewage treatment facility. Using pharmacokinetic data and environmental transformation rate data, coupled with the occurrence concentrations in sewage influent, the population-normalized total consumption/use/production for a given drug within the population of a sewage treatment service area could be back calculated; alternatively, minimum population-based consumption could be calculated simply by using uncorrected influent concentrations. By determining the concentrations of drugs or key metabolites (e.g., benzoylecgonine or ecgonine methyl ester as a surrogate for cocaine, d-amphetamine for d-methamphetamine, 11-nor-9-carboxydelta-9-tetrahydro cannabinol for delta-9 tetrahydrocannabinol, morphine for several opiates) representing the important classes of illicit drugs and drugs of abuse that enter municipal sewage treatment systems, it should be possible to conservatively estimate (i.e., provide lower estimates) the daily influx of each drug (or chemical class, for example, opiates). Dividing the daily loads of each drug (or class) by the serviced population of the sewage treatment plant would yield the lower estimate of normalized-population usage of each drug. By applying knowledge of biodegradation within sewage conveyance systems and biodegradation from gut microbiota and human metabolism (pharmacokinetics), the original concentrations of each drug could be back-estimated, yielding upper-estimates of communitywide usage. Furthermore, by monitoring drug metabolites instead of the parent drug, amounts resulting from human usage could be largely distinguished from synthesis/disposal. Provision to the public of daily, population-normalized equivalents of drug usage would offer an entirely new perspective on the overall magnitude and extent of illicit drug usage. Actual usage by the user-individual would obviously be higher than normalized total-population usage since only an unknown fraction of the populace uses illicit drugs; the approach proposed here is not capable of addressing this factor.
This proposed strategy could be implemented on the local level by whatever organizations so choose to monitor and analyze sewage influents. If successful, it could be expanded nationwide by government, public, or private organizations. Logical collaborations could be established among local/state/federal environment agencies, wastewater districts, and law enforcement forensic laboratories. As discussed later, such sewage-treatment-plant monitoring networks could be expanded to include schools and other organizations, who could participate in environmental monitoring for educational enrichment.
The proposal described here addresses one of the 10 Goals that compose the U.S. EPA's 2000 Strategic Plan ( http://www.epa.gov/ocfopage/plan/plan.htm). Among these goals, the objective of Goal 7 (Quality Environmental Information: Expand the American Public's Right to Know About Their Environment) is to facilitate easy public access to local/regional/national environmental information and thereby expand citizen involvement by providing the data required to make decisions in protecting their families, their communities, and their environment - as they see fit. The goal is to increase information exchange between scientists, public health officials, businesses, citizens, and all levels of government, with the hope of fostering greater knowledge and awareness of the environment and thereby enhance the involvement of a better-informed, empowered citizenry in formulating lasting solutions to environmental problems - all within the complex interrelationships of risks and the associated tradeoffs involved in making decisions. One specific approach to Goal 7 that has been implemented by the EPA is the President's "Environmental Monitoring for Public Access and Community Tracking" (EMPACT) Initiative (see: http://www.epa.gov/empact/). This initiative focuses on improving environmental data collection and on deploying new analytical technologies for real time / automated monitoring and promulgation of data. The monitoring approach proposed in this chapter is illustrative of these goals, and could even serve (if desired) as a possible program under the EMPACT initiative.
The two major objectives of this proposed monitoring approach are to (1) heighten the public's awareness and understanding of the many issues involving pollution by synthetic chemicals -- but especially, how the collective personal actions/activities of individuals can have a direct impact on the environment, and (2) for the first time ever, make available to the public, community-scale data on "real-time" actual consumption/usage and ultimate environmental disposal/disposition of illicit drugs. Lacking to date has been the ability to know (in a timely manner) what specific drugs are being used and in what communities. Current consumption data are hard to verify and are often qualitative at best. In the absence of such data, public discourse over the last decades on the various issues involving illicit drugs has been less than fully informed. Sewage monitoring would provide the ability to directly measure real drug use. Monitoring of sewage influents could be done on any time line desired (weekly, daily, or more frequent), and the resulting data could be conveyed to the public in any way desired (e.g., via the various mass media) with the potential for daily updates, in a manner analogous to the reporting of air or water quality parameters or the weather.
Public Awareness of Chemical Pollution Caused by Individual Actions: Periodic reporting of community-scale drug consumption would foster a better understanding and appreciation by the public that actions of individuals impact the environment -- especially with regard to the use of chemicals -- in this instance drugs. Historically, it has proved difficult for the individual to perceive their small-scale activities or actions as having any measurable impact on the larger environment - personal actions are often deemed minuscule, or discounted as inconsequential in the larger scheme. Yet it is the combined actions and activities of individuals that indeed can significantly impact the environment in a myriad of ways. A factor making it difficult for individuals to perceive the interconnectedness of their lives with the health of the environment is the lack of perceived immediacy of any untoward (or beneficial) effects -- as most actions have delayed consequences that make cause-effect relationships difficult or impossible to perceive. This temporal disconnection obscures the ultimate causes of effects, thereby negating the possibility of modifying/reinforcing behavior via feedback (positive or negative).
In addition to inadvertent discharge of bioactive drugs to the environment simply via their ingestion/administration, the disposal/dumping of precursors, catalysts, and by-products used in illicit drug manufacturing and trade could have adverse environmental consequences not yet realized. While documentation of direct environmental impacts of these illicit-drug secondary materials is sparse, obvious consequences include damaging farm practices (e.g., deforestation and over use of fertilizers/pesticides for drug crops) and resultant water pollution, all of which can be caused by the drug trade itself or by anti-drug "eradication" programs. Dumping of large quantities of toxic substances used in, or generated by, the production process (e.g., diethyl ether, acetone, and sulfuric and hydrochloric acids used in the production of cocaine hydrochloride; kerosene, diesel oil, and calcium oxide used in the production of coca paste) or dumping of unwanted product are other major sources of potential ecological damage of unknown magnitude.
While illicit drugs (DEA Schedule I) have yet to be reported in environmental samples (perhaps largely because they have not been monitored for), certain Schedule II drugs of abuse are now reported in chapters of this book -- by Snyder et al. in lake water at the tens-to-hundreds of ng/L range, including phenobarbital, primidone, hydrocodone, and codeine, and by Möhle and Metzger in sewage influents/effluents in the µg/L range (hydrocodone and dihydrocodeine) (3,4).
Limitations and Problems of Current Drug Tracking Methodologies: One can probably safely assume that the known instances of illicit drug use (by both chronic and recreational users) and manufacturing that are derived from criminal arrest data represent only a small but unknown portion of overall incidence of use. Also assumed is the difficulty in obtaining an accurate picture of societal drug use via the only three currently available means: (1) self-administered surveys of personal use, (2) by drug-testing programs, or (3) hospital admission data. Furthermore, despite the growing popularity of drug-testing programs, the legality and ethics of workplace/school drug testing continues to be debated and challenged in court. With the means proposed here to finally by-pass drug-testing programs centered on the individual, we could also avoid the potential of impairing worker morale and inadvertently providing the impetus to drug users to switch to yet more dangerous drugs that are not subject to, or amenable to, screening. Drug-testing programs are also fraught with many technical and legal difficulties with respect to interpreting the meaning of positive results - namely, whether any particular concentration of a drug, other than ethanol, actually constitutes physical impairment at a particular time.
Guidelines for drug testing also result in gross under-reporting of drug usage by most drug-testing procedures because all drugs present at lower-than-established (regulatory) "cut-off" concentrations (e.g., those specified by DOT -- 49 CFR Part 40: "Procedures for Transportation Workplace Drug and Alcohol Testing Programs, Proposed Rules" are reported as "not present"; only those procedures using "zero tolerance" (i.e., results reported as a function of method detection limit) avoid this substantial built-in negative bias. Finally, drug-testing programs targeted on the individual are severely limited to acquiring random discrete snap-shots of excreted drug/metabolites. Very recent drug usage, for example, can escape undetected in a urine drug test because the drug/metabolite has yet to appear in the urine, while older previous intake can escape because of prior metabolic clearance. In contrast, sewage monitoring would yield a more comprehensive, integrated reflection of continual/cumulative usage at the scale of an entire community. Replacement of drug-testing programs that are solely focused on the individual with one based on collective, anonymous community-scale screening would yield a more accurate reflection of total drug usage in part because pressure to circumvent drug screening tests would disappear, eliminating an historic negative bias in estimating usage.
Public Discourse of Drug Use/Abuse: Monitoring of illicit drugs in communitywide sewage could advance the stalemated, decades-old national discourse that revolves around the use of illicit drugs. By bringing to the fore the real extent and magnitude of nationwide manufacturing/trade and usage of both street (illicit) and abused prescription drugs, the debate could be furthered and better informed. Also, the levels of street drugs in sewage influents and effluents must be documented before their potential to enter natural waters and drinking waters (via treated and untreated sewage) can be evaluated; the environmental fate and transport of prescription drugs, leading to their ultimate disposition to surface, ground, and sometimes even drinking waters would not be expected to differ dramatically from that of illicit drugs. Only then can their risk to aquatic biota and to consumers of drinking water be assessed. Ultimately, should illicit drug residues (regardless of concentration) appear in domestic drinking water (as with prescription drugs), they would serve as a definitive, continual reminder of not just the magnitude of illicit drug use, but also the fact that society's combined use of drugs by multitudes of individuals has the potential to impact aquatic biota, as well as anyone who drinks water that has not been sufficiently upgraded. This monitoring approach will foster the recognition of collective and individual responsibility with respect to environmental pollution.
Implementation and Public Participation in Monitoring: A nationwide semi-quantitative screening program at the community-scale could be inexpensively established with the participation of primary, secondary, and upper school systems. Such a program would focus solely on monitoring communitywide sewage and receiving waters for illegal/abused (and perhaps certain legal) drugs.To facilitate low-cost analysis, such a network could adapt the use of readily available "home test kits" (largely based on immunoassay), which are otherwise designed for screening of individuals (see: "SAMHSA Evaluation of Non-Instrumented Drug Test Devices," http://www.health.org/workplace/summary.htm). With cooperation of local municipalities, such an approach could inexpensively and quickly supply nationwide monitoring data for sewage-treatment facilities and surface waters (to augment the quantitative data supplied by laboratories).
Such a volunteer monitoring program could also provide a unique opportunity for students of all grade levels to delve more deeply into environmental science -- promoting further participative, hands-on study of a wide spectrum of issues involving environmental pollution, including chemical analysis, identification of source/occurrence, environmental fate, exposure, effects, risk assessment, mitigation, pollution prevention, and regulation. Such a program would foster a continuing, and more objective, dialog on drug use throughout the country and would gain added meaning once historical "baselines" had been established and upon which status and trends could be amassed and inter-community comparisons made. Should home test kits prove capable of sufficiently sensitive drug detection in sewage (without sample preconcentration), then they could prove of direct use by schools in monitoring treated sewage effluent (non-sterilized influent is unsafe for school work because of safety issues involving infectious pathogens; it would be suited, however, if screened for, or sterilized of, pathogens by the treatment plant operators). If sample preconcentration is required, the drug-test kit manufacturers could redesign their assays with increased sensitivity (they are currently set for the relatively high regulatory levels). Otherwise, simple solid-phase extraction techniques could be developed (for amenable drugs) in order to lower the method detection limits.
An important adjunct tool in making use of the resulting monitoring data would be geographic information system (GIS) technology, whose role has been expanding in the public health arena. With GIS, drug monitoring data could be overlaid with health, demographic, environmental, crime, and any other conventional data tied to geographic location and sewage-service areas. As one of many examples, public health professionals would have access to another measurement to correlate with disease outbreaks (e.g., because of drug use involving shared-needle use). Another example is that data on communitywide usage could be used to answer major, long-unresolved questions such as whether illicit drug use affects economic productivity and overall health (for example, on absenteeism, overuse of health benefits and cost for rehabilitation, accidents/fatalities, disciplinary actions, turnover, and crime/delinquency - all purportedly caused by both the need to buy drugs and by the use of drugs). Questions such as these have simply not been addressable in a satisfactory manner using the only existing but highly controversial analytical tool available - drug-testing programs aimed at the individual. While these issues have long been, and continue to be, actively debated, it is widely recognized that drug testing programs are extremely costly and enormously controversial.
New Societal Perspective and Insight: With public access to actual, community-scale drug usage on a continual, "real-time" basis, this new monitoring approach could have far-ranging (and perhaps difficult-to-foresee) ramifications for society. By providing data never before available, this program would foster the recognition of the importance of collective and individual responsibility with respect to environmental pollution. More effective drug prevention could result from a greatly heightened public awareness of the actual nature and extent of drug usage at local levels and nationwide -- an awareness based on non-obtrusive scientific measurements rather than on invasive testing (which can inadvertently lead to biased data) and subjective surveys. More objectivity could be infused into what has historically proved to be a highly charged, politicized debate (5).
A continuous but non-intrusive, anonymous indicator of drug use would serve to keep the issue in the fore of public discourse and awareness. Society could gain a new tool for gaging the use of illicit drugs and mapping their use down to the community level (more specifically, the service population for a given sewage district). These collective data could serve as the input for a numeric indicator of community "health" (much as other socioeconomic and pollutant index measures are used), as a tool for educators to better develop the content (and better target the audience) for their drug-abuse programs, as well as a tool for law enforcement to better understand the types and quantities of drugs it needs to be aware of in individual communities. Finally, with an objective of promoting a national/local discourse, sewage-influent data could be obtained by (or used by) schools, health care/social workers, law enforcement, courts, public health professionals, and public officials, all of whom would then have the ability to compare usage (types, quantities, consumption patterns, trends) of drugs between and among communities. Usage patterns may vary dramatically not just from country to country, but also region to region, subculture to subculture.
Benefits to the public and law enforcement include (1) dramatically improving public awareness of (i) how the individual can have a direct impact on the environment and (ii) the magnitude of drug usage, and (2) promoting the use of "home" drug testing kits by schools to perform nationwide environmental sewage monitoring - serving as an educational exercise in both environmental and social sciences. If such data acquired from sewage treatment plant effluent or raw sewage effluent were uploaded to a nationwide web-based database, it could greatly assist environmental scientists in determining the frequency of occurrence, extent, and magnitude of drugs in the aquatic environment. The analogous data from sewage treatment plant influent could possibly offer drug and health enforcement organizations a new tool in the early detection of new drug usage activities. A nationwide program would provide perspective not just for the national prevalence of illicit drug use/manufacturing, but also on how each metropolitan area of the U.S. compares and differs with respect to types and amounts of drugs used, and would serve as a sentinel system for new trends in usage of "emerging" drugs as well as current illicit drugs. Numerous other uses can be envisioned, including elucidation of status, fluctuations, and trends, the latter of which could be used in part to help verify the effectiveness of drug prevention, interdiction, or enforcement programs.
National Drug-Use Surveys: There are numerous periodic drug-use surveys conducted at local, state, and national levels. The primary source of nationwide information in the U.S. for use/abuse of drugs has been the surveys conducted by the Substance Abuse and Mental Health Services Administration (SAMHSA) (e.g., see their most recent report: "1999 National Household Survey on Drug Abuse," released 31 August 2000, at: http://www.samhsa.gov/oas/household99.htm). Since 1971, these surveys have resulted in estimates of the prevalence and incidence of illicit drug use across the U.S. Like all surveys, the resulting statistically derived estimates have numerous caveats and shortcomings. Relying largely on population self-administration, these surveys can be costly, and they are subject to a plethora of biases, resulting from sampling error and non-response/reporting errors. The latter derive from the respondents' truthfulness and accuracy of memory, fear of self-reporting, and under-reporting or inability to report. The former includes an inability to capture heavy drug users (a small sub-population that may be responsible for a disproportionately large portion of environmental discharge of illicit drugs, especially via terrestrial run-off), exclusion of youths under 12 years old, and economic status (e.g., exclusion of the homeless from surveys).
The second SAMHSA data collection program is administered by the Office of Applied Studies (OAS). Since 1988, the Drug Abuse Warning Network (DAWN) data have been collected from a representative sample of eligible hospitals located throughout the U.S. This survey captures data from emergency room admissions where the subject's condition has been induced by or is related to the "use of an illegal drug or the nonmedical use of a legal drug." These DAWN data therefore "do not measure prevalence of drug use in the population." DAWN reports can be found at: http://www.samhsa.gov/oas/p0000018.htm. Much of SAMHSA's materials can also be found via the National Clearinghouse for Alcohol and Drug Information web site "Prevention Online" (PREVLINE), available at: http://www.health.org/.
The proposed new sewage monitoring program could be used to augment these surveys and possibly serve to "calibrate" or quality-assure the traditional survey results. Monitoring would provide real-time data, which would fulfill the need for identifying new trends in emerging drug use (as well as detecting trends in existing use). Existing surveys are merely retrospective, and therefore their timeliness lags current use by one or more years (e.g., see http://www.samhsa.gov/oas/household99.htm). An extensive discussion and survey of drug trend detection can be found in Griffiths et al. (5).
Environmental Fate of Anabolic Androgenic Steroids - Special Significance: The disposition and fate of sex steroids (both natural and synthetic) in the aquatic environment has captured a large portion of the attention cast on the overall issue of medicinal drugs in the environment as pertaining to "endocrine disruptors" (see: "Environmental Estrogens and other Hormones" at: http://www.tmc.tulane.edu/ecme/eehome; NAS report "Hormonally Active Agents in the Environment" at: http://www.nap.edu/books/0309064198/html). This debate has focused, however, on the estrogenic sex steroids at the exclusion of the hundreds of commercially available and illicit anabolic androgenic steroids (related to androgens, most being derivatives of testosterone, and which promote skeletal muscle growth coupled with male sexual characteristics). These steroids of abuse have experienced escalating use, especially among athletes and, more widely and recently, youths. Even though some of the testosterone derivatives (e.g., esters) have medicinal uses as prescription drugs (primarily for male androgen-replacement therapy), the non-prescription abusive consumption of others can be at a significantly higher (and sustained) frequency and duration and at several orders of magnitude higher doses (and in multiple combinations - referred to as "stacking"). These high doses, coupled with their acting directly at the endocrine level, could pose particular concern with respect to the health of aquatic organisms that may suffer exposures; the documented side effects in both human sexes are numerous and profound.
While it has been established that sub-ppb levels of estrogenic steroids in sewage effluent can affect aquatic and marine biota, practically no work has been performed on low-level exposure to androgens. Androgenic steroid-spiked feeds have been long-used, however, for growth enhancement and for forcing desirable sex-ratios (via sex-inversion) in aquacultured fin fish. With the issue of potential androgenic steroid release to the environment via aquaculture aside, the published aquaculture literature clearly documents that androgenic steroids (such as could be expected from abuse of illicit anabolic steroids) have the potential at low levels (ppb) to elicit aquatic effects (e.g., skewed sex-ratios), especially in light of the fact that short-term, brief immersion of fish fry in androgenic steroid-spiked water (17-methyltestosterone and 17-methyldihydrotestosterone) can induce sex inversion (6); aromatizable androgens, such as 17-methyltestosterone, can also lead to "paradoxical feminization". Although the short-term concentrations required for total sex inversion in fish are orders of magnitude higher than what could be expected in sewage, it begs the question as to what other possible effects (e.g., tumorigenic/teratogenic) could occur from continual exposures to androgens from sewage effluent, especially during critical developmental milestones. Comprehensive listings of steroids can be found in catalogs from commercial suppliers of analytical standard reference materials, such as "Steraloids Online" (http://www.steraloids.com). In addition to the completely uninvestigated burden of illicit androgens in the environment (primarily as a result of use by athletes and bodybuilders), new routes of delivery for testosterone (primarily dermal) are leading to exponentially increasing use of testosterone in replacement therapy.
Caveats: The proposed approach for back-calculating drug use is subject to the following limitations and biases, among others. Septic leach fields would not be incorporated in a collective measure (leading to underestimation of communitywide capita use). Disposal to domestic sewage of unusable clandestine manufactured product(s) or product hurriedly disposed of during drug raids - but not to landfills - would lead to further bias (but could be ascribed as such if detected as a transient spike); disposal from clandestine labs can occur by numerous routes -- many terrestrial (7). As mentioned previously, unless surrogate metabolites are monitored, the amounts contributed by use may not be distinguishable from those contributed by manufacturing/disposal. Further limitations to the proposed approach include the diminished ability (except as available through GIS or demographic means) to assign calculated usage according to age, gender, education, race/ethnicity, or employment.
The two major limitations to successfully analyzing sewage influent for drugs are (1) the need to acquire time-integrated samples as opposed to discrete "grab" samples to avoid bias caused by episodic fluctuations in concentrations (e.g., highest drug concentrations in urine are during the day's first void) or flow rates and (2) the necessity of suitable pre-concentration methods, especially for polar analytes, being that drug concentrations in the influent will be reduced orders of magnitude from when they are excreted (by way of microbial degradation, dilution, and sorption to particulates). Both of these needs have been addressed for polar analytes in a newly proposed sampling/enrichment approach (Polar Organic Chemical Integrative Sampler, POCIS), a methodology that deserves further attention (8). Known sewage marker chemicals of human chemical consumption (such as caffeine or nicotine) or activity (e.g., coprostanol, a major fecal sterol, or the major urinary product, creatinine) should also be monitored partly as an internal form of quality assurance but also as a means of providing normalized data -- especially useful for comparison across sewage treatment plants (and therefore across communities).
The levels of drugs that can easily be measured in urine are reflected by the confirmatory cut-off concentrations for those drugs subject to DOT screening/confirmation. These range from 15 ng/mL (15 ppb) for 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid to 500 ng/mL for amphetamine (and 2,000 ng/mL [2 ppm] for morphine). While these levels are orders of magnitude higher than would occur in sewage influent, they are also considerably higher than method detection limits for conventional GC/MS and immunoassay. Once the target analytes (either the parent drug or a surrogate metabolite) can be sufficiently preconcentrated to meet analytical detection limits, analysis can proceed by any of a variety of approaches, ranging from mass spectrometric to immunochemical. Analytical standard solutions (including deuterated standards) of most DEA Schedule I-IV Controlled Substances are readily available commercially without a DEA licence (e.g., see: "The United States Pharmacopeia" at: http://www.usp.org/; "Radian Services Analytical Reference Materials Group" at: http://www.radian.com/html/services/arm/genforen.htm; (defunct; changed to: http://www.cerilliant.com) "The Promochem Group" at: http://www.lgcpromochem.com/home/home_en.aspx). Whatever approaches are eventually developed for definitive analysis, a nationwide "volunteer" monitoring network would incur lower cost.
Finally, it must be noted that the metabolism of certain illicit drugs can yield other drugs (some of which may even be legal). For example, both isomers of amphetamine and methamphetamine can result from the metabolism of other drugs (e.g., see 9). If amphetamine were monitored in sewage, its origin would be nebulous - its occurrence could not be ascribed solely, for example, to the use of methamphetamine being that there are numerous amphetamine-derivative drugs; see Meatherall (10) for an example approach to GC/MS chiral determination of methamphetamine. Many drugs yield a plethora of metabolites, a fact that holds the potential to confound any monitoring plan if not properly recognized and accounted for.
Much like readily accessible weather data, it is anticipated that any real-time illicit drug data generated from local sewage treatment plants would prove of keen interest to the public. These data would perhaps prove more popular than any other measure of environmental pollution. It is also anticipated that the mass media would be anxious to broadcast the data through print, websites, television, and radio, or any other means already proposed or used under the EPA EMPACT program (http://www.epa.gov/empact/). A nationwide web-based database of collected data could prove extremely useful.
The removal efficiencies of drugs from both waste treatment and water-upgrade facilities are known to vary according to the technologies employed as well as from plant to plant. Depending on the occurrence concentrations and the effectiveness of waste treatment and drinking water treatment technologies (if any) for a particular locale, drugs could be searched for in domestic drinking waters. These concentrations would prove to be very low (ppt -- ng/L -- and below). While the presence of even minute quantities of any type of parent drug or bioactive metabolite in drinking water (which provides a source of continual exposure for people) has totally unknown consequences for human health (especially fetuses, infants, children, metabolically impaired/abnormal individuals, and other at-risk sub-populations), such occurrences would serve as the ultimate reminder that the linkage between wastewater and human reuse can be very direct.
In Bruce Alberts' 2000 President's Address to the National Academy of Sciences ("Science and Human Needs"), he addresses in part "the responsibilities of scientists" with the following words, which lend further, and final, perspective on the idea presented in this chapter (11).
"... (B)ecause political will is often short term, and misinformation about science abounds, we scientists ourselves must become much more engaged in the everyday life of our governments and our communities." As 'civic scientists', "...in the 21st century, science and scientists will be judged on how well they help solve local and world problems, not only on how well they generate new knowledge. The impact of our research is everywhere, and we must step out and make sure that our work is understood and appropriately used by the world. ...We also need to be explicit about what is not known, and be clear about the questions that science cannot answer."
Daughton, C.G.; Ternes, T.A. "Pharmaceuticals and personal care products in the environment: agents of subtle change?" Environ. Health Perspect. 1999, 107(suppl 6), 907-938.
Daughton, C.G. "Pharmaceuticals and Personal Care Products in the Environment: Overarching Issues and Overview," in Pharmaceuticals and Personal Care Products in the Environment: Scientific and Regulatory Issues; Daughton, C.G. and Jones-Lepp, T. (eds.), Symposium Series 791; American Chemical Society: Washington, D.C., 2001 (see introductory Chapter in this book).
Snyder, S. Kelly, K.L.; Grange, A.; Sovocool, G.W.; Synder, E.; Giesy. J.P. "Pharmaceuticals and Personal Care Products in the Waters of Lake Mead, Nevada," in Pharmaceuticals and Personal Care Products in the Environment: Scientific and Regulatory Issues; Daughton, C.G. and Jones-Lepp, T. (eds.), Symposium Series 791; American Chemical Society: Washington, D.C., 2001 (see chapter in this book).
Möhle, E.; Metzger, J. "Drugs in Municipal Sewage Effluents -- Screening and Biodegradation Studies," in Pharmaceuticals and Personal Care Products in the Environment: Scientific and Regulatory Issues; Daughton, C.G. and Jones-Lepp, T. (eds.), Symposium Series 791; American Chemical Society: Washington, D.C., 2001 (see chapter in this book).
Griffiths P.; Vingoe L.; Hunt N.; Mounteney J.; Hartnoll R. "Drug information systems, early warning, and new drug trends: Can drug monitoring systems become more sensitive to emerging trends in drug consumption?" Substance Use Misuse 2000, 35(6-8), 811-844.
Gale, W.L; Fitzpatrick, M.S.; Lucero, M.; Contreras-Sánchez, W.M.; Schreck, C.B. "Masculinization of Nile tilapia (Oreochromis niloticus) by immersion in androgens," Aquaculture 1999, 178(3-4), 349-357.
The Joint Federal Task Force of the Drug Enforcement Administration, the U.S. Environmental Protection Agency, the U.S. Coast Guard "Guidelines for the Cleanup of Clandestine Drug Laboratories," EPA540P90005, March 1990 (43 pp.).
Alvarez, D.A.; Petty, J.D.; Huckins, J.N. "Development of an Integrative Sampler for Polar Organic Chemicals in Water," paper #4, presented at the 219th National Meeting of the American Chemical Society, San Francisco, CA, 27 March 2000 (published in "Issues in the Analysis of Environmental Endocrine Disruptors", Preprints of Extended Abstracts, vol. 40(1), pp. 71-74, 2000).
Kraemer, T.; Theis, G.S.; Weber, A.A.; Maurer, H.H. "Studies on the metabolism and toxicological detection of the amphetamine-like anorectic fenproporex in human urine by gas chromatography-mass spectrometry and fluorescence polarization immunoassay," J. Chromatogr. B: Biomed. Sci. Applicat. 2000, 738(1), 107-118.
Meatherall, R. "Rapid GC-MS confirmation of urinary amphetamine and methamphetamine as their propylchloroformate derivatives," J. Anal. Toxicol., 1995, 19(5), 316-322.
Alberts, B. "Science and Human Needs," 2000 President's Address to the National Academy of Sciences, 137th Annual Meeting, Washington, D.C., 1 May 2000 (available at: http://www.nas.edu).
ACKNOWLEDGMENTS: The author thanks the following people for taking their valuable time to provide helpful review of both technical and policy aspects of this manuscript: James Quackenboss, Andrew Grange, Tammy Jones-Lepp, John Lyon, and Gareth Pearson (U.S. EPA's National Exposure Research Laboratory), Alan Gallaspy (Las Vegas Metropolitan Police Department Criminalistics/ Forensics Laboratory), and the American Chemical Society's anonymous reviewers, all of whom contributed to improving the quality of the manuscript.
NOTICE: The U.S. Environmental Protection Agency (EPA), through its Office of Research and Development (ORD), funded and performed the research described. This manuscript has been subjected to the EPA's peer and administrative review and has been approved for publication. Mention of trade names or commercial products does not constitute endorsement or recommendation by EPA for use.
NOTE: This chapter is reprinted with permission from the American Chemical Society. It can be cited as follows:
Daughton, C.G. "Illicit Drugs in Municipal Sewage: [also note: Post Publication Commentary. http://www.epa.gov/nerlesd1/chemistry/pharma/book-post.htm] Proposed New Non-Intrusive Tool to Heighten Public Awareness of Societal Use of Illicit/Abused Drugs and Their Potential for Ecological Consequences," in Pharmaceuticals and Personal Care Products in the Environment: Scientific and Regulatory Issues, Daughton, C.G. and Jones-Lepp, T. (eds.), Symposium Series 791; American Chemical Society: Washington, D.C., 2001, pp. 348-364.
[Posted (abstracted/excerpted) with permission from the American Chemical Society: Daughton, C.G.; Jones-Lepp, T.L. (eds.) Pharmaceuticals and Personal Care Products in the Environment: Scientific and Regulatory Issues, Symposium Series 791; American Chemical Society: Washington, D.C., 2001. Copyright 2001 American Chemical Society]