# Presentation: 525950

## Pharmaceuticals and Personal Care Products (PPCPs) as Environmental Pollutants Pollution from Personal Actions 

**Christian G. Daughton**, Ph.D.
*Chief, Environmental Chemistry Branch*
- Environmental Sciences Division
- National Exposure Research Laboratory
- Office of Research and Development
- Environmental Protection Agency
- Las Vegas, Nevada 89119
- daughton.christian@epa.gov

## Slide 2

## U.S. EPA Notice

- The U.S. Environmental Protection Agency (EPA), through its Office of Research and Development (ORD), funded this research and approved the materials that formed the basis for this presentation.                While the text for this presentation               has been peer reviewed by EPA, the oral narrative has not.

## Wealth of other materials and links to most of the ongoing work relevant to this topic are available at the U.S. EPA’s PPCPs Web Site:

**http://www.epa.gov/nerlesd1/**
**chemistry/pharma/index.htm**

## Slide 5

## “Disclaimers”

**PPCPs entering the environment: **
**End-Use vs. Manufacturing**
-  Focus of this discussion is primarily on PPCPs originating from _**end-use**_ rather than from manufacturing.
-  Emphasis is on use/disposal of PPCPs as originating primarily from activities/actions of individuals and to a lesser degree from hospitals and industry – not from the PPCP manufacturing sector (whose waste streams are much better defined, confined, and controlled/controllable).

*continued -*

## Clarification of Acronyms

- Pharmaceuticals & Personal Care Products: “**PPCPs**”
- Endocrine Disrupting Compounds:
**“****EDCs”**†
- †A plethora of other terms have often been used interchangeably with EDCs (rightly and wrongly). These include: environmental estrogens, endocrine-disruptors, endocrine-modulators, estrogenic mimics, ecoestrogens, environmental hormones, xenoestrogens, hormone-related toxicants, hormonally active agents (HAAs), endocrine-active chemicals (EACs), endocrine active substances (EASs), phytoestrogens (a naturally occurring subset). [Note: estrogens represent but one mode of action – others include androgens]

## EDCs vs. PPCPs

**PPCPs vs. EDCs               PPCPs  ********  ****EDCs**
-  PPCPs and EDCs are **not** synonymous — they are intersecting sets.
-  Must avoid confusion regarding their relationship.
-  Only a small subset of PPCPs are known/suspected of being _**direct-acting**_ EDCs (e.g., synthetic steroids); toxicological concerns usually differ. EDCs comprise members from many disparate chemical classes.

## Endocrine Modulators and Homeostasis

| Hormones: secreted from endocrine sources and some neurons; transported by blood to remote targets (nuclear receptors). Regulate gene transcription (e.g., sex steroids). Slow-acting. | 
continuum

biochemical agents for maintaining cellular, organ, and organism HOMEOSTASIS
and controlling 
physiological processes | Neurotransmitters: secreted from neurons and act on immediately adjacent target cells for a short time (e.g., acetylcholine). |
| --- | --- | --- |
| Pheromones: secreted by exocrine glands; targets outside body; integrate social activities between animals.  |  | Local signaling molecules: secreted from cells of many different tissues; act locally; quickly degraded.  |
| Endocrine Physiology | Neuroendocrinology | Neurophysiology |

**Endocrine Modulators and Homeostasis**

- C.D. Daughton, 21 November 2001
- U.S. EPA-Las Vegas

## EDCs versus PPCPs

| Hormones: secreted from endocrine sources and some neurons; transported by blood to remote targets (nuclear receptors). Regulate gene transcription (e.g., sex steroids). Slow-acting. | 
continuum

biochemical agents for maintaining cellular, organ, and organism HOMEOSTASIS
and controlling 
physiological processes | Neurotransmitters: secreted from neurons and act on immediately adjacent target cells for a short time (e.g., acetylcholine). |
| --- | --- | --- |
| Pheromones: secreted by exocrine glands; targets outside body; integrate social activities between animals.  |  | Local signaling molecules: secreted from cells of many different tissues; act locally; quickly degraded.  |
| EDCs | preponderance of action | PPCPs |

**EDCs versus PPCPs**

- C.D. Daughton, 21 November 2001
- U.S. EPA-Las Vegas

##  Identification of potential (future) environmental concerns: anticipatory research; emerging issues. Identify pivotal sources of uncertainty that affect risk estimates.
 Proactive vs. Reactive — Pollution prevention vs. remediation/restoration: Identify and foster investigation of “hidden” or potential environmental issues/concerns before they become critical ecological or human health problems.
 Foster interdisciplinary research & collaboration: Catalyze research by academe, private sector, government.
 Ruling-in/ruling-out vs. Uninformed rules: Provide bases for informed decisions. Ensure that science leads eventual decisions for guidance or to regulate/not regulate.

** ****Proactive vs. Reactive**** — Pollution prevention vs. remediation/restoration**: Identify and foster investigation of “hidden” or potential environmental issues/concerns before they become critical ecological or human health problems.
-  **Foster interdisciplinary research & collaboration****: **Catalyze research by academe, private sector, government.
-  **Ruling-in/ruling-out vs. Uninformed rules****: **Provide bases for informed decisions. Ensure that science leads eventual decisions for guidance or to regulate/not regulate.

**PPCP-Relevant Goals for the U.S. EPA’s*****Office of Research and Development***

## “PBTs”, “POPs”, “BCCs”:Only one part of the risk puzzle?

- Since the 1970s, the impact of chemical pollution has focused almost exclusively on conventional “priority pollutants”†, especially on those collectively referred to as “persistent, bioaccumulative, toxic” (PBT) pollutants, “persistent organic pollutants” (POPs), or “bioaccumulative chemicals of concern” (BCCs).
- The “dirty dozen” is a ubiquitous, notorious subset of these, comprising highly halogenated organics (e.g., DDT, PCBs).
**The conventional priority pollutants, however, are only one piece of the larger risk puzzle.**
- † it is important to recognize that the current “lists” of priority pollutants were primarily established in the 1970's in large part for expediency — that is, they could be measured with off-the-shelf chemical analysis technology.  Priority pollutants were NOT necessarily selected solely on the basis of risk.

## Slide 13

## Slide 14

## Slide 15

## Prevalence of Xenobiotic Occurrence: Some Possible Generalizations Regarding Ubiquity

-  The lower the concentration, the higher the probability of larger numbers of distinct chemicals occurring
-  **Exponentially more types of chemicals occur at exponentially lower concentrations** (*does the distribution of chemical types versus their concentrations follow a power law, as shown for such a wide array of other phenomenon?* e.g., see: M. Buchanan "Ubiquity", Crown Publishers 2000)
-  At the very lowest concentrations (zeptomolar to yoctomolar, zM - yM), the off-the-cuff truism may apply:
- "***Everything can be found everywhere***"

*continued* -

## Prevalence/Distribution of Xenobiotic Occurrence

**Prevalence/Distribution of Xenobiotic Occurrence**

## Einstein on:Environmental Monitoring

- “Not everything that can be counted counts, and not everything that counts can be counted.“    (oft attributed to Albert Einstein)
-   *corollary for environmental monitoring*
**Not everything that can be measured is worth measuring, and not everything worth measuring is measurable.**

## further truisms regardingEnvironmental Monitoring

-  What one finds usually depends on what one aims to search for.
-  Only those compounds targeted for monitoring have the potential for being identified and quantified.
-  Those compounds not targeted will elude detection.
-  The spectrum of pollutants identified in a sample represent but a portion of those present and they are of unknown overall risk significance.

## Toxicity of Complex Environmental Mixtures: Major Unanswered Question

- Is the overall toxicity (or the spectrum of unique toxic effects) of a complex mixture caused by few or many chemical constituents?
- And do these constituents comprise a small or large fraction of the total dissolved mass?

## “Emerging” Risks

- It is reasonable to surmise that the occurrence of PPCPs in waters is not a new phenomenon. It has only become more widely evident in the last decade because continually improving chemical analysis methodologies have lowered the limits of detection for a wide array of xenobiotics in environmental matrices.** ****There is no reason to believe that PPCPs have not existed in the environment for as long as they have been used commercially.**

## PPCPs as Environmental Pollutants?

-  PPCPs are a diverse group of chemicals comprising all human and veterinary drugs (available by prescription or over-the-counter; including the new genre of “biologics”), diagnostic agents (e.g., X-ray contrast media), “nutraceuticals” (bioactive food supplements such as huperzine A), and other consumer chemicals, such as fragrances (e.g., musks) and sun-screen agents (e.g., methylbenzylidene camphor); also included are “excipients” (so-called “inert” ingredients used in PPCP manufacturing and formulation).
-  Drugs differ from agrochemicals in that they often have multiple functional groups (many are amphiphilic) and usually have lower effective doses. This complicates fate/transport modeling and lends an extra dimension to the analytical techniques required for monitoring. Also designed for use by/for the individual consumer.
-  In contrast to the conventional PBTs, most PPCPs are neither bioaccumulative nor volatile; some, such as the musks, however, do indeed fulfill the criteria for PBTs.

## Inter-Connectedness of Humans and the Environment

-  Occurrence of PPCPs in the environment mirrors the intimate, inseparable, and immediate connection between the actions and activities of individuals and their environment.
-  PPCPs owe their origins in the environment to their worldwide, universal, frequent, and highly dispersed but cumulative usage by multitudes of individuals.

## Overview: Pharmaceuticalsin the Environment

-  Certain pharmaceutically active compounds (e.g., caffeine, aspirin, nicotine) have been known for over 20 years to occur in the environment.
-  Environmental occurrence primarily resulting from treated and untreated sewage effluent.
-  Only more recently has a larger picture emerged —  numerous PPCPs can occur (albeit at very low concentrations).
-  Prior discovery delayed primarily by limitations in analytical environmental chemistry (ultra-trace enrichment and detection).
-  Domestic sewage is a major source — not just hospital sewage. CAFOs are a major source of antibiotics.
*	**continued -*

## Origins of PPCPs in the Environment

-  Portions of most ingested drugs are excreted in varying unmetabolized amounts (and undissolved states, primarily because of protection by excipients) primarily via the urine and feces.
-  Other portions sometimes yield metabolites that are still bioactive.  Still other portions are excreted as conjugates.
-  Free excreted drugs and derivatives can escape degradation in municipal sewage treatment facilities (removal efficiency is a function of the drug’s structure and treatment technology employed); the conjugates can be hydrolyzed back to the free parent drug.
-  Un-degraded molecules are then discharged to receiving surface waters or find their way to ground waters, e.g., leaching, recharge.
- 					*continued -*

## Overview: Pharmaceuticalsin the Environment

-  Continual input of PPCPs to aquatic environment via sewage can impart a persistent quality to those compounds that otherwise possess no inherent environmental stability.
-  The full extent, magnitude, and ramifications of their presence in the aquatic environment are largely unknown.
-  Vast majority of all ecological monitoring studies to date have been performed in Europe (with exception of USGS).
-  Use/release of **antibiotics** and natural/synthetic **steroids** to the environment has generated most of the controversy to date, **but a plethora of other PPCPs have yet to be examined**. Scope of overall issue is ill-defined.
- 			     *continued* -

## Overview: Pharmaceuticalsin the Environment

-  Toxicological significance for both humans and ecological exposure to multiple chemicals at trace concentrations (ppb-ppt) for long durations is poorly understood.
-  If PPCPs eventually prove to be an environmental concern, it is unknown whether sewage treatment facilities could be cost-effectively modified to reduce emissions.
-  Source control (aimed at both disposal and medical practices) may prove more effective (“environmental stewardship” programs).
-  Focus should be on proper and sufficient science for establishing occurrence, exposure, susceptibility/effects, so that sound decisions can be made regarding human and ecological health.
- - *concluded* -

## Slide 28

## Origins of PPCPs in the Environment

-  Other potential routes to the environment include leaching from municipal landfills, runoff from confined animal feeding operations (CAFOs) and medicated pet excreta, loss from aquaculture, spray-drift from agriculture, direct discharge of raw sewage (storm overflow events & residential “straight piping”), sewage discharge from cruise ships (millions of passengers per year), oral contraceptives used as soil amendment and plant growth tonic (urban legend), and transgenic production of proteinaceous therapeutics by genetically altered plants (aka “molecular farming” — “biopharming”).
-  Direct discharge to the environment also occurs via dislodgement/washing of externally applied PPCPs.
*- continued*

## Unanticipated Routes of Exposure

-  Given that the predominate route of release of drugs to the environment is probably via effluents from municipal sewage and CAFOs, the major route of inadvertent ecological and human exposure is via water (and secondarily sludges and sediments).
-  Despite this generalization, additional routes of release and exposure could prove to be highly significant in certain local situations. One such route of exposure to drugs rarely considered is inhalation (especially since few drugs are volatile).
-  Despite low volatility, sorption of drugs to respirable particulates could serve as a route of exposure.
-  For example, dust from confined animal feeding operations where drugs are used to supplement feed and administered directly to animals for therapeutic and prophylactic purposes.  Pig house dust can originate from feed (e.g., antibiotics), bedding, feces, and shedding. In dust samples from a 20-year period, five antibiotics were found in combined concentrations up to 12.5 mg/kg dust.

*Source: *Antibiotics in dust originating from a pig fattening farm: a new source of health hazard for farmers? Hamscher G, Pawelzick HT, Sczesny S, Nau H, and Hartung J. 2003. *Environ. Health Perspect*. (on-line 18 June 2003).

**Notes:**
Diagnose before prescribing

## 		Available: http://www.epa.gov/nerlesd1/chemistry/pharma/image/drawing.pdf

- 		**Available: http://www.epa.gov/nerlesd1/chemistry/pharma/image/drawing.pdf**

## Nationwide studies relevant to potential for PPCP occurrence and distribution in the environment

-   1999-2000: USGS implemented **first-ever U.S. national ****	****	****	****	****reconnaissance of “emerging pollutants” in waters**	- objective was to establish baseline occurrence data	- included were some commonly used PPCPs	- data collected from 142 streams, 55 wells, 7 effluents (in 36 states)	- findings published in 15 March 2002 issue of:
- 		 _***Environmental Science and Technology***_
- 	- detailed information available at:												http://toxics.usgs.gov/highlights/whatsin.html
-   2001: **first-ever study published on geographic variation** (across 		U.S.) **of prescription drug usage**:
***	******	***_***Prescription Drug Atlas***_ (Express Scripts, 2001), available at: http://www.express-scripts.com/other/news_views/outcomes_research/atlas2002/atlas_ex_sum.htm

## Significance of the USGS Monitoring Study

-  The PPCPs documented in the USGS study to occur in US surface waters probably represent but a fraction of all those that actually occur.
-  Whether the potential for health effects from this subset of PPCPs is eventually demonstrated is in large part irrelevant.
-  More importantly, these occurrence data demonstrate the potential for ANY consumer-use chemical to enter the environment, and thereby **give us the advance opportunity to be watchful regarding the future introduction to commerce of drugs with new mechanisms of action and ever-increasing biochemical potencies.**

## Drugs Having Double Uses:Medicinals and Pest-Control Agents(alternative sources for introduction to the environment)

- Some chemicals serve double duty as both existing/experimental drugs and as pest-control agents. While this shows the broad utility of certain drugs, it also poses the possibility that these alternative uses serve as additional sources for their introduction to the environment. The potential significance of these alternative uses as sources for environmental release has never been explored. *Examples include:*
** ****4-aminopyridine**: experimental multiple sclerosis drug and an avicide** **
** ****warfarin**: anticoagulant and a rat poison
-  **triclosan**: general biocide and gingivitis agent used in toothpaste
-  **azacholesterols**: antilipidemic drugs and avian/rodent reproductive 	inhibitors [e.g., Ornitrol]
-  certain **antibiotics**: used for orchard pathogens
-  **acetaminophen**: an analgesic and useful for control of Brown Tree snake
-  **caffeine: **stimulant and approved for control of *coqui *frog in Hawaii; also repels and kills snails and slugs at concentrations exceeding 0.5%.

## Caffeine for control of frog pests

- U.S. EPA approved (27 Sept 2001) specific exemption from FIFRA allowing use of caffeine to control *coqui* frogs in Hawaii.
- Exemption allows application of 100-200 pounds per acre (max total 1,200 lbs/year).
- In absence of natural predators, *coqui* frog can reproduce to high densities (10,000/acre).

- Out-compete native birds by massive consumption of insects.
- Chirping frequency is extremely piecing and annoying (upwards of 100 db).

- single

- chorus

## Acetaminophen for control of Brown Tree snakes

- Brown Tree snakes (*Boiga irregularis* ), native to eastern
- Indonesia, become invasive pests on Guam starting
- in the 1940's/1950's.
- Without natural predators, the Brown Tree snake's
- population in Guam is estimated at upwards of 15,000
- per square mile.
- Have decimated certain native bird, bat, and reptile populations, as well as caused extensive economic losses (agriculture, pets, human bites, electric grid outages/repairs).
- No safe and effective chemical-controls until discovery by USDA that **acetaminophen (80 mg) will effectively kill Brown Tree snakes within 3 days** of even a brief exposure to baited, dead mice.
- Acute effects of larger doses of acetaminophen on local non-target species have not been detected.
- [see:  J. J. Johnston et al. "Risk Assessment of an Acetaminophen Baiting
- Program for Chemical Control of Brown Tree Snakes on Guam: Evaluation
- of Baits, Snake Residues, and Potential Primary and Secondary Hazards,"
*Environ. Sci. Technol*. 2002, 36(17):3827-3833; also: _[http://www.aphis.](http://www.iconbazaar.com/molecules/drugs/mood_elevators/prozac.html#return)__[usda](http://www.iconbazaar.com/molecules/drugs/mood_elevators/prozac.html#return)__[.](http://www.iconbazaar.com/molecules/drugs/mood_elevators/prozac.html#return)__[gov](http://www.iconbazaar.com/molecules/drugs/mood_elevators/prozac.html#return)__[/](http://www.iconbazaar.com/molecules/drugs/mood_elevators/prozac.html#return)__[lpa](http://www.iconbazaar.com/molecules/drugs/mood_elevators/prozac.html#return)__[/inside_aphis/features10d.html](http://www.iconbazaar.com/molecules/drugs/mood_elevators/prozac.html#return)_].

## Decline of Gyps spp. Vultures in Pakistan & India – Possible Link with Diclofenac

-  At the *6th World Conference on Birds of Prey and Owls *(Budapest, Hungary, 18-23 May 2003), Prof. J. Lindsay Oaks (Washington State University) presented evidence that (at least in Pakistan) the die-offs may have resulted from diclofenac poisoning.
-  Diclofenac, although primarily a human NSAID, is used in veterinary medicine in certain countries. In India, diclofenac is used for cattle, whose carcasses are a major food source for G*yps*.

-  Beginning in the early 1990s, vultures (especially white-backed vultures such as *Gyps bengalensis*) have experienced dramatic population declines (as great as 95%) in Southern Asia – particularly India and spreading to Pakistan and Nepal.
-  Various hypothesized causes have ranged from pathogens to pesticides.  The causative agent(s) result in acute renal failure (manifested as visceral gout from accumulation of uric acid), leading to death of the breeding population.

-  Diclofenac seems to be selectively toxic to *Gyps *spp. versus other carrion-eating raptors.
-  Health hazards grow from the accumulation of uneaten cattle carcasses (as well as human), which now serve to attract growing packs of dangerous feral dogs, which can also carry rabies.

## PPCPs in Receiving Waters:A Global, Ubiquitous Process with Unique Local Expression

-  Important to recognize that ALL municipal sewage, regardless of location, will contain PPCPs.  Issue is not unique to any particular municipal area.
-  Each geographic area will differ only with respect to the types, quantities, and relative
- abundances of individual PPCPs.

## PPCPs in Receiving Waters

-  Occurrence differences in:
**	**_**raw sewage**_ are a function of: **(i)** local prescribing and usage customs, **(ii)** confluence of hospitals, **(iii)** state policies and customs regarding disposal of unused PPCPs, and **(iv)** local manufacture and usage of illicit and abused drugs.
** ****	**_**surface and ground waters**_ are a function of:
**(i)** whether treatment technologies are employed (straightpiping, malfunctioning septic systems, overflow events), **(ii)** types of treatment technologies employed for sewage, potable water, or reinjection waters, and
**(iii)** local/seasonal fluctuations in biophysicochemical transformation potential (e.g., biodegradation, photolysis).
** *****- concluded -***

## Sources of Raw Sewage in U.S.released to streams, lakes, estuaries, oceans, groundwater

** ****combined sewer overflows** (CSOs) = **4.5 X 10****12**** L/year**
-  [CSOs handle rainwater runoff, domestic sewage, and industrial wastewater, and are designed to discharge untreated sewage during adverse storm events] †
- † _[http://cfpub.epa.gov/npdes/home.cfm?program_id=5](http://www.aphis.usda.gov/lpa/inside_aphis/features10d.html)_
** ****sanitary sewer overflows** (SSOs) [severe weather, system malfunction, improper system operation/maintenance]
** ****leakage** from sewage transport infrastructure [sewer pipe cracks caused by tree roots and defective/collapsed pipes]
-  failing **septic systems**  [1990 U.S. census showed ca 25% of all housing units use on-site wastewater handling system (e.g., septic system); see "SepticStats: An Overview", Graham Knowles, 1998: _[http://www.nesc.wvu.edu/images/SepticStat.pdf](http://www.rtc-sra.org/)_. In certain locales, the percentage is much higher.
-  unpermitted **privies**
** ****straight-piping**

*continued -*

## Drinking & Waste Water Infrastructure Needs

***2001 Report Card for America's Infrastructure***
- American Society of Civil Engineers (ASCE)
- (http://www.asce.org/reportcard/index.cfm?reaction=full)
- Nationwide grades of “D” assigned for both drinking water and wastewater infrastructures
- (http://www.asce.org/reportcard/index.cfm?reaction=full&page=2)
- Over $20 billion dollars annually is the estimated need for rectifying the nation’s degenerating water/waste infrastructures:
- “The nation's 54,000 drinking water systems face an annual shortfall of $11 billion needed to replace facilities that are nearing the end of their useful life and to comply with federal water regulations. Non-point source pollution remains the most significant threat to water quality.”
- “The nation's 16,000 wastewater systems face enormous needs. Some sewer systems are 100 years old. Currently, there is a $12 billion annual shortfall in funding for infrastructure needs in this category; however, federal funding has remained flat for a decade. More than one-third of U.S. surface waters do not meet water quality standards.”

## Subtle (currently unrecognized) Effects:  a Troubling Scenario? 

-  Uses for which PPCPs were designed differ radically from those of industrial and agro-chemicals.
-  Intended biological targets (receptors) are numerous and frequently exquisitely specific and sensitive.
-  Intended/unintended receptors of exposure and effects can differ greatly from those of currently regulated pollutants.
-  Receptors in non-target species could differ from those in humans. 				c*ontinued -*

## Subtle (currently unrecognized) Effects:

*some examples*:
-  Profound effects on development, spawning, and wide array of other behaviors in shellfish, ciliates, and other aquatic organisms by SSRI and tricyclic antidepressants.
-  Dramatic inhibition of sperm activity in certain aquatic organisms by calcium-channel blockers.
-  Antiepileptic drugs (e.g., phenytoin, valproate, carbamazepine) have potential as human neuroteratogens, triggering extensive apoptosis in the developing brain  neurodegeneration.
-  ppm and sub-ppm levels of various drugs (NSAIDS, glucocorticoids, anti-fibrotics) affect collagen metabolism in teleost fish, leading to defective/blocked fin regeneration
-  Multi-drug transporters (efflux pumps) are common defensive strategies for aquatic biota —  possible significance of efflux pump inhibitors in compromising aquatic health?
- c*ontinued -*

## Subtle (currently unrecognized) Effects: a Troubling Scenario? 

-  Could immediate biological actions on non-target species be imperceptible but nonetheless lead to adverse impacts as a result of continual accretion over long periods of time? For example, latent damage, only surfacing later in life. The issue of “resiliency”.
-  Could subtle effects accumulate so slowly (perhaps seeming to be part of natural variation) that major outward change cannot be ascribed to the original cause?
-  Effects that are sufficiently subtle that they are undetectable or unnoticed present a challenge to risk assessment (especially ecological) — e.g., subtle shifts in behavior or intelligence.
-  Advances required in developing/implementing new aquatic toxicity tests to better ensure that such effects can be detected.
- - c*oncluded -*

## Sidebar: Incremental Poisoning Designed to Appear “Natural” – a “Popular” Historical Practice

- The use of slow poisoning in homicides (usually administered by food and drink) was practiced widely in Europe from the early to late 1600s – with a resurgence in the 1800s:
- “The atrocious system of poisoning, by poisons so slow in their operation, as to make the victim appear, to ordinary observers, as if dying from a gradual decay of nature, has been practised in all ages.”
- “Those who are curious in the matter may refer to Beckmann on Secret Poisons, in his History of Inventions, in which he has collected several instances of it from the Greek and Roman writers. Early in the sixteenth century the crime seems to have gradually increased, till, in the seventeenth, it spread over Europe like a pestilence. It was often exercised by pretended witches and sorcerers, and finally became a branch of education amongst all who laid any claim to magical and supernatural arts. In the twenty‐first year of Henry VIII. an act was passed, rendering it high‐treason: those found guilty of it, were to be boiled to death.”
*The Slow Poisoners* in
- _Extraordinary Popular Delusions and the Madness of Crowds_
- by Charles MacKay, 1841

## Aquatic organisms — captive to continual, life-cycle chemical exposures

-  Aquatic Exposure is Key: Any chemical introduced via sewage to the aquatic realm can lead to
- continual, multigenerational exposure for
- aquatic organisms.
-  Re-evaluation of “Persistence”: Chemicals  continually infused to the aquatic environment essentially become “persistent” pollutants even if their half-lives are short — their supply is continually replenished (analogous to a bacterial chemostat). These can be referred to as ***pseudo-persistent***** chemicals** (**P2’s**).

##  Exposure to Multiple, Trace-Level PPCPs Below Human “Therapeutic” Doses

- _Potential Toxicological Significance Can Exist as a Result of_:
- (1) *Risk Cup* body burden: Potential for _**additive effects**_ from multiple agents sharing common MOAs to exceed an effects level. This becomes especially important if the exogenous PPCPs add to a pre-existing burden of endogenous toxicants that share the same MOA.
- (2) Possible _**interactive effects**_, especially synergism. Drug industry attempts to avoid developing new candidate drugs with potential adverse drug reactions. But the strategy is based upon focusing on those drug combinations that are most probably encountered in practice (e.g., a candidate cardiac drug would be screened against drugs that cardiac patients typically take), as opposed to all drugs (a currently economically infeasible approach).
- c*ontinued -*

## Potential Toxicological Significance Can Exist as a Result of:

- (3) _**Non-target species receptor repertoires**_ not as well characterized. Variation in receptor repertoires across species, and unknown overlap with humans leads to countless questions regarding potential effects.
- (4) _**Hormesis**_ – Effects below NOELs. “U-shaped” curves. Data acquired solely at higher “therapeutic” doses (where testing is usually performed) has no predictive capability for the type or amplitude of response at lower concentrations.
- (5) Comparatively little research performed at _**extremely low concentrations**_ (nM-pM and below). Some agents have ability to impart effects at “ultra-trace” concentrations.
- (6) Susceptible _**genetic outliers**_ within species.
- (7) _**MOAs not fully understood**_. Most drugs can each have a multitude of effects. Most remain to be discovered.
-  - c*oncluded -*

## Collateral Benefits of R&D Efforts with PPCPs

-  Regardless of whether PPCPs as trace pollutants eventually prove to pose ecological or human health concerns, there are several major reasons for developing the means for reducing their introduction to the environment.
-  These reasons have been largely unrecognized or unappreciated and they are unrelated to PPCPs themselves, and they involve the numerous collateral benefits that would automatically accrue to people and their environment.
-  Two of these reasons center around various actions to reduce the purposeful (for example, disposal of unused PPCPs via toilets) and inadvertent (primarily through physiological excretion) release of PPCPs to the environment.

- c*ontinued -*

## Collateral Benefits of R&D Efforts with PPCPs (con't) – Waste Treatment Research –

- The first major collateral benefit derives from optimizing or improving existing wastewater/sludge treatment technologies (primarily for POTWs) or developing or implementing new, cost-effective technologies for further lowering the trace levels of PPCPs.
-  Any improvements in engineering treatment technology targeted for the removal of trace levels of PPCPs from waste and drinking waters **will more than likely also serve to remove numerous other unregulated pollutants from water, many which have yet to be identified, and others which will derive from chemicals new to commerce**.

- c*ontinued -*

## Collateral Benefits of R&D Efforts with PPCPs (con't) – Cradle-to-Cradle Stewardship –

-  A wide array of activities and efforts centered on pollution prevention (source reduction, minimization, elimination) could have significant consequences for improved consumer health and economy. These pollution prevention efforts fall under the umbrella of "Cradle-to-Cradle Stewardship." Most of these actions would originate from a broad range of sectors in the healthcare industry but some would also originate with the consumer.
-  Design and implementation of a successful voluntary compliance approach to life-cycle stewardship of PPCPs (a holistic "cradle-to-cradle" approach) could not only minimize any potential for adverse environmental impact, but **could also improve medical healthcare outcomes and consumer safety as well as reduce healthcare costs**.

- c*ontinued -*

## Collateral Benefits of R&D Efforts with PPCPs (con't) – Cradle-to-Cradle Stewardship –

- Numerous suggestions for a pollution prevention program centered on environmental stewardship have been compiled in a two-part monograph published in *Environmental Health Perspectives 111*, 2003:
-  **(1)** Cradle-to-Cradle Stewardship of Drugs for Minimizing Their Environmental Disposition while Promoting Human Health. I.* Rationale and Avenues toward a Green Pharmacy* (Daughton, CG), 757-774.
-  **(2)** Cradle-to-Cradle Stewardship of Drugs for Minimizing Their Environmental Disposition while Promoting Human Health. II.* Drug Disposal, Waste Reduction, and Future Direction* (Daughton, CG), 775-785.

- c*ontinued -*

## Wealth of materials and links for: Environmental Stewardship of PPCPs at the U.S. EPA’s web page on theGreen Pharmacy:

- http://www.epa.gov/nerlesd1/
- chemistry/ppcp/greenpharmacy.htm

*- concluded -*

## Communicating Risk

***Communicating Risk***
***More Effectively***

- Growing importance of public acceptance of wastewater re-use for human consumption (especially "toilet-to-tap" re-use programs) highlights the need for vastly improved approaches to risk communication.

-  Points to need for scientists to better convey the significance of their work to the public.
-  Points to need for exploring more effective means for aligning the long-troubling disconnect of disparate views of risks as held by scientists versus the public: *real hazard vs. risk perception*.
-  Receiving little attention is the more substantive role that could be played by the cognitive sciences (social scientists and psychologists) in helping to bridge the communications gap.

***Water Re-Use***

## Importance of Forging Collaborations between Environmental Scientists & Medical Community

-  Existing literature almost exclusively a result of efforts from environmental scientists (primarily analytical chemists).
-  Much could be contributed from the many fields of medical science and practice.
-  Cross-communication and collaborations would prove extremely useful.
-  Partly in an attempt to catalyze inter-disciplinary efforts, the British medical journal *The Lancet* recently published a commentary that covers this topic and others:
**“****Environmental stewardship and drugs as pollutants”** (C.G. Daughton), *The Lancet*, **2002**, *360*:1035-1036**  **

**Notes:**
Diagnose before prescribing

## 
 Ensuring safety of drinking water supplies. Ensure adequate removal of PPCPs and other unregulated pollutants from treated wastewater, especially water destined for aquifer recharge
 Improvement of decaying water/sewage infrastructure and development of cost-effective technologies for optimal removal of PPCPs from sewage and source control (e.g., raw sewage discharge)
 Concerns regarding introduction of PPCPs to environment from molecular farming

-  Ensuring safety of drinking water supplies. Ensure adequate removal of PPCPs and other unregulated pollutants from treated wastewater, especially water destined for aquifer recharge
-  Improvement of decaying water/sewage infrastructure and development of cost-effective technologies for optimal removal of PPCPs from sewage and source control (e.g., raw sewage discharge)
-  Concerns regarding introduction of PPCPs to environment from molecular farming

- c*ontinued -*

-  **Major Future Areas to Consider Regarding PPCPs as Environmental Pollutants**

**Notes:**
Diagnose before prescribing

## 
 Development of integrated industry-consumer stewardship programs for minimizing the introduction of PPCPs to the environment (pollution prevention, source control)
 Development of cohesive national (or international) guidance for disposal/recycling of PPCPs
NOTE: Progress in most of these could also afford collateral benefits to consumers and the environment in other, unrelated and previously unanticipated ways

-  Development of integrated industry-consumer stewardship programs for minimizing the introduction of PPCPs to the environment (pollution prevention, source control)
-  Development of cohesive national (or international) guidance for disposal/recycling of PPCPs
*NOTE*: Progress in most of these could also afford collateral benefits to consumers and the environment in other, unrelated and previously unanticipated ways

-  **Major Future Areas to Consider Regarding PPCPs as Environmental Pollutants**

**Notes:**
Diagnose before prescribing

## Slide 58

## Questions

***Questions***

*feel free to contact:*
**Christian Daughton, ****Ph.D.**
- Chief, Environmental Chemistry Branch
- Environmental Sciences Division
- National Exposure Research Laboratory
- U.S. Environmental Protection Agency
- daughton.christian@epa.gov
- 702-798-2207

**http://www.epa.gov/nerlesd1/chemistry/pharma/**

## prepared for: 

Emerging Pollutants Workshop
11-14 August 2003
Chicago, IL
Christian Daughton, Ph.D.
Chief, Environmental Chemistry Branch
Environmental Sciences Division
National Exposure Research Laboratory
U.S. Environmental Protection Agency
daughton.christian@epa.gov
702-798-2207

prepared 5 August 2003

- Emerging Pollutants Workshop
- 11-14 August 2003
- Chicago, IL
**Christian Daughton, Ph.D.**
- Chief, Environmental Chemistry Branch
- Environmental Sciences Division
- National Exposure Research Laboratory
- U.S. Environmental Protection Agency
- daughton.christian@epa.gov
- 702-798-2207
- prepared 5 August 2003

**Notes:**
Presentation prepared for: 

"Pharmaceuticals and Personal Care Products in the Environment: Introduction and Overview," invited presentation to U.S. EPA Emerging Pollutants Workshop, U.S. EPA Region 5 Office, Chicago, IL, 11-14 August 2003.

Presented via the phone from ORD-Las Vegas