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Pharmaceuticals and Personal Care Products PPCPs as Environmental Pollutants Pollution from Personal

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Title: Pharmaceuticals and Personal Care Products PPCPs as Environmental Pollutants Pollution from Personal


1
Pharmaceuticals and Personal Care Products
(PPCPs) as Environmental Pollutants Pollution
from Personal Actions lt
  • 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_at_epa.gov

2
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3
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.

4
Wealth of other materials and links to most of
the ongoing work relevant to this topic are
available at the U.S. EPAs PPCPs Web Site
  • http//www.epa.gov/nerlesd1/
  • chemistry/pharma/index.htm

5
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6
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 -
7
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

8
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.

9
Endocrine Modulators and Homeostasis
C.D. Daughton, 21 November 2001 U.S. EPA-Las Vegas
10
EDCs versus PPCPs
C.D. Daughton, 21 November 2001 U.S. EPA-Las Vegas
11
PPCP-Relevant Goals for the U.S. EPAsOffice of
Research and Development
  • 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.

12
PBTs, POPs, BCCsOnly 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.

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16
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 -
17
Prevalence/Distribution of Xenobiotic Occurrence
18
Einstein onEnvironmental 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.
19
further truisms regardingEnvironmental 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.

20
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?
21
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.

22
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.

23
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.

24
Overview Pharmaceuticalsin 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 -

25
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 drugs 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 -

26
Overview Pharmaceuticalsin 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 -

27
Overview Pharmaceuticalsin 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 -

28
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29
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

30
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).
31
Available http//www.epa.gov/nerlesd1/chemistry
/pharma/image/drawing.pdf
32
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/w
    hatsin.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.c
    om/other/news_views/outcomes_research/atlas2002/at
    las_ex_sum.htm

33
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.

34
Drugs Having Double UsesMedicinals 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.

35
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
36
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.usda.gov/
lpa/inside_aphis/features10d.html.
37
Decline of Gyps spp. Vultures in Pakistan India
Possible Link with Diclofenac
  • 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.
  • 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 Gyps.
  • 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.

38
PPCPs in Receiving WatersA 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.

39
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 -

40
Sources of Raw Sewage in U.S.released to
streams, lakes, estuaries, oceans, groundwater
  • combined sewer overflows (CSOs) 4.5 X 1012
    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_id5
  • 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.pd
    f. In certain locales, the percentage is much
    higher.
  • unpermitted privies
  • straight-piping

continued -
41
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?reactio
nfull) Nationwide grades of D assigned for
both drinking water and wastewater
infrastructures (http//www.asce.org/reportcard/i
ndex.cfm?reactionfullpage2) Over 20 billion
dollars annually is the estimated need for
rectifying the nations 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.
42
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. continued -

43
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?
  • continued -

44
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.
  • - concluded -

45
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

46
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 (P2s).

47
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).
  • continued -

48
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.
  • - concluded -

49
Collateral Benefits of RD 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.

continued -
50
Collateral Benefits of RD 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.

continued -
51
Collateral Benefits of RD 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.

continued -
52
Collateral Benefits of RD 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.

continued -
53
Wealth of materials and links for Environmental
Stewardship of PPCPs at the U.S. EPAs web page
on theGreen Pharmacy
  • http//www.epa.gov/nerlesd1/
  • chemistry/ppcp/greenpharmacy.htm

- concluded -
54
Water Re-Use
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.

55
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,
    3601035-1036

56
Major Future Areas to Consider Regarding PPCPs
as Environmental Pollutants
  • 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

continued -
57
Major Future Areas to Consider Regarding PPCPs
as Environmental Pollutants
  • 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

58
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59
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_at_epa.gov
  • 702-798-2207

http//www.epa.gov/nerlesd1/chemistry/pharma/
60
  • 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_at_epa.gov
  • 702-798-2207
  • prepared 5 August 2003
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