[Pharmwaste] Damming the Flow of Drugs into Drinking Water

[Tenace, Laurie]

http://ehp.niehs.nih.gov/members/2005/113-10/spheres.html
Damming the Flow of Drugs into Drinking Water=20
Roughly 100 pharmaceuticals have now been identified in rivers, lakes, =
and
coastal waters throughout Europe and the United States in concentrations =
of
parts per billion to parts per trillion. The first major European =
studies on
this topic--in journals such as volume 67, issue 1-4 (1997) of the
International Journal of Environmental Analytical Chemistry and the =
November
1998 issue of Water Research--examined German ground and surfaces =
waters, and
found occurrences of drugs including cholesterol regulators, analgesics, =
and
antiseizure medications. Since that time, numerous other studies have
documented the presence of pharmaceuticals, including potential =
endocrine
disruptors, in other locales as well.=20
So far there is no evidence of adverse human health effects due to =
traces of
pharmaceuticals in water. But scientists have linked certain =
pharmaceuticals
with disturbing ecosystem changes. For example, in volume 8 (1994) of
Chemistry and Ecology, researchers demonstrated that the feminization of
fish--male carp and trout producing vitellogenin, an egg protein usually
found only in females--was associated with exposure to sewage effluent =
now
known to contain ethinyl estradiol, the active ingredient in birth =
control
pills.=20

There is much concern about what is not known: ecotoxicity data are =
available
for less that 1% of human pharmaceuticals, according to estimates =
published
in the April 2004 issue of Regulatory Toxicology and Pharmacology. =
Today,
intensive research is under way to investigate the effect of human
medications on the environment.=20

In 1999, in response to these concerns, the European Medicines Agency =
(EMEA)
began drafting guidance that outlined an environmental risk assessment
procedure to accompany pharmaceutical companies' applications to market =
new
drugs in Europe. The latest draft was published in January 2005, after
several revisions, and the public comment period closed in April 2005.
Scientists and pharmaceutical companies alike hope the guidance will be
finalized later this year.=20

The proposed European guidance is the first to recommend long-term
ecotoxicity testing for environmental risk assessment of pharmaceuticals =
from
the outset of the proposed testing program (in contrast, U.S. Food and =
Drug
Administration [FDA] requirements for chronic ecotoxicity testing come =
later
in that agency's assessment). The European guidance is also the first to =
take
into account the possibility of environmental effects from extremely low
concentrations of bioactive substances, such as endocrine disruptors.=20

If finalized, the guidance could call for substantially more testing of =
new
drugs than has been demanded thus far. Its implementation would also =
generate
much-needed chronic ecotoxicity data. "The main advance in this draft
guideline is that we really address this issue and get more information =
on
the toxicity of these compounds," says Thomas Heberer, an environmental
chemist at the Technical University of Berlin and coauthor of many =
papers on
the topic, including the 1997 International Journal of Environmental
Analytical Chemistry report.=20

What the Draft Guidance Covers
The draft guidance outlines the risk assessment procedure for new active
pharmaceutical substances, their metabolites, and possibly excipients =
(the
inert substances in which a drug is delivered) if they are deemed =
similar to
chemicals with known adverse environmental effects. It does not apply to
drugs already on the market. If an environmental risk is found, the =
guidance
recommends that the manufacturer take appropriate precautionary and =
safety
measures to limit the product's environmental impact. The guidance
specifically recommends the labeling of pharmaceuticals when there is a
possibility of an environmental risk, to educate people about how best =
to
dispose of expired or unused medicines.=20

The guidance applies only to potential environmental risks that are a
consequence of people storing, taking, and excreting medicines. The =
potential
risks posed by the manufacture of drugs are not addressed, nor does the
guidance apply to "orphan" drugs used only to treat rare diseases. =
Separate
guidance governs medicinal products containing genetically modified
organisms.=20

Proposed EMEA Protocols=20
The EMEA risk assessment protocol is a tiered process that begins with a
rough calculation of the aquatic predicted environmental concentration =
(PEC)
of the new drug. During this Phase I prescreening, substances whose PEC =
is
deemed too low to be of concern to environmental health are ruled out =
for
further assessment. Vitamins, electrolytes, amino acids, peptides, and
proteins are exempted by the guidance because they are not tailored =
active
ingredients (unlike, for example, a drug that interacts with a receptor) =
and
thus are deemed "unlikely to result in significant exposure of the
environment." However, the guidance does note that certain substances =
that
are likely to cause effects at very low concentrations, such as =
endocrine
disruptors, may need to be addressed regardless of the quantity released =
into
the environment.=20

Phase II begins with Tier A testing, which aims to determine the aquatic =
fate
and effects of the drug. Its degradability, potential to bioaccumulate,
adsorption on sewage sludge, and toxicity to sewage microbial =
populations are
evaluated from the results of standard tests also used in the FDA risk
assessment. Also included in Tier A of the EMEA protocol is the =
long-term
testing of fish, Daphnia (water fleas), and algae to assess the =
predicted "no
effect" concentration (PNEC) of the new drug for each of these species. =
The
PEC is further refined at this stage in the EMEA assessment by taking =
into
account the pharmaceutical company's projected sales forecast for the =
drug.=20

The risk assessment is terminated if the outcome of Tier A testing =
results in
a PEC lower than the PNEC. However, if the PEC is greater than the PNEC =
in
either water, sediment, the sewage treatment plant, or soil (where =
sewage
sludge has been spread as a fertilizer), this indicates a potential =
risk, and
further Tier B testing is initiated. These tests follow the protocol in =
the
European Technical Guidance Document to further investigate the risk =
posed by
the drug to the environment. For instance, where there is a potential =
risk to
soil, tests would be conducted to determine the drug's biodegradation in
soil, its toxicity to soil invertebrates, and its acute effects on =
plants and
soil microorganisms.=20

At this stage, data on the drug metabolism and excretion profile may be
consulted to allow a more accurate calculation of the PEC and determine
whether metabolites need to be tested. The EMEA guidance recommends that
metabolites exceeding 10% of the drug residue should be assessed for
environmental risk. If this round of testing indicates that the PEC of =
the
drug will be greater than the PNEC, then pharmaceutical companies =
following
the European approach must propose recommendations to limit the drug's =
impact
on the environment.=20

There are two major differences between the proposed EMEA approach and =
the
existing FDA approach. First, the FDA protocol turns to chronic testing =
only
if acute testing indicates a risk or if there is an indication that the =
drug
could bioaccumulate. The latest scientific research suggests that acute
testing is not a reliable indicator of all chronic effects, however, and =
the
EMEA document reflects this finding.=20

Second, the trigger concentrations of pharmaceuticals that prompt risk
assessment under the FDA and EMEA guidance differ by a factor of 10 when
dilution is taken into account. "The way the two guidelines express this
trigger may be confusing," says Virginia Cunningham, director of
environmental sustainability sciences for GlaxoSmithKline. She explains =
that
the EMEA's trigger of 0.01 microgram per liter (=B5g/L) reflects a =
surface
water concentration, whereas the FDA's 1.0 =B5g/L trigger reflects an =
"expected
introduction concentration," or the concentration of a compound in =
sewage
effluent.=20

The EMEA trigger of 0.01 =B5g/L is calculated from the maximum daily =
dose of
the drug per patient and the assumption that 1% of the population is =
treated
daily with the drug; this is divided by the amount of wastewater per =
person
per day and a dilution factor of 10. The FDA trigger corresponds to a =
PEC in
surface water of 0.1 =B5g/L, assuming a dilution factor of 10, and is
calculated from manufacturers' sales estimates.=20

The consideration given to metabolites and the provision for the =
introduction
of scientific experts into the risk assessment process--both part of the
revisions to the 2003 guidance--are welcomed by scientists. "It allows =
for
experts to be drawn into the discussion and give their opinions rather =
than
be sticking blindfolded to a number," says Evelyn O'Brien, a scientist =
in the
Ecotoxicology Workgroup at the University of Konstanz in Germany and =
coauthor
of a discussion of the draft guideline published in the July 2004 Trends =
in
Biotechnology.=20

One caution added by zoologist Theo Colborn, whose seminal 1996 work Our
Stolen Future uncovered the dangers of endocrine disruptors in the
environment, is that conflict of interests for experts working in =
academia
but funded by drug companies must be revealed. "The important thing is," =
she
says, "that in [the United States] they're selecting experts to do =
things
like this on campuses where the particular department that that =
individual is
working in oftentimes receives tremendous amounts of grant money from =
the
pharmaceutical company. Openly admitting conflict of interest is so
important."=20

The EMEA website notes that members of the agency's scientific =
committees
"are not permitted to have any direct financial or other interests in =
the
pharmaceutical industry. . . . They are required to make an annual
declaration of their financial interests and also any indirect interests
which could relate to the pharmaceutical industry." Colborn also hails =
the
guidance for including excipients as well as active ingredients in the =
risk
assessment process. For instance, phthalates such as diethyl phthalate =
and
dibutyl phthalate, used as plasticizers in the coating of some =
site-directed
drugs, may be a potential source of phthalates for people taking these =
drugs,
as reported in the May 2004 issue of EHP.=20

Limitations of the Guidance=20
There are certain serious, though perhaps unavoidable, limitations to =
the
guidance. One is the fact that they are not retroactive. "The only thing =
that
[researchers] are concerned about is that the guidance only concerns =
those
pharmaceuticals that are not yet on the market," says Heberer. "It's our =
main
concern about this guideline, but compared to the situation in the past =
it's
really an advance." But even if future legislation required the =
environmental
risk assessment of drugs already on the market, the big question would =
be who
should do the testing since the originator of a drug is often no longer =
the
main manufacturer.=20

Another major problem is that monitoring may be difficult. "There are
problems detecting certain substances that have been on the market for
years," says O'Brien. Examples of such hard-to-detect drugs include the
antidepressants known as selective serotonin reuptake inhibitors (which
include Paxil, Prozac, and Zoloft). "So the analysis can be quite =
difficult,"
she says, "and that's one of the main stumbling features."=20

Further, it is not clear how drugs that pose risks will be handled, =
apart
from the addition of labels to recommend appropriate disposal of expired
drugs. Another emerging area of concern in North America and Europe =
alike is
the disposal of used birth control patches and hormone replacement =
patches.
Because pharmaceuticals can save lives, the guidance does not suggest
removing them from the market even when a risk is found.=20

"I think there's going to be a lot of emphasis on labeling, and also on
treatment processes," says Alistair Boxall, a senior lecturer at York
University and Central Science Laboratory in England. "So perhaps if =
you've
got a hospital where cancer drugs are being used, it may be that we have =
to
start putting treatment processes on the end of the [sewer] pipes of =
those
hospitals to remove some of the drugs."=20

Drug take-back programs for expired pharmaceuticals are in place in =
parts of
Europe, so labeling drugs with instructions to return unused portions to =
a
pharmacy makes sense. By comparison, in the United States, the =
Controlled
Substances Act complicates such schemes because it prohibits patients =
from
transferring controlled medicines to anyone other than a law enforcement
official. However, a drug return program has recently been legislated =
(though
not implemented) in Maine.=20

Another limitation, also difficult to avoid, is that the draft guidance =
only
briefly addresses the possibility of additive or synergistic effects, =
noting
that an assessment factor of 10 is applied to the PNEC to account for
extrapolation from lab data to field impacts. "It's worth pointing out =
that
the guidance is written as if the concern is for a single drug in =
isolation,"
says Christian Daughton, chief of the environmental chemistry branch at =
the
Environmental Protection Agency National Exposure Research Laboratory. =
"But
if a drug shares a common mechanism of action with other drugs, or even =
other
pollutants, there's the possibility for additive effects."=20

Some scientists and drug companies are concerned that assumptions in the
guidance could lead to unrealistic PECs. The initial calculation assumes =
the
worst-case scenario: that the drug is not metabolized or degraded at =
all, so
the full dose ends up in the environment (this is one of 30 points =
raised by
the Pharmaceutical Research and Manufacturers of America in their =
comments on
the guidance). But others worry that actual concentrations in the =
environment
could be higher than the calculated PEC due to the guidance's assumed =
1:10
dilution factor for sewage effluent entering rivers. In farming areas, =
water
levels drop precipitously in dry weather when water is drawn for crops =
and
cattle, so the 1:10 dilution factor could be too high. Colborn, a =
Colorado
resident, says, "Most of the river water that's in this part of the West =
is
coming from returned sewage treatment plants." O'Brien argues the same =
point
in cities where the influx of people stretches the capacity of sewage
treatment plants.=20

Another problem noted by O'Brien is that peak or seasonal variations are =
not
taken into account--flu epidemics, drought, or heavy snowfall could
temporarily increase drug concentrations in specific places to values =
higher
than the calculated PEC. Colborn also comments that local use of
pharmaceuticals differs, reflecting, for example, recent visits by
pharmaceutical representatives telling doctors about new drugs. "To =
estimate
that pharmaceuticals will be released homogeneously across a particular
region is, I think, mistaken," she says. Daughton addressed these and =
related
issues in greater detail in the May 2003 issue of EHP.=20

One worry for pharmaceutical companies is that the increased amount of
testing required could translate into costly delays for the release of =
new
drugs. About 50 new drugs come onto the market in the United States each
year, and approximately a dozen of those are predicted to occur above =
the
trigger concentration requiring them to undergo the first level, or Tier =
A,
of risk assessment testing.=20

But only one new drug in the last few years has gone on to the next =
level to
be tested for environmental risks through chronic ecotoxicity tests,
according to Florian Zielinski, a chemist at the FDA Center for Drug
Evaluation and Research. "In fact, in the States, almost all =
pharmaceuticals
in the Tier A assessment will come out at under one microgram per =
liter,"
says Chris Metcalfe, a professor in the Environmental and Resource =
Studies
Program at Trent University in Ontario, "whereas in the EU there will be =
a
fair number of pharmaceuticals which will move from the Tier A to the =
Tier B
as a result of their lower thresholds." British labs put about 20 new
pharmaceutical products on the market each year.=20

Forging Ahead=20
Since neither the EMEA guidance nor its U.S. sister document addresses
pharmaceuticals already on the market, there is much research into =
whether
wastewater treatment can economically remove pharmaceuticals. Increased
retention time within treatment plants, chlorination, ozonation, and the
natural reduction of a compound's mass or concentration over time due to
processes such as biodegradation all increase the removal of some drugs =
from
wastewater; more advanced treatments such as adding activated carbon or
reverse osmosis can remove even more. "But there's never a silver =
bullet,"
says Shane Snyder, research and development project manager of the =
Southern
Nevada Water Authority. "There's always a catch."=20

The catch with ozone treatment is that it forms bromate, which is a =
regulated
disinfection by-product; with chlorination, the catch is that chlorine
combines with ammonia in the sewage treatment system to form =
chloramines,
which are not strong oxidants and so cannot break down compounds such as
estrogens. However, chlorination can destroy almost all the estrogens if
ammonia is removed first, says Snyder. But even with the use of reverse
osmosis (which removes pharmaceuticals down to parts per trillion) and =
the
addition of activated carbon, there's the problem of what to do with the
retained contaminants.=20

Although Europe has been at the forefront of recognizing and addressing =
the
potential environmental hazard posed by pharmaceuticals, other countries =
are
perhaps beginning to catch up. In the United States, for example, the =
Federal
Interagency Task Group on Pharmaceuticals and Personal Care Products was
formed in September 2004. This group comprises seven federal agencies =
and is
chaired by the FDA. The group had its first face-to-face meeting in July =
2005
to identify federal research needs and gaps. One of the questions raised =
was
how much of the estrogen in wastewater comes from synthetic sources.=20

In Canada, the Environmental Impact Initiative was formed in 2001 in =
response
to growing evidence that pharmaceutical substances are being found in =
the
environment. The initiative, which accepted public comments through =
September
2005 on proposed options for regulating these substances, may result in =
new
rules for the environmental assessment of substances in products =
regulated
under the Food and Drugs Act, according to Health Canada. Japan is also =
in
the process of formulating a plan for environmental risk assessment of
pharmaceuticals with sales exceeding one ton per year.=20

In the meantime, the EMEA draft guidance is seen as an appropriate =
response
to an emerging issue which includes possible risks not just from
pharmaceuticals but also from personal care products. "What has come =
into the
scientific literature is that most pharmaceuticals do not show acute
ecotoxicity, so the whole mindset is shifting to chronic toxicity, and I
think the EMEA guideline is trying to reflect that," says Cunningham. =
"None
of the people I talk to have a problem with that."

Laurie J. Tenace
Environmental Specialist
Florida Department of Environmental Protection
2600 Blair Stone Road, MS 4555
Tallahassee, Florida 32399-2400
PH: (850) 245-8759
FAX: (850) 245-8811
Laurie.Tenace@dep.state.fl.us
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view our mercury web pages at:=20
http://www.dep.state.fl.us/waste/categories/mercury/default.htm
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