Damming the Flow of Drugs into Drinking Water 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.
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.
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.
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.
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.
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.
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.
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.
Proposed EMEA Protocols
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.
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.
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.
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.
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.
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 (µg/L) reflects
a surface water concentration, whereas the FDA’s 1.0 µg/L
trigger reflects an “expected introduction concentration,” or
the concentration of a compound in sewage effluent.
The EMEA trigger of 0.01 µg/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 µg/L, assuming a dilution
factor of 10, and is calculated from manufacturers’ sales
estimates.
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.
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.”
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.
Limitations of the Guidance
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.
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.”
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.
“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.”
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.
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.”
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.
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.
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.
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.
Forging Ahead
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.”
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.
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.
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.
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.”
Pat Hemminger |