Pharmaceuticals

1
Pharmaceuticals

• In the environment

Darren Grover November 2005
2
Introduction

• Pharmaceuticals are known as the most diverse
  group of chemicals there are over 3000 licensed
  for human use in the UK
• They are classed as emerging risks, which have
  until recently not even been recognised as
  pollutants, but are now known to be ubiquitous in
  the aquatic environment3

3
Properties
Fluoxetine (Prozac)
Acetaminophen (Paracetamol)
2-(p-isobutylphenyl) propionic acid (Ibuprofen)
4
Properties (2) Conflicts
Adapted from Kummerer, 2003
5
Properties (3)

• Pharmaceuticals can be excreted unmetabolised, or
  as active metabolites
• Removal by sewage treatment is dependant on the
  parent compound properties, and the technology
  implemented in the treatment works - metabolites
  can in fact be reconverted into the active parent
  compound by sewage treatment
• The use of pharmaceuticals is not static
• New drugs are constantly being developed

6
Sources

• Human pharmaceuticals enter the environmental
  mainly through sewage outfalls which includes
• Hospital waste
• Pharmaceuticals Industry waste
• Agricultural/veterinary waste (also enters rivers
  through run-off)
• Domestic

7
Sources (2)
8
Mobility and fate

• The mobility of a given pharmaceutical depends
  upon
• (a) Ratio of forms (unchanged/conjugate/metabolite
  )
• ? Of which, stability, solubility and
  bioavailability etc. are a function
• (b) Water salinity/pH/eH
• ?Of which, the solubility, stability, and
  bioavailability etc. are a function
• (c) climate weather
• Of which, photodegredation rate and sorption,
  etc. are a function

9
Mobility and fate (2) issues

• Although we have some idea about what might
  affect the mobility and fate of pharmaceuticals
  in the environment, it is difficult to ascertain
  the effects each of these factors will have, most
  notably because many pharmaceuticals occur below
  the detection limits of analytical equipment
• The variability of the pharmaceutical cocktails
  found in the environment makes it difficult to
  infer patterns of behaviour3
• The lifetime of pharmaceuticals varies greatly
  between compounds (anything between less than an
  hour to a week1), but constant input leads to
  psuedo-persistance

10
Concentrations

• Concentrations of pharmaceuticals in the
  environment are scarcely known
• One approach has been to estimate the usage (from
  sales/prescription data) of drugs, and use
  computer and mathematical models to calculate
  Predicted Environmental Concentrations (PEC).
• Another, is to measure selected pharmaceuticals
  directly - Measured Environmental Concentrations
  (MEC) however, concentrations are often below the
  detection limits of even the latest analytical
  technologies (e.g. GC-MS and HPLC-MS)

11
Concentrations (2)

• Comparisons between PEC and MEC are poor, with a
  difference of often a factor between 2-15.
• A developing method is to measure concentrations
  of indicator or tracer pharmaceuticals, which are
  found in detectable concentrations, to make
  inferences about the concentrations of other
  chemicals

12
Concentrations (3)
Concentrations of selected pharmaceuticals in
Canadian WWTP outfalls and adjacent surface
water, 1999-2002

Adapted from Metcalfe et Al. (2004) after
Metcalfe et Al. (2003), Miao et Al. (2003) Hua
et Al. (2004)
13
Receptor exposure

• Receptor organisms include bacteria, algae,
  insects, plants, fish, aquatic mammals, birds,
  terrestrial mammals, and even humans
• The exposure of aquatic organisms is clear
  since they inhabit the contaminated water, but
  how are terrestrial mammals, birds and humans
  exposed?

14
Receptor exposure (2)

• Terrestrial mammals and birds may predate on
  species which inhabit contaminated water they
  may drink from contaminated water they may
  inhabit flood plain areas they may inhale
  pharmaceuticals from the air, etc.
• Little is known about methods of exposure in
  reality, the list above is just speculative
• The exposure route for humans is similar, if more
  complex.

15
Receptor exposure (3) Humans

• Humans may be exposed to pharmaceuticals in the
  environment by
• Consuming contaminated foodstuffs
• Bathing in contaminated water bodies
• Drinking water (pharmaceuticals are not mentioned
  in the EU drinking water directive)
• Of these, drinking water as an exposure route has
  received the most attention, and is recognised as
  the most likely route of exposure

16
Effects to receptors

• The effects of most pharmaceuticals in the
  environment are varied, and largely unknown
• The initial wanted human effect, is often the
  most common side effect in the environment, but
  to non-target species
• It is important to note that pharmaceuticals are
  designed to be stable, particularly in organisms
  and so may bioaccumulate
• The effects vary between chemical, between
  different environmental conditions, and between
  species

17
Effects to receptors (2)

• Carbamazepine, an anti-epileptic drug, is known
  to be teratogenic in humans, with chronic
  exposure, and has an LD50 of 158mg/kg in rats,
  although this is much higher than the
  concentrations found in the environment (up to
  3.7µgl-1), but bioaccumulation, and
  biomagnification may occur
• 17a-ethinyloestradiol, used in the contraceptive
  pill is a known Endocrine Disrupting Chemical
• Antibiotic release into the environment is
  associated with bacterial resistance
• The list of possible side effects is almost
  endless

18
Effects to receptors (3) Dual-use drugs

• Warfarin is a anticoagulent and a rat poison
• Triclosan is a general biocide, and used in
  toothpaste
• Caffeine, a stimulant, and also used to control
  frogs, snails and slugs
• In these cases, their use is intentional, but all
  three chemicals have been found to be present in
  sewage

19
Risk

• Requirements for pharmaceutical companies to
  perform Environmental Assessments (EA) before a
  drug can be licensed should remove much of the
  risk, BUT
• In the US, pharmaceuticals that do not
  individually significantly affect the human
  environment are ordinarily excluded from the
  requirement to perform an EA
• Laboratory testing and modelling cannot
  completely represent the environment
• Definitions are broad, often leading to
  confusion, and legal loopholes

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Risk (2)

• Risk is estimated by comparing Predicted
  Environmental Concentrations (PEC) with Predicted
  No-Effect Concentrations (PNEC).
• PNEC values are calculated using E(L)C50 data,
  obtained by laboratory tests
• But with little understanding of the hazards,
  risk assessment is made more difficult
• The consensus amongst the literature is that the
  risk is probably low, but with the large
  uncertainties, it is best to limit release and
  exposure as much as practicable
• Amendments to the EU REACH programme could enable
  better estimation of use, and hence load of
  pharmaceuticals into the environment

21
References

• Daughton, C., (2002), Pharmaceuticals and
  Personal Care Products (PPCPs) as environmental
  pollutants, US EPA
• Jones, O.A.H., N. Voulvoulis, and J.N. Lester,
  (2002), Aquatic environmental assessmentof the
  top 25 English prescription pharmaceuticals.
  Water Research, 3650135022
• Kummerer, K., (Ed., 2004), Pharmaceuticals in the
  environment sources, fate, effects and risks,
  (Second Edition) Springer-Verlag, Berlin
• McMichael, T, 2001), Human Frontiers,
  environments and disease, Cambridge University
  Press, UK
• Zuccato, E., (2002), Pharmaceuticals in the
  environment Results of a monitoring program in
  Italy, Mirio Negri Institute of Pharmacological
  research, Milan
• Author unknown, (1978), Wastes from the
  Manufacture of Pharmaceuticals, Toiletries and
  Cosmetics A technical memorandum on Arisings,
  Treatment and Disposal including a code of
  practice, Waste Management Paper no. 19,
  Department of the Environment, UK
• Author unknown, (2003), Human Pharmaceuticals
  Position Statement, Environment Agency, UK
• Author unknown, (2005), The New EU Chemicals
  legislation REACH, Department of Enterprise and
  Industry, European Commission, EUROPA