Pharmaceuticals and water
A proportion of the pharmaceuticals that are consumed everyday by the public are excreted unmetabolized, or as conjugates that may subsequently be reactivated, into the sewage treatment system. Sewage treatment plants (STPs) often cannot completely eliminate these compounds entirely , and as a result, trace levels are discharged into surface waters. Increasingly, researchers have identified over 100 such compounds contaminating surface and groundwater environments [2–4]. At present, there are no regulatory requirements to monitor pharmaceuticals in the environment or statutory maximum emission levels .
Many researchers have focused on unintended effects that discharged pharmaceuticals may have on wildlife due to their biological mode of action. Previous examples of an impact on wildlife that have been demonstrated include the significant role of ethinylestradiol in the sexual disruption of fish  and the role of diclofenac in kidney failure and death in vultures in the Asian subcontinent . Surface water is an important source of drinking water. In parts of England, drinking water supplies are extracted from rivers, stored in reservoirs, treated, and distributed to the public. Now that pharmaceutical contaminants have been reported in some American [8,9] and European drinking water supplies [3,10] the possibility that human health risk exists must be considered. A number of risk assessments have predicted that low levels of pharmaceuticals in drinking water are unlikely to be of concern to the general adult population and that thousands of millions of liters would need to be consumed to reach a therapeutic dose [11,12]. However, the issue of drugs that act on DNA synthesis together with vulnerable sections of the population have not yet been specifically addressed together and require closer examination. Collier  identified special subgroup populations, such as pregnant women, their fetuses, and breastfeeding infants, as particularly vulnerable to highly potent pharmaceuticals. Cytotoxic drugs, used in chemotherapy, are designed to disrupt or prevent cellular proliferation, usually by interfering in some way with DNA synthesis. Due to their high pharmacological potencies and fetotoxic, genotoxic (mutagenic), and teratogenic properties , they are potentially the most dangerous contaminants of our water system.
Because few references exist on the presence  or absence of cytotoxic drugs in river water, the present study undertook to use the best available information to predict what such concentrations might be at drinking water abstraction points in a real river environment and compare these with effect concentrations for these drugs. Literature was collected for 13 cytotoxic drugs on the consumption per capita, typical human excretion, and estimated proportion of residue escaping from a typical STP. These values were used to give an effluent emission per capita per day and used in the Low Flows 2000™ Water Quality Extension (LF2000-WQX) model for the Thames catchment. Subsequently, the predicted concentrations at drinking water abstraction points were calculated. These predicted raw water concentrations were then compared with effects or assumed safe levels for human consumption.
River Thames catchment as a source of drinking water
The Thames River Basin in England spans an area of 12,935 km2 and is home to 14 million people (http://www.environment-agency.gov.uk/aboutus/organisation/78374.aspx). Mean annual rainfall for the Thames is 720 mm, runoff is 249 mm , and annual maximum temperature is 14.7°C and annual minimum temperature is 6.7°C (http://www.metoffice.gov.uk/climate/uk/averages/19712000/sites/oxford.html). The River Thames flows 330 km from Thames Head Bridge in the Cotswolds to Shoeburyness where it joins the North Sea near Essex, passing through towns such as Oxford, Maidenhead, Reading, and the London metropolis . River water is abstracted as a source of drinking water throughout the year at Farmoor, West of Oxford, and at a number of locations around London. At Walton, the furthest downstream abstraction point on the Thames, between 20 and 40 m3/s is abstracted throughout the year. For example, in July 2003 the mean naturalized flow upstream of Walton was only 34 m3/s, but the mean abstraction was 22 m3/s; thus two-thirds of the flow was diverted for drinking water, a not untypical summer occurrence .
Cytotoxic drugs and chemotherapy treatment
Cytotoxic drugs may be administered intravenously, orally, or topically and dosed according to the patients' weight (g/kg) or body surface area (g/m2) [13,17,18]. To enhance cytotoxicity during cancer treatment, combination therapy is often employed . Combination therapy is the use of two or more drugs, often simultaneously, to treat a medical condition. A number of scientists have suggested that chemicals or drugs with similar modes of action [3,20–22] could also act additively in the environment. Therefore, in assessments of the risk that cytotoxic drugs pose to the environment and to human health, it is important to examine families of similarly acting compounds that may be present together rather than the individual compounds acting alone.
In 2005, 239,000 new cases of malignant cancer were registered in England (http://www.statistics.gov.uk/cci/nugget.asp?id=915). Due to an aging population, the Thames Cancer Registry predicts cancer rates to increase by one-third in England by 2020 . The popularity of chemotherapy as a treatment is also increasing [24,25]. Thus, the use of cytotoxic drugs is destined to increase. The ability to carry out a study of such drugs in water requires good information on per capita drug consumption. Therefore, the choice of drugs examined in the present study was largely based on their inclusion in the most recent Department of Health (DoH) study . Specifically, we focused on three important cytotoxic drug groups: alkylating agents, antimetabolites, and anthracycline antibiotics. It is important to acknowledge that the information provided in the DoH study  is 4-year-old data and is likely to be an underestimate of today's use because of the increasing popularity of chemotherapy in the United Kingdom .
Important cytotoxic groups
Physical and chemical properties. In general, cytotoxic drugs are highly water soluble with low log Kow values. (Table 1). This property is helpful from the pharmacological point of view, because it increases bioavailability and rapid clearance from the body . From the point of view of a drinking water risk assessment, this is also an important property, because oral ingestion of water is the main route of exposure considered here. All cytotoxic drugs reviewed in the present study have been reported to be water soluble and orally bioavailable (Table 1). The Kow values of cisplatin and gemcitabine have not been publicly reported. Where data was available, the vapor pressures for these drugs ranged from 8.99 × 10-25 to 4.45 × 10-5 mm Hg. A low vapor pressure indicates it is unlikely that a compound will volatilize under normal conditions (25°C).
Alkylating agents. Alkylating cytotoxic drugs are nonspecific chemotherapy drugs used to stop tumor growth. They function by attaching an alkyl group onto the DNA helix [17,27]. By doing so, alkylating agents inhibit or alter DNA replication, resulting in mutation or cell death [17,28]. A potential outcome of alkylating agents' mutagenic capability is the possibility of teratogenic effects. Unwanted side effects of alkylating agents include bone marrow suppression, fertility impairment, development of acute myeloid leukemia, and urinary disorders . In this class, five alkylating agents oxaliplatin, temozolomide, cisplatin, carboplatin, and cyclophosphamide were examined. Information on their excretion suggests that 5 to 68% [29–34] of the alkylating agent dosed is expelled from the body unchanged (Table 2).
In a sorption study using 3 to 10 g/L suspended solids activated sludge, the removal rates recorded for oxaliplatin, cisplatin, and carboplatin were 74 ± 6%, 96 ± 8%, and 70 ± 6%  at pH 7. In a further study , a pilot membrane bioreactor (MBR) system associated with an oncology ward in Vienna, Austria, removed 51 to 64% of these platinum-containing drugs. Degradation of temozolomide has only been reported with base hydrolysis and oxidation experiments at <5% . No reports to date have indicated that temozolomide is removed from wastewater via activated sludge treatment.
The fate of cyclophosphamide has been studied in a range of laboratory activated sludge systems by Steger-Hartmann et al. [38,39] without appreciable removal being detected. Similarly, little or no removal was observed in a comparison of real sewage influent and effluent at a Swiss STP . This apparent persistence and mobility in sewage systems together with its resistance to ultraviolet photolysis  suggests that cyclophosphamide removal will remain in the water column and persist in freshwater systems .
To summarize, reports so far suggest that 70 to 96% of the small, platinum-containing compounds could be removed in sewage treatment primarily through sorption mechanisms onto the sludge. Little information is available on temozolomide. Laboratory and field observations indicate little or no cyclophosphamide can be anticipated in sewage treatment.
Antimetabolites. Antimetabolite cytotoxic drugs are a cell-specific class of compounds that hinder cellular metabolism and the production of DNA. They target cells typically in the G1-S phase of mitosis . Antimetabolite agents mimic essential DNA precursors and therefore interfere with cell division metabolic pathways . Because antimetabolite agents are mistaken by the cell as a normal metabolite, they either inhibit critical enzymes involved in nucleic acid synthesis or become incorporated into the nucleic acid . As a result, DNA replication is inhibited or incorrect codes are synthesized, thus causing apoptosis. In this class, gemcitabine, fludarabine, and fluorouracil (5-FU, a metabolite to the prodrug capecitabine) were examined. Information on their excretion suggests that 5 to 65% of the antimetabolite dosed is expelled from the body unchanged [29,30,41,43] (Table 3).
Fluorouracil has been demonstrated to be very susceptible to biodegradation in an activated sludge microcosm study, with approximately 90% transformation in 10 h at a concentration of 5 mg/L . Using a laboratory-scale sewage treatment plant, Kiffmeyer et al.  conducted a test at milligram per liter concentrations and reported 92% removal of 5-FU after 10 d.
|Family||Drug||Structurea||Bioavailabilityb||Water solubility (g/L) 19−25°Cb,c||log Kowa||Vapor pressure, (mm Hg) at 25°Cb|
A test conducted with activated sludge, hospital wastewater, and 1,660 mg/L gemcitabine reported 50% biodegradation . No degradation or absorption studies were found for fludarabine. However, because it is an analog of gemcitabine, the same STP elimination was assumed in the present study.
To summarize, it would seem that biodegradation in activated sludge is important for capecitabine/5-FU, with up to 99% degradation, whereas gemcitabine and fludarabine may be biodegraded by 50%. However, it should be noted that the hydraulic retention time in activated sludge tanks is typically 10 to 14 h (a shorter duration than most of the experimental studies reported here) and the environmental concentrations would be approximately five orders of magnitude lower than those used in these microcosm studies; therefore, these values may be a guide only.
Anthracycline antibiotics. Anthracycline antibiotics originate from a microorganism belonging to the genus Streptomyces. Although the exact mechanism of action is not yet understood, it is known that anthracycline antibiotics bind tightly to and intercalate with double-stranded DNA, thus preventing replication [17,46]. In this class, epirubicin and doxorubicin were examined. Information on their excretion suggests that 6 to 45% of the anthracycline antibiotic dosed is expelled from the body unchanged [29,32] (Table 4).
Using a pilot MBR system connected to an oncology ward, Mahnik et al.  reported 90% removal of epirubicin and doxorubicin spiked at a concentration of 2.5 mg/L. It was assumed that activated sludge flocs would behave the same as those in a MBR; thus, this removal rate was used in our exposure assessment. Analysis of the sewage sludge indicates that the elimination of anthracycline antibiotics seems to be mainly by adsorption [14,44]. It is not clear if these compounds were also biodegraded [44,47].