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Emerging chemicals of concern: Pharmaceuticals and personal care products (PPCPs) in Asia, with particular reference to Southern China
Marine Pollution Bulletin 50 (2005) 913–920 www.elsevier.com/locate/marpolbul
Viewpoint
Emerging chemicals of concern: Pharmaceuticals and personal care products (PPCPs) in Asia, with particular reference to Southern China Bruce J. Richardson a
a,*
, Paul K.S. Lam a, Michael Martin
b
Department of Biology and Chemistry, Research Centre for Coastal Pollution and Conservation, City University of Hong Kong, 83 Tat Chee Avenue, Kowloon, Hong Kong b Office of Spill Prevention and Response, California Department of Fish and Game, 20 Lower Ragsdale Drive, Suite 100, Monterey, CA 93940, USA
Abstract In many western nations, pharmaceuticals and personal care products (PPCPs) are present in aquatic environments, raising concerns amongst chemists and toxicologists regarding their potential environmental fates and effects. However, there are few published reports of PPCPs in environmental samples from Southeast Asia. Whilst the environmental toxicology of PPCPs is not well understood, several effects cause concern, such as feminisation or masculinisation by hormones and xenoestrogens, synergistic toxicity from complex mixtures at low concentrations, potential creation of resistant strains in natural bacterial populations, and other potential concerns for human health. Whilst both the presence and distributions of PPCPs in Southeast Asia and China are not well known, observations elsewhere suggest that they may be important contaminants in the aquatic environment. This is particularly emphasised by the enormous production and widespread use of many PPCPs in China, particularly antibiotics utilised in human and veterinary medicine applications. This Viewpoint presents a general description of the issue, characterises the current status of PPCP analyses and reporting in the Southeast Asian region, and proposes a recommended approach for monitoring and chemical assessment of one group of PPCPs, antibiotics, in the aquatic environments of Hong Kong and the Pearl River Delta. 2005 Elsevier Ltd. All rights reserved. Keywords: Pharmaceuticals and personal care products (PPCPs); Southeast Asia
1. Introduction Pharmaceuticals and personal care products (PPCPs) are a diverse group of environmental chemicals that have captured the attention of scientists and the public, especially in the more developed western countries of North America, the United Kingdom, and Europe. There are more than 3000 different substances used as medicines, including painkillers, antibiotics, contraceptives, beta-blockers, lipid regulators, tranquilizers, and *
Corresponding author. Tel.: +852 2788 7042; fax: +852 2788 7406. E-mail address: [email protected] (B.J. Richardson).
0025-326X/$ - see front matter 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.marpolbul.2005.06.034
impotence drugs (Ternes et al., 2004). During and after treatment, humans and animals excrete a combination of intact and metabolised pharmaceuticals, many of which are generally soluble in water and have been discharged to the aquatic environment with little evaluation of possible risks or consequences to humans and the environment. In addition, chemicals that are components of personal care products number in the thousands, and are contained in skin care products, dental care products, soaps, sunscreen agents and hair care products. Annual production exceeds 1 · 106 tonnes worldwide (for example, >553,000 tonnes were produced in Germany alone in 1993; Daughton and Ternes,
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1999). Included in this category are fragrances (e.g., nitro- and polycyclic-musks), UV blockers (e.g., methylbenzylidene camphor), and preservatives (e.g., parabens). Unlike pharmaceuticals, personal care products enter wastewater and the aquatic environment after regular use during showering or bathing. The environmental fates and effects of many cosmetic ingredients are poorly known, although considerable persistence and bioaccumulation in aquatic organisms have been reported (see Daughton and Ternes, 1999). In almost every aquatic environment in North America and Europe, pharmaceuticals, hormones, metabolites, biocides, musks, and flame retardants have been measured (Ternes, 1998; Kolpin et al., 2002; Hirsch et al., 1999; Hilton and Thomas, 2003). One of the principal sources is the release of municipal wastewater, because people either excrete pharmaceuticals during normal medical treatment or they dispose of excess drugs in toilets; in addition, personal care products can enter aquatic environments via showering and bathing. Pharmaceuticals that do not readily biodegrade enter receiving waters through the discharge of waste treatment plant effluents or direct application in fish foods, and have been measured in water (Weigel et al., 2002) and sediments (Samuelsen et al., 1992) from the marine environment. What is the potential for these chemicals to occur in China and other Southeast Asian nations? Currently, there are few published reports of PPCPs in the region, although we are aware of a recent PPCPs (alkylated musks) survey of sewage treatment plants in Guangdong, China (Zheng et al., 2005) and a second report of antibiotics associated with mariculture in Viet Nam (Le and Munekage, 2004). At a pharmaceutical plant in Taizhou, China, deaths and illnesses of workers, assigned to chemical runoff from the factory into an open creek running beside the plant, have been reported (Kahn, 2003); however, it appears that these are not directly related to PPCP-induced toxicity. ChinaÕs use of antibiotic products is legendary, although accurate statistics on dosage and use amongst its citizens are not available. Press reports have indicated that more than 70% of the drug prescriptions nationwide in China are for antibiotics, and in contrast, this figure is approximately 30% in western countries. Other uses of antibiotics are in farming and aquaculture, and for this reason Chinese shrimp and prawns have been banned in Europe and the United States (Chao, 2003). The use of antibiotics in livestock and bird farming has not been evaluated in China or other Southeast Asian nations; however, Australia has published figures on the practical uses and relative distribution of antibiotics: 36% for human medicine, 8% for veterinary medicine, and 56% mixed into stock feed; pigs and poultry receive the highest proportions of antibiotic dosage to livestock (JETACAR, 1999).
In 2003, China was the worldÕs largest producer of pharmaceutical products, with an annual production of 28,000 tonnes of penicillin (60% of the world total), 10,000 tonnes of terramycin (65% of world total), and is ranked first amongst nations for doxycyline hydrochloride (a tetracycline species) and cephalosporins (http://www.inpharma.com/news/ng.asp?id=53300). In contrast, Germany produces 900 tonnes of penicillin per year (Hirsch et al., 1999) and Denmark 87 tonnes of antibiotics (Halling-Sørensen et al., 1998). At present, little is known about the adverse effects of human and veterinary pharmaceuticals on aquatic organisms, although standard acute toxicity data have been reported for some pharmaceuticals (Halling-Sørensen et al., 1998, 2000; Pascoe et al., 2003). To date, information on the fates and effects of PPCPs in the environment is derived from studies conducted in Europe, the UK, and the USA. No environmental data for the fate and effects of PPCPs have been produced in Asia. In this Viewpoint, we review the issues facing Hong Kong and the Pearl River Delta, southern China, with respect to current knowledge of PPCPsÕ environmental distributions, and their potential for risk to the marine and estuarine environments: (a) potential sources and amounts in Southeast Asia and China; (b) comparative abiotic and tissue data in the northern hemisphere and (c) their toxicological properties, including bioaccumulation potential, environmental transformation and decomposition.
2. What do we know about PPCPs in China and Southeast Asia? The continued growth of the human population in Hong Kong and the Pearl River Delta (HK/PRD) has created an increased demand for the protection of aquatic ecosystems and associated environmental resources, as well as increased disposal of treated and untreated wastes to the aquatic environment. Several persistent organic pollutants (POPs), such as polychlorinated biphenyls (PCBs), hexachlorocyclohexanes (HCHs), and DDTs have been measured and verified in the HK/PRD marine biota, sediments, and water (Richardson et al., 2000; Zheng et al., 2000, 2002; Connell et al., 2003; Mu¨ller et al., 2002), as well as the polybrominated diphenyl ethers (PBDEs) (Zheng et al., 2004) and perfluorinated compounds (PFCs) (So et al., 2004). These compounds are generally characterized by their low degradability, and high bioaccumulation factors. Since 2000, northern hemisphere scientists have paid more attention to more polar compounds, some of which (e.g., the PPCPs) may act as if they are persistent because of their continuous input and permanent presence in aquatic environments (Daughton and Ternes, 1999).
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Knowledge of the presence of these compounds in the marine ecosystem is limited (Weigel et al., 2002), although persistence of certain more lipophilic pharmaceuticals has been shown in marine sediments of the North Sea (Hektoen et al., 1995). There are no published scientific data, and little reliable information, on the presence of pharmaceuticals in HK/PRD and in mainland China environments. Thus, the detection of PPCPs in sediments or waters in the region would confirm their ubiquitous nature observed in other regions, and could lead to new information on their mobility and persistence in the aquatic environment. PPCPs are a diverse group of chemicals comprising all human and veterinary drugs (including the newer ‘‘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., synthetic musks), insect repellents (e.g., DEET or N,N-diethyl-3-toluamide) and sunscreen agents (e.g., methylbenzylidene camphor) (Daughton, 2003). Although many drugs are designed to elicit a wide range of therapeutic endpoints at low physiological doses (mg kg 1), some are more potent and can elicit effects at ng kg 1 concentrations. Most have ill-defined biochemical mechanisms of action, and many interact with multiple non-therapeutic receptors, resulting in potentially adverse effects in non-targeted receptors, such as wildlife species. PPCPs are designed to stimulate a specific physiological response in humans, plants, and animals (Daughton and Ternes, 1999; Halling-Sørensen et al., 1998). Surprisingly, however, little is known about the extent of environmental occurrence, transport, and the ultimate fate of such synthetic organic chemicals after their intended use, particularly hormonally active chemicals (this is also the case with PBDEs, see Martin et al., 2004; and PFCs, So et al., 2004). Toxicological concerns regarding the environmental release of PPCPs include inducement of abnormal physiological processes and reproductive impairment, increased incidences of cancer, development of antibiotic resistant bacteria, and the potential for increased toxicities when chemical mixtures occur in the environment. For many PPCPs, the potential effects on humans and the aquatic environment are not clearly understood. A prime reason for this lies in analytical capabilities to detect PPCPs in the environment: currently, there is a lack of suitable protocols for the identification and measurement of PPCPs without the use of highly expensive technological methods. Environmental concentrations of PPCPs have been reported in the literature for Japan (Yamagishi et al., 1983; Okumura and Nishikawa, 1996), Viet Nam (Le and Munekage, 2004), Denmark (Halling-Sørensen et al., 1998), Germany (Hirsch et al., 1999), UK estuaries (Thomas and Hilton, 2004), the North Sea (Weigel et al., 2002), Brazil rivers (Stumpf et al., 1999), and
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US streams (Kolpin et al., 2002; Boyd et al., 2004). The largest suite of these chemicals (95 organic wastewater contaminants or OWCs) were analysed in the US study (Kolpin et al., 2002), using 5 separate analytical methods. The OWCs are associated with human, industrial, and agricultural wastewaters and include antibiotics, other prescription drugs, non-prescription drugs, steroids, reproductive hormones, personal care products, products of oil use and combustion, and other extensively used chemicals. The most frequently detected compounds were coprostanol (a faecal steroid), cholesterol (a plant and animal steroid), N,N-diethyl-3toluamide or DEET (an insect repellent), caffeine (a widely used psychoanaleptic stimulant), triclosan (an antimicrobial disinfectant), tri (2-chloroethyl) phosphate (a fire retardant), and 4-nonylphenol (a non-ionic detergent metabolite) (Kolpin et al., 2002). Weigel et al. (2002) report a wide distribution of clofibric acid, caffeine, and DEET in concentrations up to 19, 16, and 1.1 ng l 1, respectively, throughout the North Sea, off Scotland, the outer and inner German Bight, as well as the Danish and Norwegian coasts. Clorfibric acid (a metabolite of 3 separate lipid regulating drugs) has been reported from wastewater in the US (Hignite and Azarnoff, 1977), rivers in the UK (Waggott, 1981), and wastewater/surface waters in Brazil (Stumpf et al., 1999). Concentrations of clorfibric acid ranged from the lower 100 ng l 1 range in wastewater to <10 ng l 1 in river waters, although up to 60 ng l 1 were reported from the Brazilian study in surface drinking water supplies (Stumpf et al., 1999). Samples collected from UK estuaries had clorfibric acid concentrations of approximately 100 ng l 1 in 2 samples (Thomas and Hilton, 2004). Other frequently measured pharmaceutical compounds found in UK estuaries included clotrimazole (a topical antifungal agent; 59% of samples, up to 22 ng l 1), ibuprofen (an analgesic, in 50% of samples, up to 928 ng l 1), trimethoprim (an antibiotic, in 50% of samples, up to 569 ng l 1), propranolol (an antihypertensive drug in 41% of samples, up to 56 ng l 1), with several other drugs appearing in approximately one third of the samples at lower concentrations (Thomas and Hilton, 2004). As is the case for many other parts of the world, the environmental sources and loadings of PPCPs have not received study in China largely because they have not been viewed historically as potential environmental pollutants. We estimate the 2004 human usage of antibiotics alone in HK/PRD region at 15,770 tonnes per annum, with equal or possibly larger quantities used in the agricultural sector as food supplements for cattle and poultry or veterinary applications. Because of the enormous quantities of antibiotics (penicillins, tetracyclines, sulfonamids, and macrolid antibiotics) produced, imported, and used in mainland China and Hong Kong, we believe there is substantive potential
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for PPCPs (and particularly antibiotics) to occur in higher concentrations, and possibly with wider distributions, than those found in western countries (Europe, UK, and USA). Daughton and Ternes (1999) summarized the environmental fate of PPCPs as follows. The low concentrations of individual PPCPs (possibly exceeding the catabolic enzyme affinities of sewage microbiota), coupled with their metabolic ‘‘novelty’’ and their physical properties (i.e., Kows) lead to their variable removal efficiencies from sewage treatment works (STWs). Compared with persistent organic pollutants (POPs), there is a paucity of information regarding biotransformation and phototransformation of PPCPs. The low volatility of PPCPs means that their distribution through the environment will primarily occur through aqueous transport and food chain dispersal. The polar, non-volatile nature of most drugs prevents their escape from the aquatic realm, and suggests that ‘‘global distillation’’, seen in POPs, will not be a factor with PPCPs. Drug conjugates potentially act as storage ‘‘reservoirs’’ from which the free parent drug can later be released (e.g., via hydrolysis) into the environment. The ecotoxicological effects of these compounds are even less well studied than their environmental distributions. Here, the precautionary advice of Daughton and Ternes (1999) should be noted. These authors identify the major threats of PPCPs as subtle, continual but undetectable or unnoticed effects, which accumulate so slowly that major change goes undetected until the cumulative level of effects finally cascades to irreversible change. Adverse effects which have been noted on aquatic organisms include: (a) green algae toxicity (ciprofloxacin; Halling-Sørensen et al., 2000); (b) endocrine disruption in fish (ethynylestradiol (EE2) and 4 alkylphenols, Jobling et al., 1996); (c) amphipod population effects and sex-ratio changes (EE2, Watts et al., 2002); (d) inhibition of cytochrome P4501A and other P450 enzymes of gizzard shad liver cells (Levine et al., 1997) and (e) spotted sea trout estrogen receptor antagonist (tamoxifen, Thomas and Smith, 1993).
Hong Kong environment ranging from the non-polar PCBs, dioxins, polycyclic aromatic hydrocarbons, and pesticides to the more polar PFCs and PBDEs. Detection and monitoring of organic compounds involves the selection of analytical techniques which ‘‘target’’ specific compounds; those compounds that are not targeted will not be identified, and hence with every analytical scheme there is a spectrum of contaminants that are present but not measured. Another element of a PPCPs survey in the environment is the selection of the proper media, as well as sampling in the proper locations. All municipal sewage, confined agricultural waste effluents, and specific personal product manufacturing plant effluents will contain these chemicals. Each geographic area will vary in the types, quantities and relative abundances of the various PPCP species. As we have indicated earlier, China is one of the leading producers and consumers of certain PPCPs (i.e., antibiotics), and, as such, the local aquatic environments should arguably contain these chemicals, at least in concentrations and areas similar to those in western nations. The aquatic environment, and more specifically, the marine environment of Hong Kong and the PRD, is subjected to continuous exposure of treated and untreated sewage. Conditions in Hong Kong and the PRD may even be more acute than those in other areas, as evidenced by the large number of toxic plankton blooms reported for marine waters (HKEPD, 2002). Historically, three factors are presumably important in causing these conditions: (a) an uncommon type of sewage treatment scheme for Hong Kong (primary treatment of saltwater sewage); (b) manufacturing and municipal waste disposal (1.4 billion tonnes per year) in Guangdong, Pearl River Delta and (c) intensive livestock and poultry raising operations in Guangdong (which has the largest Chinese confined pig farm with 10% of ChinaÕs annual pig production and 30% of ChinaÕs poultry production).
3. PPCPs in China: What needs to be done first?
Antibiotics are an important group of pharmaceuticals in ChinaÕs human and veterinary medicine, and China ranks first in the world in terms of annual production of penicillin, vitamin C, terramycin, doxycycline hydrochloride, and cephalosporin antibiotics. Although current human usage is not known, limited studies (Kumana et al., 1989) and press reports (see: http:// www.augustachronicle.com/stories/031702/tec_1246558. shtml) indicate that the Chinese consume larger quantities of antibiotics than in other places in the world. Daughton and Ternes (1999) reviewed the broad span of drug classes and their environmental fates and distributions. The potential adverse environmental effects
To a great extent, knowledge of new chemicals, including PPCPs, depends upon what chemical one looks for. Since the first unexpected detection of PCBs and DDTs in marine animals from Sweden (Jensen, 1966), analytic techniques have evolved to provide measurements of organic pollutants, ranging from gas chromatography for non-polar compounds to more recent liquid chromatography-tandem MS measurements of polar organic pollutants in liquid and solid matrices. This evolution of organic techniques generally has coincided with the discoveries of ‘‘new’’ chemicals in the
4. Antibiotics as PPCP target compounds for the Pearl River Delta and Hong Kong
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include increased pathogen resistance and genotoxicity. Hypothetically, sufficiently high concentrations of antibiotics could also have negative effects on naturally occurring bacteria. In turn, this could lead to altered microbial community structures, and ultimately adverse effects on higher food web components. Even excluding the potential direct toxicity and ecological significance of antibiotics, their occurrence can be viewed as a ‘‘chemo-marker’’ of the presence of other PPCPs. Findings from a recent study of antibiotics entering the aquatic environment indicated increased resistance to two antibiotics with bacteria from receiving waters (Costanzo et al., 2005). A large body of literature on antibiotics in the environment indicates the principal sources and origins are from veterinary medicine/livestock husbandry practices, aquaculture, and human medicinal treatment (Daughton and Ternes, 1999; Ternes, 1998). Hirsch et al. (1999) analysed sewage treatment plant effluents and river waters for 18 target antibiotic substances from the classes of macrolid antibiotics, sulfonamides, penicillins, and tetracyclines. Erythromycin–H2O, roxithromycin, sulfamethoxazole, and trimethoprim were found in many samples of STW effluents and river waters. Penicillins (susceptible to hydrolysis) and tetracyclines (which can precipitate with calcium and similar ions) were not found as free molecules, but are probably bound to suspended particulates and sediments. Halling-Sørensen et al. (1998) identified anticipated exposure routes to the environment for different types of pharmaceuticals. This framework suggests three possible fates of pharmaceuticals: (1) labile with mineralization to carbon dioxide and water; (2) lipophilic and not readily degradable, being retained in sludge or particulate matter and (3) metabolised to a more hydrophilic form but still persistent, passing through the treatment process and ending up in receiving waters. The previously mentioned explanation by Hirsch et al. (1999) for the lack of tetracyclines and amoxicillin and ampicillin in river water samples is worthy of note here. Medical substances used in fish farming will be directly placed in receiving waters, because they are usually dosed as feed additives (Halling-Sørensen et al., 1998). Large quantities of feed are not consumed and accumulate on the sea floor (Jacobsen and Berglind, 1988; Samuelsen et al., 1992) and may have adverse effects on other aquatic organisms.
5. Marine monitoring research needs for PPCPs in the Pearl River Delta and Hong Kong Daughton (2004) has outlined a list of important needs and gaps for PPCP research in the aquatic environment, centred on the urgent need for an internationally coordinated research strategy to minimise
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duplication of effort and maximise the impact of limited resources. With respect to monitoring, he suggests the following: (a) a standardised approach, applicable to all types of samples, including time-integrated samples; (b) a definitive approach (based upon scientific rationale) for selecting target analytes; (c) selection criteria for target analytes using important controlling variables for guidance (e.g., potency, use rates, etc.); (d) inclusion of a real-time GIS data base for usage data; (e) emphasis on monitoring for outcomes of exposures (such as biomarkers for increased inhibition/induction of cellular stress responses); (f) evaluation of the utility of toxicogenomics and computational toxicology; (g) maintenance of an emphasis and focus on unknown compounds, whilst pursuing ‘‘target’’ PPCPs; (h) development of an early warning water monitoring system based upon ‘‘change detection’’ and (i) improvement in determination of antibacterial resistance. In Asia, inventories and assessments of environmental distributions of PPCPs have not been made, and future research should include identification of the volumes of PPCPs that are being manufactured, as well as the volumes involved in the numerous waste streams, such as STWs or waste effluents from intensive animal and poultry raising operations. PPCPs are most likely present in the environment, so that the recommendations for further research and needs of Daughton (2004) apply to future PPCB research in Asia. The existing database on environmental levels, particularly in aquatic systems, needs to be expanded geographically, as there is essentially no data available for the PRD and Hong Kong. Data from adjacent terrestrial farming localities (i.e., Guangdong) are needed to complete an understanding of the fates of some of the frequently utilised veterinary and animal husbandry activities. Fish farming operations should also be evaluated for suspected releases of antibiotics. Water and sediment samples are necessary to evaluate both those PPCPs that are lipophilic and others that are more water soluble. For each of the groups of PPCPs, different analytical methods are necessary to allow accurate measurements of target analytes (see Kolpin et al., 2002). In Hong Kong and the PRD region, we believe that there is an urgent need for the measurement of antibiotics in receiving waters, sediments, and STW effluents for the reasons provided earlier. The most suitable method for antibiotic measurements in water, sewage, and sediments are based upon methods that are widely used for medium polarity substances (Hirsch et al., 1998). These methods use solid-phase extraction (SPE) with high performance liquid chromatography/high resolution mass spectrometry positive-ion electrospray analysis (except for chloramphenicol). Target compounds can be selected from the large number of chemical possibilities based upon usage, toxicity, potential hormonal activities, and
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Table 1 ‘‘Target’’ antibiotic compounds that may occur in, or provide sources for aquatic habitats of Hong Kong and the Pearl River Delta Substance
Previous occurrence in aquatic habitats
BCF
Clarithromycin Erythromycin Roxithromycin Sulfamethazine Sulfamethoxazole Trimethoprim Chloramphenicol Chlortetracycline Doxycycline Oxytetracycline Tetracycline Cloxacillin Dicloxacillin Methicillin (Staphcillin) Nafcillin Oxacillin Penicillin G Penicillin V
Yes Yes Yes Yes Yes Yes Soil Yes No Yes Yes Sewage-soil Sewage-soil Sewage-soil Sewage-soil Sewage-soil Sewage-soil Sewage-soil
54 45 26 3.2 3.2 3.2 0.34 3.2 3.2 3.2 3.2 3.2 3.2 3.2 3.2 3.2 3.2 3.2
predicted persistence in the environment. Appropriate reference compounds for the target substances should be utilized to match sample spectra and ion abundance ratios. Table 1 lists the selected antibiotic analytes that we believe should be considered in the monitoring in the South China region. Analyte recoveries have been variable in previous studies (Hirsch et al., 1998; Hilton and Thomas, 2003), so the recoveries for the individual antibiotic species need to be determined for specific laboratories and techniques. Recoveries of analytes, and laboratory blank tests must be performed to determine the precision and accuracy of the extraction and analytical procedures. There are no recognized international consensus samples or authentic standards for most PPCP antibiotics. Thus, the accuracy of the instrumental analyses needs to be verified by the use of matrix spike and matrix spike duplicates with a seawater and estuarine water matrix. Antibiotics have been shown to occur in water and may bioconcentrate in aquatic organisms, including fish and shellfish. Increased usage (and overuse) of antibiotics in China has been reported in the press (http:// www.abc.net.au/rn/talks/8.30/helthrpt/stories/s1073435. html) as well as the scientific literature (Kumana et al., 1989). Asian fish products have been restricted for import into the US (shrimp for chloramphenicol from China, Thailand, and Vietnam; see (http://www.seafood. com/news/current/88631.html). This suggests increasing releases of antibiotics to the environment of China and its neighbouring countries. A comparison should be made to provide an initial assessment of the scale of the problem in the HK/PRD environment by comparing
concentrations of selected antibiotics in water with data reported from other studies. Where there are definitive toxicological data available, assessments of the severity of exposure can be assessed by comparison of measured environmental concentrations with known threshold effect levels. However, it is unlikely that sufficient threshold toxicity effect data are available to be able to conduct a risk assessment in this manner, and a second approach following Halling-Sørensen et al. (2000) may allow an environmental risk assessment where sufficient data can be developed.
6. Conclusions and recommendations It is clear that there has not been adequate evaluation of PPCPs in environmental media from the Southeast Asian region. Evaluation and reporting of inventories of production and usage of PPCPs in all countries of Southeast Asia is a critical need. A standardised approach, with application to all types of samples, including time-integrated samples, needs to be developed for the region. A first step should be for all countries in the region is to coordinate their activities in order to determine individual interests in evaluating PPCPs followed by evaluation of individual capabilities and resources to be able to accomplish PPCP measurements. The approach and framework of the Southeast Asian Mussel Watch studies (Monirith et al., 2003) is an appropriate means to organise local scientists and researchers into the focused and common aim of contaminant measurement. Since analytical facilities, technical capabilities and resources are a critical element to the successful measurement of PPCPs, target analyte selection (based upon presence, use, and potency of PPCPs) needs to be evaluated amongst laboratories, researchers, and national interests pursuing this research. A companion effort to concurrently evaluate monitoring approaches for outcomes of exposures (or biomarkers) and inclusion of a real-time GIS database should be considered in programme development. Future considerations should emphasise currently ‘‘unknown’’ compounds, whilst pursuing the monitoring and evaluation of ‘‘target’’ PPCPs. For the future, we hope that the accurate analysis and reporting of PPCPs for selected geographical sections of the region can be accomplished, to allow the data usage for toxicological assessments and comparisons to move forward on a regional basis.
Acknowledgements This research has been supported by funding from a Strategic Research Grant (7001818) of the City University of Hong Kong.
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antibiotic resistant bacteria in animals and humans. Report by Commonwealth Department of Health and Aged Care and Commonwealth Department of Agriculture, Fisheries and Forestry Australia, Canberra, ACT, 238 pp. Kahn, J., 2003. Foul Water and air part of cost of the boom in ChinaÕs exports. New York Times, February 4, 2003, Late Edition Final, Section A, Page 1, Column 1. Kolpin, D.W., Furlong, E.T., Meyer, M.T., Thurman, E.M., Zaugg, S.D., Barber, L.B., Buxton, H.T., 2002. Pharmaceuticals, hormones, and other organic wastewater contaminants in US streams, 1999–2000: a national reconnaissance. Environ. Sci. Technol. 36, 1202–1211. Kumana, C.R., Li, K.Y., Kou, M., Chan, S.C., 1989. Cephalosporin and aminoglycoside utilization in different parts of the world. J. Antimicrob. Chemother. 24, 1001–1010. Le, T.X., Munekage, Y., 2004. Residues of selected antibiotics in water and mud from shrimp ponds in mangrove areas in Viet Nam. Mar. Pollut. Bull. 49, 922–929. Levine, S.L., Czosnyka, H., Oris, J.T., 1997. Effect of clotrimazole on the bioconcentration of benzo[a]pyrene in gizzard shad (Dorosoma cependianum) in vivo and in vitro inhibition of cytochrome P4501A activity. Environ. Toxicol. Chem. 16, 3006–3011. Martin, M., Lam, P.K.S., Richardson, B.J., 2004. An Asian quandary: Where have all of the PBDEs gone? Mar. Pollut. Bull. 49, 375– 382. Monirith, I., Ueno, D., Takahashi, S., Nakata, H., Sudaryanto, A., Subramanian, A., Karuppiah, S., Ismail, A., Muchtar, M., Zheng, J., Richardson, B., Prudente, M., Hue, N.D., Tana, T.S., Tkalin, A.V., Tanabe, S., 2003. Asia–Pacific mussel watch: monitoring contamination of persistent organochlorine compounds in coastal waters of Asian countries. Mar. Pollut. Bull. 46, 281–300. Mu¨ller, J.F., Gaus, C., Prange, J.A., Paepke, O., Poon, K.F., Lam, M.H.W., Lam, P.K.S., 2002. Polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans in sediments from Hong Kong. Mar. Pollut. Bull. 45, 372–378. Okumura, T., Nishikawa, Y., 1996. Gas chromatography-mass spectrometry determination of triclosans in water, sediment, and fish samples via methylation with diazomethane. Anal. Chem. Acta 325 (3), 175–184. Pascoe, D., Karntanut, W., Mu¨ller, C.T., 2003. Do pharmaceuticals affect freshwater invertebrates? A study with the cnidarian Hydra vulgaris. Chemosphere 51, 521–528. Richardson, B.J., Lam, P.K.S., Wu, R.S.S., 2000. The coast of Hong Kong. In: Sheppard, C. (Ed.), Seas at the Millennium: An Environmental Evaluation, vol. II. Elsevier Science, pp. 535– 547. Samuelsen, O.B., Torsvik, V., Ervik, A., 1992. Long-range changes in oxytetracycline concentration and bacterial resistance towards oxytetracycline in a fish farm sediment after medication. Sci. Total Environ. 114, 25–36. So, M.K., Taniyasu, S., Yamashita, N., Giesy, J.P., Zheng, J., Fang, Z., Im, S.H., Lam, P.K.S., 2004. Perfluorinated compounds in coastal waters of Hong Kong, South China and Korea. Environ. Sci. Technol. 38, 4056–4063. Stumpf, M., Ternes, T.A., Wilken, R.-D., Rodrigues, S.V., Baumann, W., 1999. Polar drug residues in sewage and natural waters in the state of Rio de Janeiro, Brazil. Sci. Total Environ. 225, 135– 141. Ternes, T.A., 1998. Occurrence of drugs in German sewage treatment plants and rivers. Water Res. 32 (11). Ternes, T.A., Joss, A., Siegrist, H., 2004. Scrutinizing pharmaceuticals and personal care products in wastewater treatment. Environ. Sci. Technol. 38 (20), 392A–399A. Thomas, K.V., Hilton, M.J., 2004. The occurrence of selected human pharmaceutical compounds in UK estuaries. Mar. Pollut. Bull. 49, 436–444.
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Thomas, P., Smith, J., 1993. Binding of xenobiotics to the estrogen receptor of spotted seatrout: a screening assay for potential estrogenic effects. Mar. Environ. Res. 35, 147–151. Waggott, A., 1981. In: Cooper, W. (Ed.), Trace organic substances in the River Lee [Great Britain]. Chem. Water Reuse J., 55–99. Ann Arbor Science, Ann Arbor, Michigan. Watts, M.W., Pascoe, D., Carroll, K., 2002. Population responses of the freshwater amphipod (Gammarus pulex L.) to an environmental estrogen, 17a-ethinylestradiol. Environ. Toxicol. Chem. 21 (2), 445–450. Weigel, S., Kuhlmann, J., Hu¨hnerfuss, H., 2002. Drugs and personal care products as ubiquitous pollutants: occurrence and distribution of clorfibric acid, caffeine and DEET in the North Sea. Sci. Total Environ. 295, 121–141. Yamagishi, T., Miyazaki, T., Horii, S., Kaneko, S., 1983. Synthetic musk residues in biota and water from Tama River and Tokyo Bay (Japan). Arch. Environ. Contam. Toxicol. 12, 83–89.
Zheng, G.J., Lam, M.H.W., Lam, P.K.S., Richardson, B.J., Man, B.K.W., Li, A.M.Y., 2000. Concentrations of persistent organic pollutants in surface sediments of the mudflat and mangroves at Mai Po Marshes Natural Reserve, Hong Kong. Mar. Pollut. Bull. 40, 1210–1214. Zheng, G.J., Man, B.K.W., Lam, J.C.W., Lam, M.H.W., Lam, P.K.S., 2002. Distribution and sources of polycyclic aromatic hydrocarbons in the sediment of a subtropical coastal wetland. Water Res. 36, 1457–1468. Zheng, G.J., Martin, M., Richardson, B.J., Yu, H., Liu, Y., Zhou, C., Li, J., Hu, G., Lam, M.H.W., Lam, P.K.S., 2004. Concentrations of polybrominated diphenyl ethers (PBDEs) in Pearl River Delta sediments. Mar. Pollut. Bull. 49, 520–524. Zeng, X., Sheng, G., Xiong, Y., Fu, J., 2005. Determination of polycyclic musks in sewage from Guangdong China using gas chromatography–electron impact-mass spectrometry. Chemosphere 60 (6), 817–823.
Viewpoint
Emerging chemicals of concern: Pharmaceuticals and personal care products (PPCPs) in Asia, with particular reference to Southern China Bruce J. Richardson a
a,*
, Paul K.S. Lam a, Michael Martin
b
Department of Biology and Chemistry, Research Centre for Coastal Pollution and Conservation, City University of Hong Kong, 83 Tat Chee Avenue, Kowloon, Hong Kong b Office of Spill Prevention and Response, California Department of Fish and Game, 20 Lower Ragsdale Drive, Suite 100, Monterey, CA 93940, USA
Abstract In many western nations, pharmaceuticals and personal care products (PPCPs) are present in aquatic environments, raising concerns amongst chemists and toxicologists regarding their potential environmental fates and effects. However, there are few published reports of PPCPs in environmental samples from Southeast Asia. Whilst the environmental toxicology of PPCPs is not well understood, several effects cause concern, such as feminisation or masculinisation by hormones and xenoestrogens, synergistic toxicity from complex mixtures at low concentrations, potential creation of resistant strains in natural bacterial populations, and other potential concerns for human health. Whilst both the presence and distributions of PPCPs in Southeast Asia and China are not well known, observations elsewhere suggest that they may be important contaminants in the aquatic environment. This is particularly emphasised by the enormous production and widespread use of many PPCPs in China, particularly antibiotics utilised in human and veterinary medicine applications. This Viewpoint presents a general description of the issue, characterises the current status of PPCP analyses and reporting in the Southeast Asian region, and proposes a recommended approach for monitoring and chemical assessment of one group of PPCPs, antibiotics, in the aquatic environments of Hong Kong and the Pearl River Delta. 2005 Elsevier Ltd. All rights reserved. Keywords: Pharmaceuticals and personal care products (PPCPs); Southeast Asia
1. Introduction Pharmaceuticals and personal care products (PPCPs) are a diverse group of environmental chemicals that have captured the attention of scientists and the public, especially in the more developed western countries of North America, the United Kingdom, and Europe. There are more than 3000 different substances used as medicines, including painkillers, antibiotics, contraceptives, beta-blockers, lipid regulators, tranquilizers, and *
Corresponding author. Tel.: +852 2788 7042; fax: +852 2788 7406. E-mail address: [email protected] (B.J. Richardson).
0025-326X/$ - see front matter 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.marpolbul.2005.06.034
impotence drugs (Ternes et al., 2004). During and after treatment, humans and animals excrete a combination of intact and metabolised pharmaceuticals, many of which are generally soluble in water and have been discharged to the aquatic environment with little evaluation of possible risks or consequences to humans and the environment. In addition, chemicals that are components of personal care products number in the thousands, and are contained in skin care products, dental care products, soaps, sunscreen agents and hair care products. Annual production exceeds 1 · 106 tonnes worldwide (for example, >553,000 tonnes were produced in Germany alone in 1993; Daughton and Ternes,
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1999). Included in this category are fragrances (e.g., nitro- and polycyclic-musks), UV blockers (e.g., methylbenzylidene camphor), and preservatives (e.g., parabens). Unlike pharmaceuticals, personal care products enter wastewater and the aquatic environment after regular use during showering or bathing. The environmental fates and effects of many cosmetic ingredients are poorly known, although considerable persistence and bioaccumulation in aquatic organisms have been reported (see Daughton and Ternes, 1999). In almost every aquatic environment in North America and Europe, pharmaceuticals, hormones, metabolites, biocides, musks, and flame retardants have been measured (Ternes, 1998; Kolpin et al., 2002; Hirsch et al., 1999; Hilton and Thomas, 2003). One of the principal sources is the release of municipal wastewater, because people either excrete pharmaceuticals during normal medical treatment or they dispose of excess drugs in toilets; in addition, personal care products can enter aquatic environments via showering and bathing. Pharmaceuticals that do not readily biodegrade enter receiving waters through the discharge of waste treatment plant effluents or direct application in fish foods, and have been measured in water (Weigel et al., 2002) and sediments (Samuelsen et al., 1992) from the marine environment. What is the potential for these chemicals to occur in China and other Southeast Asian nations? Currently, there are few published reports of PPCPs in the region, although we are aware of a recent PPCPs (alkylated musks) survey of sewage treatment plants in Guangdong, China (Zheng et al., 2005) and a second report of antibiotics associated with mariculture in Viet Nam (Le and Munekage, 2004). At a pharmaceutical plant in Taizhou, China, deaths and illnesses of workers, assigned to chemical runoff from the factory into an open creek running beside the plant, have been reported (Kahn, 2003); however, it appears that these are not directly related to PPCP-induced toxicity. ChinaÕs use of antibiotic products is legendary, although accurate statistics on dosage and use amongst its citizens are not available. Press reports have indicated that more than 70% of the drug prescriptions nationwide in China are for antibiotics, and in contrast, this figure is approximately 30% in western countries. Other uses of antibiotics are in farming and aquaculture, and for this reason Chinese shrimp and prawns have been banned in Europe and the United States (Chao, 2003). The use of antibiotics in livestock and bird farming has not been evaluated in China or other Southeast Asian nations; however, Australia has published figures on the practical uses and relative distribution of antibiotics: 36% for human medicine, 8% for veterinary medicine, and 56% mixed into stock feed; pigs and poultry receive the highest proportions of antibiotic dosage to livestock (JETACAR, 1999).
In 2003, China was the worldÕs largest producer of pharmaceutical products, with an annual production of 28,000 tonnes of penicillin (60% of the world total), 10,000 tonnes of terramycin (65% of world total), and is ranked first amongst nations for doxycyline hydrochloride (a tetracycline species) and cephalosporins (http://www.inpharma.com/news/ng.asp?id=53300). In contrast, Germany produces 900 tonnes of penicillin per year (Hirsch et al., 1999) and Denmark 87 tonnes of antibiotics (Halling-Sørensen et al., 1998). At present, little is known about the adverse effects of human and veterinary pharmaceuticals on aquatic organisms, although standard acute toxicity data have been reported for some pharmaceuticals (Halling-Sørensen et al., 1998, 2000; Pascoe et al., 2003). To date, information on the fates and effects of PPCPs in the environment is derived from studies conducted in Europe, the UK, and the USA. No environmental data for the fate and effects of PPCPs have been produced in Asia. In this Viewpoint, we review the issues facing Hong Kong and the Pearl River Delta, southern China, with respect to current knowledge of PPCPsÕ environmental distributions, and their potential for risk to the marine and estuarine environments: (a) potential sources and amounts in Southeast Asia and China; (b) comparative abiotic and tissue data in the northern hemisphere and (c) their toxicological properties, including bioaccumulation potential, environmental transformation and decomposition.
2. What do we know about PPCPs in China and Southeast Asia? The continued growth of the human population in Hong Kong and the Pearl River Delta (HK/PRD) has created an increased demand for the protection of aquatic ecosystems and associated environmental resources, as well as increased disposal of treated and untreated wastes to the aquatic environment. Several persistent organic pollutants (POPs), such as polychlorinated biphenyls (PCBs), hexachlorocyclohexanes (HCHs), and DDTs have been measured and verified in the HK/PRD marine biota, sediments, and water (Richardson et al., 2000; Zheng et al., 2000, 2002; Connell et al., 2003; Mu¨ller et al., 2002), as well as the polybrominated diphenyl ethers (PBDEs) (Zheng et al., 2004) and perfluorinated compounds (PFCs) (So et al., 2004). These compounds are generally characterized by their low degradability, and high bioaccumulation factors. Since 2000, northern hemisphere scientists have paid more attention to more polar compounds, some of which (e.g., the PPCPs) may act as if they are persistent because of their continuous input and permanent presence in aquatic environments (Daughton and Ternes, 1999).
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Knowledge of the presence of these compounds in the marine ecosystem is limited (Weigel et al., 2002), although persistence of certain more lipophilic pharmaceuticals has been shown in marine sediments of the North Sea (Hektoen et al., 1995). There are no published scientific data, and little reliable information, on the presence of pharmaceuticals in HK/PRD and in mainland China environments. Thus, the detection of PPCPs in sediments or waters in the region would confirm their ubiquitous nature observed in other regions, and could lead to new information on their mobility and persistence in the aquatic environment. PPCPs are a diverse group of chemicals comprising all human and veterinary drugs (including the newer ‘‘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., synthetic musks), insect repellents (e.g., DEET or N,N-diethyl-3-toluamide) and sunscreen agents (e.g., methylbenzylidene camphor) (Daughton, 2003). Although many drugs are designed to elicit a wide range of therapeutic endpoints at low physiological doses (mg kg 1), some are more potent and can elicit effects at ng kg 1 concentrations. Most have ill-defined biochemical mechanisms of action, and many interact with multiple non-therapeutic receptors, resulting in potentially adverse effects in non-targeted receptors, such as wildlife species. PPCPs are designed to stimulate a specific physiological response in humans, plants, and animals (Daughton and Ternes, 1999; Halling-Sørensen et al., 1998). Surprisingly, however, little is known about the extent of environmental occurrence, transport, and the ultimate fate of such synthetic organic chemicals after their intended use, particularly hormonally active chemicals (this is also the case with PBDEs, see Martin et al., 2004; and PFCs, So et al., 2004). Toxicological concerns regarding the environmental release of PPCPs include inducement of abnormal physiological processes and reproductive impairment, increased incidences of cancer, development of antibiotic resistant bacteria, and the potential for increased toxicities when chemical mixtures occur in the environment. For many PPCPs, the potential effects on humans and the aquatic environment are not clearly understood. A prime reason for this lies in analytical capabilities to detect PPCPs in the environment: currently, there is a lack of suitable protocols for the identification and measurement of PPCPs without the use of highly expensive technological methods. Environmental concentrations of PPCPs have been reported in the literature for Japan (Yamagishi et al., 1983; Okumura and Nishikawa, 1996), Viet Nam (Le and Munekage, 2004), Denmark (Halling-Sørensen et al., 1998), Germany (Hirsch et al., 1999), UK estuaries (Thomas and Hilton, 2004), the North Sea (Weigel et al., 2002), Brazil rivers (Stumpf et al., 1999), and
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US streams (Kolpin et al., 2002; Boyd et al., 2004). The largest suite of these chemicals (95 organic wastewater contaminants or OWCs) were analysed in the US study (Kolpin et al., 2002), using 5 separate analytical methods. The OWCs are associated with human, industrial, and agricultural wastewaters and include antibiotics, other prescription drugs, non-prescription drugs, steroids, reproductive hormones, personal care products, products of oil use and combustion, and other extensively used chemicals. The most frequently detected compounds were coprostanol (a faecal steroid), cholesterol (a plant and animal steroid), N,N-diethyl-3toluamide or DEET (an insect repellent), caffeine (a widely used psychoanaleptic stimulant), triclosan (an antimicrobial disinfectant), tri (2-chloroethyl) phosphate (a fire retardant), and 4-nonylphenol (a non-ionic detergent metabolite) (Kolpin et al., 2002). Weigel et al. (2002) report a wide distribution of clofibric acid, caffeine, and DEET in concentrations up to 19, 16, and 1.1 ng l 1, respectively, throughout the North Sea, off Scotland, the outer and inner German Bight, as well as the Danish and Norwegian coasts. Clorfibric acid (a metabolite of 3 separate lipid regulating drugs) has been reported from wastewater in the US (Hignite and Azarnoff, 1977), rivers in the UK (Waggott, 1981), and wastewater/surface waters in Brazil (Stumpf et al., 1999). Concentrations of clorfibric acid ranged from the lower 100 ng l 1 range in wastewater to <10 ng l 1 in river waters, although up to 60 ng l 1 were reported from the Brazilian study in surface drinking water supplies (Stumpf et al., 1999). Samples collected from UK estuaries had clorfibric acid concentrations of approximately 100 ng l 1 in 2 samples (Thomas and Hilton, 2004). Other frequently measured pharmaceutical compounds found in UK estuaries included clotrimazole (a topical antifungal agent; 59% of samples, up to 22 ng l 1), ibuprofen (an analgesic, in 50% of samples, up to 928 ng l 1), trimethoprim (an antibiotic, in 50% of samples, up to 569 ng l 1), propranolol (an antihypertensive drug in 41% of samples, up to 56 ng l 1), with several other drugs appearing in approximately one third of the samples at lower concentrations (Thomas and Hilton, 2004). As is the case for many other parts of the world, the environmental sources and loadings of PPCPs have not received study in China largely because they have not been viewed historically as potential environmental pollutants. We estimate the 2004 human usage of antibiotics alone in HK/PRD region at 15,770 tonnes per annum, with equal or possibly larger quantities used in the agricultural sector as food supplements for cattle and poultry or veterinary applications. Because of the enormous quantities of antibiotics (penicillins, tetracyclines, sulfonamids, and macrolid antibiotics) produced, imported, and used in mainland China and Hong Kong, we believe there is substantive potential
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for PPCPs (and particularly antibiotics) to occur in higher concentrations, and possibly with wider distributions, than those found in western countries (Europe, UK, and USA). Daughton and Ternes (1999) summarized the environmental fate of PPCPs as follows. The low concentrations of individual PPCPs (possibly exceeding the catabolic enzyme affinities of sewage microbiota), coupled with their metabolic ‘‘novelty’’ and their physical properties (i.e., Kows) lead to their variable removal efficiencies from sewage treatment works (STWs). Compared with persistent organic pollutants (POPs), there is a paucity of information regarding biotransformation and phototransformation of PPCPs. The low volatility of PPCPs means that their distribution through the environment will primarily occur through aqueous transport and food chain dispersal. The polar, non-volatile nature of most drugs prevents their escape from the aquatic realm, and suggests that ‘‘global distillation’’, seen in POPs, will not be a factor with PPCPs. Drug conjugates potentially act as storage ‘‘reservoirs’’ from which the free parent drug can later be released (e.g., via hydrolysis) into the environment. The ecotoxicological effects of these compounds are even less well studied than their environmental distributions. Here, the precautionary advice of Daughton and Ternes (1999) should be noted. These authors identify the major threats of PPCPs as subtle, continual but undetectable or unnoticed effects, which accumulate so slowly that major change goes undetected until the cumulative level of effects finally cascades to irreversible change. Adverse effects which have been noted on aquatic organisms include: (a) green algae toxicity (ciprofloxacin; Halling-Sørensen et al., 2000); (b) endocrine disruption in fish (ethynylestradiol (EE2) and 4 alkylphenols, Jobling et al., 1996); (c) amphipod population effects and sex-ratio changes (EE2, Watts et al., 2002); (d) inhibition of cytochrome P4501A and other P450 enzymes of gizzard shad liver cells (Levine et al., 1997) and (e) spotted sea trout estrogen receptor antagonist (tamoxifen, Thomas and Smith, 1993).
Hong Kong environment ranging from the non-polar PCBs, dioxins, polycyclic aromatic hydrocarbons, and pesticides to the more polar PFCs and PBDEs. Detection and monitoring of organic compounds involves the selection of analytical techniques which ‘‘target’’ specific compounds; those compounds that are not targeted will not be identified, and hence with every analytical scheme there is a spectrum of contaminants that are present but not measured. Another element of a PPCPs survey in the environment is the selection of the proper media, as well as sampling in the proper locations. All municipal sewage, confined agricultural waste effluents, and specific personal product manufacturing plant effluents will contain these chemicals. Each geographic area will vary in the types, quantities and relative abundances of the various PPCP species. As we have indicated earlier, China is one of the leading producers and consumers of certain PPCPs (i.e., antibiotics), and, as such, the local aquatic environments should arguably contain these chemicals, at least in concentrations and areas similar to those in western nations. The aquatic environment, and more specifically, the marine environment of Hong Kong and the PRD, is subjected to continuous exposure of treated and untreated sewage. Conditions in Hong Kong and the PRD may even be more acute than those in other areas, as evidenced by the large number of toxic plankton blooms reported for marine waters (HKEPD, 2002). Historically, three factors are presumably important in causing these conditions: (a) an uncommon type of sewage treatment scheme for Hong Kong (primary treatment of saltwater sewage); (b) manufacturing and municipal waste disposal (1.4 billion tonnes per year) in Guangdong, Pearl River Delta and (c) intensive livestock and poultry raising operations in Guangdong (which has the largest Chinese confined pig farm with 10% of ChinaÕs annual pig production and 30% of ChinaÕs poultry production).
3. PPCPs in China: What needs to be done first?
Antibiotics are an important group of pharmaceuticals in ChinaÕs human and veterinary medicine, and China ranks first in the world in terms of annual production of penicillin, vitamin C, terramycin, doxycycline hydrochloride, and cephalosporin antibiotics. Although current human usage is not known, limited studies (Kumana et al., 1989) and press reports (see: http:// www.augustachronicle.com/stories/031702/tec_1246558. shtml) indicate that the Chinese consume larger quantities of antibiotics than in other places in the world. Daughton and Ternes (1999) reviewed the broad span of drug classes and their environmental fates and distributions. The potential adverse environmental effects
To a great extent, knowledge of new chemicals, including PPCPs, depends upon what chemical one looks for. Since the first unexpected detection of PCBs and DDTs in marine animals from Sweden (Jensen, 1966), analytic techniques have evolved to provide measurements of organic pollutants, ranging from gas chromatography for non-polar compounds to more recent liquid chromatography-tandem MS measurements of polar organic pollutants in liquid and solid matrices. This evolution of organic techniques generally has coincided with the discoveries of ‘‘new’’ chemicals in the
4. Antibiotics as PPCP target compounds for the Pearl River Delta and Hong Kong
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include increased pathogen resistance and genotoxicity. Hypothetically, sufficiently high concentrations of antibiotics could also have negative effects on naturally occurring bacteria. In turn, this could lead to altered microbial community structures, and ultimately adverse effects on higher food web components. Even excluding the potential direct toxicity and ecological significance of antibiotics, their occurrence can be viewed as a ‘‘chemo-marker’’ of the presence of other PPCPs. Findings from a recent study of antibiotics entering the aquatic environment indicated increased resistance to two antibiotics with bacteria from receiving waters (Costanzo et al., 2005). A large body of literature on antibiotics in the environment indicates the principal sources and origins are from veterinary medicine/livestock husbandry practices, aquaculture, and human medicinal treatment (Daughton and Ternes, 1999; Ternes, 1998). Hirsch et al. (1999) analysed sewage treatment plant effluents and river waters for 18 target antibiotic substances from the classes of macrolid antibiotics, sulfonamides, penicillins, and tetracyclines. Erythromycin–H2O, roxithromycin, sulfamethoxazole, and trimethoprim were found in many samples of STW effluents and river waters. Penicillins (susceptible to hydrolysis) and tetracyclines (which can precipitate with calcium and similar ions) were not found as free molecules, but are probably bound to suspended particulates and sediments. Halling-Sørensen et al. (1998) identified anticipated exposure routes to the environment for different types of pharmaceuticals. This framework suggests three possible fates of pharmaceuticals: (1) labile with mineralization to carbon dioxide and water; (2) lipophilic and not readily degradable, being retained in sludge or particulate matter and (3) metabolised to a more hydrophilic form but still persistent, passing through the treatment process and ending up in receiving waters. The previously mentioned explanation by Hirsch et al. (1999) for the lack of tetracyclines and amoxicillin and ampicillin in river water samples is worthy of note here. Medical substances used in fish farming will be directly placed in receiving waters, because they are usually dosed as feed additives (Halling-Sørensen et al., 1998). Large quantities of feed are not consumed and accumulate on the sea floor (Jacobsen and Berglind, 1988; Samuelsen et al., 1992) and may have adverse effects on other aquatic organisms.
5. Marine monitoring research needs for PPCPs in the Pearl River Delta and Hong Kong Daughton (2004) has outlined a list of important needs and gaps for PPCP research in the aquatic environment, centred on the urgent need for an internationally coordinated research strategy to minimise
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duplication of effort and maximise the impact of limited resources. With respect to monitoring, he suggests the following: (a) a standardised approach, applicable to all types of samples, including time-integrated samples; (b) a definitive approach (based upon scientific rationale) for selecting target analytes; (c) selection criteria for target analytes using important controlling variables for guidance (e.g., potency, use rates, etc.); (d) inclusion of a real-time GIS data base for usage data; (e) emphasis on monitoring for outcomes of exposures (such as biomarkers for increased inhibition/induction of cellular stress responses); (f) evaluation of the utility of toxicogenomics and computational toxicology; (g) maintenance of an emphasis and focus on unknown compounds, whilst pursuing ‘‘target’’ PPCPs; (h) development of an early warning water monitoring system based upon ‘‘change detection’’ and (i) improvement in determination of antibacterial resistance. In Asia, inventories and assessments of environmental distributions of PPCPs have not been made, and future research should include identification of the volumes of PPCPs that are being manufactured, as well as the volumes involved in the numerous waste streams, such as STWs or waste effluents from intensive animal and poultry raising operations. PPCPs are most likely present in the environment, so that the recommendations for further research and needs of Daughton (2004) apply to future PPCB research in Asia. The existing database on environmental levels, particularly in aquatic systems, needs to be expanded geographically, as there is essentially no data available for the PRD and Hong Kong. Data from adjacent terrestrial farming localities (i.e., Guangdong) are needed to complete an understanding of the fates of some of the frequently utilised veterinary and animal husbandry activities. Fish farming operations should also be evaluated for suspected releases of antibiotics. Water and sediment samples are necessary to evaluate both those PPCPs that are lipophilic and others that are more water soluble. For each of the groups of PPCPs, different analytical methods are necessary to allow accurate measurements of target analytes (see Kolpin et al., 2002). In Hong Kong and the PRD region, we believe that there is an urgent need for the measurement of antibiotics in receiving waters, sediments, and STW effluents for the reasons provided earlier. The most suitable method for antibiotic measurements in water, sewage, and sediments are based upon methods that are widely used for medium polarity substances (Hirsch et al., 1998). These methods use solid-phase extraction (SPE) with high performance liquid chromatography/high resolution mass spectrometry positive-ion electrospray analysis (except for chloramphenicol). Target compounds can be selected from the large number of chemical possibilities based upon usage, toxicity, potential hormonal activities, and
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Table 1 ‘‘Target’’ antibiotic compounds that may occur in, or provide sources for aquatic habitats of Hong Kong and the Pearl River Delta Substance
Previous occurrence in aquatic habitats
BCF
Clarithromycin Erythromycin Roxithromycin Sulfamethazine Sulfamethoxazole Trimethoprim Chloramphenicol Chlortetracycline Doxycycline Oxytetracycline Tetracycline Cloxacillin Dicloxacillin Methicillin (Staphcillin) Nafcillin Oxacillin Penicillin G Penicillin V
Yes Yes Yes Yes Yes Yes Soil Yes No Yes Yes Sewage-soil Sewage-soil Sewage-soil Sewage-soil Sewage-soil Sewage-soil Sewage-soil
54 45 26 3.2 3.2 3.2 0.34 3.2 3.2 3.2 3.2 3.2 3.2 3.2 3.2 3.2 3.2 3.2
predicted persistence in the environment. Appropriate reference compounds for the target substances should be utilized to match sample spectra and ion abundance ratios. Table 1 lists the selected antibiotic analytes that we believe should be considered in the monitoring in the South China region. Analyte recoveries have been variable in previous studies (Hirsch et al., 1998; Hilton and Thomas, 2003), so the recoveries for the individual antibiotic species need to be determined for specific laboratories and techniques. Recoveries of analytes, and laboratory blank tests must be performed to determine the precision and accuracy of the extraction and analytical procedures. There are no recognized international consensus samples or authentic standards for most PPCP antibiotics. Thus, the accuracy of the instrumental analyses needs to be verified by the use of matrix spike and matrix spike duplicates with a seawater and estuarine water matrix. Antibiotics have been shown to occur in water and may bioconcentrate in aquatic organisms, including fish and shellfish. Increased usage (and overuse) of antibiotics in China has been reported in the press (http:// www.abc.net.au/rn/talks/8.30/helthrpt/stories/s1073435. html) as well as the scientific literature (Kumana et al., 1989). Asian fish products have been restricted for import into the US (shrimp for chloramphenicol from China, Thailand, and Vietnam; see (http://www.seafood. com/news/current/88631.html). This suggests increasing releases of antibiotics to the environment of China and its neighbouring countries. A comparison should be made to provide an initial assessment of the scale of the problem in the HK/PRD environment by comparing
concentrations of selected antibiotics in water with data reported from other studies. Where there are definitive toxicological data available, assessments of the severity of exposure can be assessed by comparison of measured environmental concentrations with known threshold effect levels. However, it is unlikely that sufficient threshold toxicity effect data are available to be able to conduct a risk assessment in this manner, and a second approach following Halling-Sørensen et al. (2000) may allow an environmental risk assessment where sufficient data can be developed.
6. Conclusions and recommendations It is clear that there has not been adequate evaluation of PPCPs in environmental media from the Southeast Asian region. Evaluation and reporting of inventories of production and usage of PPCPs in all countries of Southeast Asia is a critical need. A standardised approach, with application to all types of samples, including time-integrated samples, needs to be developed for the region. A first step should be for all countries in the region is to coordinate their activities in order to determine individual interests in evaluating PPCPs followed by evaluation of individual capabilities and resources to be able to accomplish PPCP measurements. The approach and framework of the Southeast Asian Mussel Watch studies (Monirith et al., 2003) is an appropriate means to organise local scientists and researchers into the focused and common aim of contaminant measurement. Since analytical facilities, technical capabilities and resources are a critical element to the successful measurement of PPCPs, target analyte selection (based upon presence, use, and potency of PPCPs) needs to be evaluated amongst laboratories, researchers, and national interests pursuing this research. A companion effort to concurrently evaluate monitoring approaches for outcomes of exposures (or biomarkers) and inclusion of a real-time GIS database should be considered in programme development. Future considerations should emphasise currently ‘‘unknown’’ compounds, whilst pursuing the monitoring and evaluation of ‘‘target’’ PPCPs. For the future, we hope that the accurate analysis and reporting of PPCPs for selected geographical sections of the region can be accomplished, to allow the data usage for toxicological assessments and comparisons to move forward on a regional basis.
Acknowledgements This research has been supported by funding from a Strategic Research Grant (7001818) of the City University of Hong Kong.
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