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Ecotoxicology (2008) 17:526–538 DOI 10.1007/s10646-008-0209-x

Hazard assessment of commonly used agricultural antibiotics on aquatic ecosystems Sujung Park Æ Kyungho Choi

Accepted: 3 April 2008 / Published online: 1 May 2008 Ó Springer Science+Business Media, LLC 2008

Abstract In this study, eleven commonly used antibiotics including sulfonamides, tetracyclines, aminoglycosides, fluoroquinolones, and beta-lactams were evaluated for their acute and chronic aquatic toxicities using standard test organisms e.g., Vibrio fischeri, Daphnia magna, Moina macrocopa, and Oryzias latipes. Among the antibiotics tested for acute toxicity, neomycin was most toxic followed by trimethoprim, sulfamethoxazole and enrofloxacin. Sulfamethazine, oxytetracycline, chlortetracycline, sulfadimethoxine and sulfathiazole were of intermediate toxicity, while ampicillin and amoxicillin were least toxic to the test organisms. There were no trends in sensitivity among test organisms or among different classes of the antibiotics. Only the beta-lactam class was the least toxic. In chronic toxicity test, neomycin affected reproduction and adult survival of D. magna and M. macrocopa with low mg/l levels exposure. Predicted no effect concentrations (PNECs) were derived from the acute and chronic toxicity information gleaned from this study and from literature. When the PNECs were compared with measured environmental concentrations (MECs) reported elsewhere for the test compounds, hazard quotients for sulfamethoxazole, sulfathiazole, chlortetracycline, oxytetracycline, and amoxicillin exceeded unity, which suggests potential ecological implication. Therefore, further studies including monitoring and detailed toxicological studies are required to assess potential ecological risk of these frequently used veterinary antibiotics.

S. Park K. Choi (&) School of Public Health, Seoul National University, Seoul 110-799, Korea e-mail: [email protected]

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Keywords Veterinary antibiotics Hazard assessment Acute toxicity test Chronic toxicity tests Predicted no effect concentration

Introduction A variety of drugs and feed additives are approved for use in livestock farming and companion animal medicine (Boxall et al. 2002; Sarmah et al. 2006). Among the drugs employed in agriculture, antibiotics are among the most widely used for animal health and management. Their major use in livestock farming is not only to treat diseases but also to enhance growth and feed efficiency in livestock (Levey 1992). Antibiotics play a major role in modern agriculture and livestock industries and their use has been on the rise in many parts of the world (Sarmah et al. 2006). For example, annual consumption of antibiotics in 1997 in Denmark exceeded more than 150 ton, out of which [100 ton was used as growth promoters. In US, there was an increase of nearly 80-fold in antibiotic usage for growth promotion within a span of four decades (Jensen 2001). Approximately 23,000 ton of antibiotics are produced each year and about 40% of the total are used in agriculture (Nawaz et al. 2001). A similar increase in antibiotic usage has been observed in several other countries, such as Australia, New Zealand, and EU (Sarmah et al. 2006). In Korea, relatively more amounts of antibiotics are being used in agriculture. The total amounts of veterinary antibiotics used in therapeutic purposes and as feeding additives were approximately 1,000 ton and 500 ton, respectively, in 2005 (KFDA 2005). The use of veterinary medicinal products eventually leads to their release into the various compartments of the environment. Veterinary medicines may release directly to

Hazard assessment of commonly used agricultural antibiotics on aquatic ecosystems

the environment, through the application to surface water as in aquaculture. These compounds may also find their way into the environment through several indirect pathways. Veterinary antibiotics may release to the soil environment by manure spreading on the agricultural fields (Isidori et al. 2005), which would eventually be directed to the water through wash-off during rainfall events. Many veterinary antibiotics have been detected in various compartments of the aquatic environment such as in sewage, surface, ground and drinking waters (Hirsh et al. 1999; Andreozzi et al. 2003; Halling-Sørensen et al. 1998; Ternes 1998; Daughton and Ternes 1999; Zuccato et al. 2000; K} ummerer 2001). Antibiotics, like other pharmaceuticals, would receive metabolism after administration, and be excreted after a series of pharmacokinetics processes. The excretion rates of antibiotics vary with the type of antibiotic, the dosage level, as well as the type and the age of the animal (Katz 1980). Elmund et al. (1971) reported that 25–75% of antibiotics ingested by food animals were excreted in urine and feces. Hirsch et al. (1999) determined elimination rates of ampicillin and amoxicillin were ranging between 60 and 90%. Although most antibiotics are designed to target specific metabolic pathways in humans and domestic animals, they can have numerous often unknown effects on non-target organisms (Daughton and Ternes 1999). In this study, ecological hazards of major veterinary antibiotics were assessed using standard aquatic toxicity model species representing various trophic levels, including Vibrio fischeri, Daphnia magna, Moina macrocopa, and Oryzias latipes. The ecological risk of these compounds was estimated using the measured environmental concentrations (MECs) reported for major antibiotics and the predicted no effect concentrations (PNECs) of the test antibiotics that were derived from toxicity values in this study and other literatures.

Materials and methods Test antibiotics Eleven major veterinary antibiotics, sulfonamide (sulfamethoxazole, sulfathiazole, sulfamethazine, sulfadimethoxine and trimethoprim); tetracycline (chlortetracycline and oxytetracycline); aminoglycoside (neomycin); fluoroquinolone (enrofloxacin); and beta-lactam (amoxycilin and ampicillin), were selected as test compounds based on sales amount in Korea (KFDA 2005). All the test compounds were purchased from Sigma Chemical (St. Louis, MO, USA), and their purities ranged between 97 and 99%. The test concentrations were directly prepared in dilution water, except for

527

sulfadimethoxine, chlortetracycline and oxytetracycline, that were prepared with solvent carrier, 0.5% of dimethylsulphoxide (DMSO). The overview of the physicochemical characteristics of the test antibiotics are summarized in Table 1. Test organisms and maintenance Daphnia magna and M. macrocopa were cultured in-house in moderately hard water manufactured according to the U.S. Environmental Protection Agency guideline (2002), and Oh (2007), respectively under a photoperiod of 16 h light/8 h dark. Daphnia magna culture was maintained at 21 ± 1°C in 6 l glass jars and M. macrocopa culture was maintained at 25 ± 1°C in 3 l glass beakers in Environmental Toxicology Laboratory at Seoul National University. Daphnia magna and M. macrocopa were fed daily with Yeast, Alfalfa, and TetraminÒ (YCT = 1:1:1) and green algae Selenastrum capricornutum. Water quality parameters, including hardness, alkalinity, pH, conductivity, temperature and dissolved oxygen were routinely monitored. The culture water was changed two times a week. Reference tests using sodium chloride as a reference toxicant were performed on a monthly basis to confirm the comparable sensitivity of the test organisms over time (data not shown). Oryzias latipes was in-house cultured in an incubation room at 25 ± 1°C at Environmental Toxicology Laboratory. The fish were kept in dechlorinated tap water prepared by three way filters under a photoperiod of 16 h light/8 h dark and fed Artemia nauplii (\24 h after hatching) twice a day. Acute toxicity tests Vibrio fischeri toxicity test Microtox Model 500 analyzer (Microbics Corp., Calsbad, CA, USA) was used for the bacterial toxicity assay. The ‘‘81.9% Basic test’’ procedure was utilized after a minor modification. The bacterial luminescence, the endpoint of this assay, was measured for each antibiotic after 5 and 15 min of exposure at 15°C. Water quality parameters such as pH and dissolved oxygen of the test solutions were measured before the exposure. Daphnia magna and M. macrocopa acute toxicity test Among freshwater zooplankton, cladocerans, especially D. magna are universally employed in routine bioassays of water for safety standards (Sarma and Nandini 2006; Vesela and Vijverberg 2007). Some typical cladocerans, such as Diaphanosoma and Moina, which have a wide distribution in both tropical and temperate waterbodies

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S. Park, K. Choi

Table 1 Physico-chemical properties of the test antibiotics Antibiotics

Molecular weight

Solubility (mg/l)

Vapor logKow pKa pressure (mmHg)

Sulfonamide Sulfamethoxazole

253.3

1,382

1.3E-7

0.89

Koc

Half-life in environment

8.8 ± 0.5 4.44 at pH 7

No degradation in sewage treatment

7.2 2.65

– 20% degradation after 180 d in marine sediment:

1.4 ± 0.1 Sulfathiazole Sulfamethazine

255.3 278.3

600 1,500

5.84E-15 2.6E-7

0.05 0.89

Sulfadimethoxine

310.3

340

1.49E-9

1.63

945 60

6.2 ± 0.5 95.73

[21 d photodegradation in water

2.4 ± 0.5 Trimethoprim

290.3

400

7.52E-9

6.6

905

No degradation over 42 d in water

478.9

600

3.06E-28 -0.62

6.50

95.22

44% removal after 30d in soil and chicken manure (30°C)

Oxytetracycline

460.4

300

9.05E-23 -1.22

3.27

27,792

96% degradation after 9 d in water

Neomycin Enrofloxacin

614.6 359.4

25,0000 849.7

1.6E-28 -9.41 3.06E-12 1.10

6.27 8.30

10 99,980

– –

Tetracyclines Chlortetracycline

Beta lactam

0.91

Ampicillin

349.4

50,000

2.84E-13

1.45

2.53

534.4

48% biodegradation in sewage treatment

Amoxicillin

365.4

4,000

4.69E-14

0.87

2.40

865.5

30% degradation after 3 months in laying hen feces 34% degradation after 8 d broiler feces

Physico-chemical properties of test antibiotics were gleaned from available literatures

(Petrusek 2002), have been gaining importance, as an alternative to Daphnia in ecotoxicological evaluations. Among these organisms, we chose M. macrocopa in this study since this species is indigenous to Korea. The acute toxicity tests were performed for determining the 48 h EC50 for D. magna. Four replicates of five juveniles (\24 h old) were exposed to various concentrations of antibiotics. All details of the acute toxicity test using daphnids were in accordance with the US EPA guideline (US EPA 2002). Acute toxicity test using M. macrocopa were conducted following the method outlined for D. magna acute toxicity test except for the test temperature which was 25 ± 1°C. Each test vessel contained four replicates of five daphnids in 40 ml of test medium. Immobilization was employed as an endpoint and considered to happen if no movement was detected for 15 s after gentle shaking of the test vehicle. Water quality parameters of pH, temperature, and dissolved oxygen were measured after 48 h exposure. Range-finding experiments were performed to determine the appropriate dose range for tests chemicals. Based on the results of the range-finding tests, ranges for definitive tests were determined. Oryzias latipes acute toxicity test Juveniles (10–14 day post hatch) were exposed to chemicals for 96 h. There were four replicates of five fish each in 50 ml test vessels for each treatment or control. Test

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solution was changed after 48 h, and water quality parameters of pH, temperature, and dissolved oxygen were measured. Test was conducted at 25°C ± 1 and under a photoperiod of 16 h light/8 h dark. At the end of the tests, mortality of fish was recorded (OECD 1993b). Daphnia magna and M. macrocopa chronic toxicity tests The adverse effects of long term exposure to antibiotics on the reproduction and growth of D. magna and M. macrocopa were assessed by 21 d and 8 d exposure, respectively. For D. magna chronic toxicity test, the guideline outlined in OECD (1993a) was followed. For M. macrocopa chronic assay, a test protocol that was developed in house (Oh 2007) was followed. Five antibiotics (sulfamethoxazole, sulfathiazole, trimethoprim, neomycin and enrofloxacin) were chosen since their EC50s were estimated under 150 mg/l in D. magna 48 h acute tests. Daphnia magna and M. macrocopa neonates \24 h old were employed for the test. Test organisms were maintained individually, with each vessel with 50 ml of medium and observed for 21 d (D. magna) and 8 d (M. macrocopa) for survival and reproduction characteristics. Test organisms were exposed to five different concentrations of the antibiotics in serial dilution ratio of three factors. The medium was renewed at least three times per week. Daphnids were fed daily with 100 ll YCT and 200 ll algae. Mortality of neonates was counted and recorded


everyday. Test was conducted in a temperature controlled incubator (Precision 30 MR, Precision Sci., USA) at a temperature of 21 ± 1°C for D. magna and 25 ± 1°C for M. macrocopa. A photoperiod of 16 h light/8 h dark was applied. Neonates were counted daily. At the end of the tests, time to the first reproduction, total numbers of neonates per female, number of broods, size (body length) were monitored. Growth of the surviving adults of each treatment was determined after 21 d and 8 d, respectively. After chronic test, the population growth rate (r) was calculated: Rlx mx e-rx = 1; where lx is the proportion of individuals surviving to age x, mx is the age-specific fecundity (number of neonates produced per surviving female at age x), and x is days. The r integrates the measures of age specific survival and fecundity to estimate the effect of toxicant exposures on population growth (Van Leeuwen et al. 1985). Statistical analyses The median effective or lethal concentrations (E/LC50s) and associated confidence intervals were calculated by the US EPA probit analysis, the Spearman-Karber and the Trimmed Spearman-Karber method using a computer program TOXSTAT (West Inc., Cheyenne, WY, USA). For the chronic toxicity data analyses, a statistical software SPSS (SPSS, Chicago, IL, USA) was used. One-way ANOVA were used and if there were significant differences, Fisher’s Exact Test with a Bonferonni correction was performed after being tested for normality of distribution and homogeneity of variance tests. Risk characterization Hazard quotients (HQs) for the aquatic environment were calculated from the literature reported MECs of the test pharmaceuticals and the respective PNECs derived from the current study and literatures using the following equation, Eq. 1. HQ ¼ MEC=PNEC

ð1Þ

A PNEC value for a given test antibiotic was derived by dividing lowest EC50 or chronic NOEC value obtained from either this study or from the literature, by an appropriate assessment factor (Eq. 2). When only acute toxicity test results were available, an AF of 1,000 was used following the recommendation of EMEA (EMEA 2006). When chronic toxicity data such as NOECs were used for the calculation of PNECs, an AF of 100 was used. If a HQ is calculated to be less than 1, ecological impact is not expected for the given antibiotics.

PNEC ¼

529

Lowest EC50 or NOEC AF

ð2Þ

Results and discussion Acute toxicity of test antibiotics Table 2 showed acute toxicity results of all test organisms. Neomycin showed the highest toxic effect on D. magna (EC50, 42.1 mg/l), M. macrocopa (EC50, 34.1 mg/l) and O. latipes (LC50, 80.8 mg/l). Enrofloxacin was most toxic to D. magna among the test organisms (48 h EC50, 56.7 mg/l). This result corresponds with Bayer (1997) which reported EC50 of D. magna to be [10 mg/l (24 h exposure). Among the sulfonamides, trimethoprim and sulfamethoxazole showed more toxic effects than other compounds on M. macrocopa (54.8 and 70.4 mg/l). Sulfathiazole did not illicit highly toxic effect on D. magna at 24 h (24 h EC50, 616.7 mg/l), however, after 48 h of exposure, the toxicity of D. magna increased by four times (48 h EC50, 149.3 mg/l). With Ceriodaphnia dubia, EC50 of sulfamethoxazole was reported 0.21 to [100 mg/l, and that for trimethoprim was reported 123 mg/l (Ferrari et al. 2003; Halling-Sørensen et al. 1998; Isidori et al. 2005; Nunes et al. 2005). Chlortetracycline and oxytetracycline were more toxic on V. fischeri (15 min IC50, 13.0 and 87.0 mg/l, respectively) among the test organisms. Backhaus and Grimme (1999) studied the toxicity of antibiotics with V. fischeri, and reported the most toxic compound was tetracycline hydrochloride (24 h EC50, 0.0251 mg/l) among the test antibiotics. Isidori et al. (2005) reported V. fischeri 30 min LC50 of 64.50 mg/l for this compound. In addition, toxicity data for tetracyclines are available for several aquatic organisms. Eguchi et al. (2004) reported growth inhibition of oxytetracycline using Selenastrum capricornutum (EC50, 0.342 mg/l) and Chlorella vulgaris (EC50, 7.05 mg/l). Schallenberg and Armstrong (2004) also reported that tetracyclines are bacteriostatic, inhibiting growth and/or reproduction of bacterial cells without resulting in immediate death of the affected bacterial cells. Beta-lactam antibiotics, ampicilin and amoxycilin were less toxic to all test organisms. The toxicity values reported for ampicillin employing other organisms, for example, S. capricornutum and C. vulgaris, were reported [1000 mg/l (Eguchi et al. 2004). In addition, other investigators reported the toxicity of amoxicillin on algae. For amoxicillin, Holten-Lu¨tzhøft et al. (1999) reported EC50s of 0.0037 mg/l, and Brain et al. (2004) reported LOEC of [1 mg/l using Lemna gibba.

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562.5* (NA) [500* (NA) [500 (NA) [500 (NA) [100* (NA) 78.9 (64.2–93.6) 110.1 (69.82–150.3) 80.8 (63.7–97.9) [100 (NA) [1000 (NA) [1000 (NA) [750* (NA) [500* (NA) [500 (NA) [500 (NA) [100* (NA) 88.4 (60–100) 215.4 (19.30–411.6) 138.8 (107.1–170.5) [100 (NA) [1000 (NA) [1000 (NA)

Daphnia magna and M. macrocopa chronic toxicity of test antibiotics

84.9 (37.9–132.8) 430.1 (371.2–488.9) 310.9 (243.9–378.0) 296.6 (171.3–421.9) 144.8 (117.3–172.4) 515 (398.8–631.1) 137.1 (87.88–186.2) 61.9 (54–69.7) 285.7 (176.87–394.5) [1000 (NA) [1000 (NA) * Toxicity data from Kim et al. (2007)

Sulfamethoxazole Sulfathiazole Sulfamethazine Sulfadimethoxine Trimethoprim Chlortetracycline Oxytetracycline Neomycin Enrofloxacin Ampicillin Amoxicillin

74.2* (46.4–118.7) [1000* NA NA 165.1* (149.1–182.9) [20 235.4 (167–333) [1000 (NA) 425.0 (NA) 1056.0 (562–199) 1320.0 (973–179)

78.1* (24.0–25.4) [1000* NA NA 176.7* (158.8–196.6) 13.0 (10.0–17.2) 87.0 (50.8–148.9) [1000 (NA) 326.8 (NA) 2627.0 (384.8–17930) 3597.0 (519.5–24760)

123.1 (101.21–144.9) 149.3* (115.8–192.5) 215.9 (169.65–274.9) 248.0* (199.20–296.8) 92.0 (72.63–111.4) 225 (192–258) 621.2 (437.71–804.8) 42.1 (33.5–50.8) 56.7 (46.78–66.6) [1000 (NA) [1000 (NA)

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An overview of the toxicity data on bacteria, invertebrate and fish, found in the literature are summarized in Table 3. The concentration ranges that resulted in toxic effect on aquatic organisms are mostly found at mg/l level. Also, there are a lot of algae toxicity data rather than invertebrate and fish. Davy et al. (2001) reported that aquatic plants are important components of aquatic ecosystems for a number of reasons. Thus, they are an appropriate assessment endpoint in ecotoxicology and for environmental protection (Brain et al. 2008).

70.4 (57.1–100) 391.1 (341.9–440.3) 110.7 (89.50–136.9) 183.9 (151.83–215.9) 54.8 (52.15–57.5) 272 (224–320) 126.7 (88.6–164.7) 34.1 (27.5–40.8) [200 (NA) [1000 (NA) [1000 (NA)

96 h

[200 (NA) 616.7 (291.7–1303.6) 506.3 (390.69–622.0) 639.8 (396.10–883.5) 155.6 (147.44–163.7) 380.1 (318–422.2) 831.6 (396.51–1267) 116.6 (86.5–146.7) 131.7 (107.9–155.3) [1000 (NA) [1000 (NA)

M. macrocopa (EC50)

24 h 48 h

D. magna (EC50)

24 h 15 min

V. fischeri (IC50)

5 min

Antibiotics

Table 2 Summary of the acute toxicity of the test antibiotics to V. fischeri, D. magna, M. macrocopa, and O. latipes

48 h

48 h

S. Park, K. Choi

O. latipes (LC50)

530

The EC50, LOEC and NOEC values for select antibiotics obtained from chronic D. magna and M. macrocopa tests are summarized in Table 4. Similar to the acute test, neomycin was most toxic among the test pharmaceuticals. The EC50s of neomycin on adult survival were estimated 0.09 mg/l for D. magna and 0.74 mg/l for M. macrocopa. These values are approximately 500 and 50 times lower than the acute EC50 determined for each species, respectively. The EC50 and NOEC of enrofloxacin were calculated 11.47 mg/l and 5 mg/l based on the adult D. magna survival test. Daphnia reproduction was affected at the same levels of exposure. However, survival and reproduction of M. macrocopa was not affected even at the highest experimental concentration of 15 mg/l. Trimethopirm and sulfathiazole affected several reproduction related endpoints such as the first day of reproduction and number of female. For example, trimethoprim delayed the first day of reproduction (on average 14th day) compared to the control group (9th day). Based on this, reproduction NOEC for trimethoprim was estimated 6 mg/l. The endpoints such as adult survival and reproduction capacity of two cladocerans affected net reproductive rates (R0) as well as rate of population growth (r) (Figs. 1 and 2). Population level effects on D. magna and M. macrocopa were observed in a dose-dependent way following exposure to sulfathiazole, trimethoprim, neomycin and enrofloxacin. It appears that population decrease was affected by adult mortality: For example, for neomycin the mortality at the highest exposure concentration lead to low number of offspring and hence influenced R0 and r value. Porter and Orcutt (1977) reported R0 of D. magna were normally 59–83, however, in this study, four antibiotics such as sulfathiazole, trimethoprim, neomycin and enrofloxacin had lower R0 values at the high test concentration (Fig. 1b–e). For M. macrocopa, only neomycin showed toxic effect on the first day of reproduction (Table 4) and R0 (Fig. 2d). Population size and age at first reproduction have great ecological significance for a population (Roff 2001). Moreover, size at maturity does to some extent


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Table 3 Aquatic toxicity data of test antibiotics from literature review Antibiotics/Taxonomic group

Species

Endpoint/Duration

Conc. (mg/l)

Reference

Sulfamethoxazole Bacteria

V. fischeri

30 min EC50

[84

Ferrari et al. (2003)

Bacteria

V. fischeri

30 min LC50

23.3

Isidori et al. (2005)

Algae

C. meneghiniana

96 h EC50

2.4


Algae

C. meneghiniana

96 h NOEC

1.250


Algae

P. subcapitata

96 h EC50

0.146


Algae

P. subcapitata

96 h NOEC

0.09


Algae

L. gibba

7 d LOEC

1

Brain et al. (2004)

Algae

L. gibba

7 d EC50

0.682

Brain et al. (2004)

Algae

L. gibba

7 d EC50

0.081

Brain et al. (2004)

Algae Algae

S. capricornutum S. leopoliensis

72 h EC50 96 h EC50

1.53 0.03

Eguchi et al. (2004) Nunes et al. (2005)

Algae

S. leopoliensis

96 h EC50

26.8


Algae

S. leopoliensis

3 d EC50

0.520


Invertebrate

C. dubia

48 h EC50

15.51

Nunes et al. (2005)

Invertebrate

C. dubia

48 h LC50

[100


Invertebrate

D. magna

48 h LC50

[100


Invertebrate

D. magna

24 h LC50

25.20


Invertebrate

C. dubia

48 h LC50

15.51


Invertebrate

C. dubia

7 d LC50

0.21


Invertebrate

C. dubia

7 d NOEC

0.25


Invertebrate

D. magna

48 h EC50

205.2

Jung et al. (2008)

Invertebrate

D. magna

96 h EC50

177.6

Jung et al. (2008)

Fish

D. rerio

10 d NOEC

[8


Algae

L. gibba

7 d LOEC

0.1

Brain et al. (2004)

Algae Invertebrate

L. gibba A. salina

7 d EC50 24 h LC50

3.552 1866

Brain et al. (2004) Migliore et al. (1993)

Invertebrate

A. salina

48 h LC50

851

Migliore et al. (1993)

Invertebrate

D. magna

48 h EC50

135.7

Jung et al. (2008)

Invertebrate

D. magna

96 h EC50

78.9

Jung et al. (2008)

Fish

L. punctatus

48 h LC50

[100

Wilford (1966)

Fish

L. macrochirus

48 h LC50

[100

Wilford (1966)

Fish

O. mykiss

48 h LC50

[100

Wilford (1966)

Fish

S. trutta

48 h LC50

[100

Wilford (1966)

Fish

S. fontinalis

48 h LC50

[100

Wilford (1966)

Fish

S. namaycush

48 h LC50

[100

Wilford (1966)

Algae

L. gibba

7 d EC50

1.277

Brain et al. (2004)

Invertebrate

D. magna

48 h EC50

185.3

Jung et al. (2008)

Invertebrate

D. magna

96 h EC50

147.5

Jung et al. (2008)

Sulfathiazole

Sulfamethazine

Sulfadimethoxine Algae

S. capricornutum

72 h EC50

2.30

Eguchi et al. (2004)

Algae

S. capricornutum

72 h NOEC

0.529


Algae

C. vulgaris

72 h EC50

11.2


Algae

C. vulgaris

72 h NOEC

\20.3


Algae

L. gibba

7 d EC50

0.248

Brain et al. (2004)

Invertebrate

A. salina

24 h LC50

1866


123

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S. Park, K. Choi

Table 3 continued Antibiotics/Taxonomic group

Species

Endpoint/Duration

Conc. (mg/l)

Reference

Invertebrate

A. salina

48 h LC50

851


Invertebrate

A. salina

72 h LC50

537


Invertebrate

A. salina

96 h LC50

19.5


Algae

M. aeruginosa

7 d EC50

112

Halling-Sørensen et al. (1998)

Algae

S. capricornutum

7 d EC50

110

Algae

S. capricornutum

7 d EC50

130

Halling-Sørensen et al. (1998) Holten-Lu¨tzhøft et al. (1999)

Algae

R. salina

16

Holten-Lu¨tzhøft et al. (1999)

Trimethoprim

Algae

S. capricornutum

72 h EC50

80.3


Algae

S. capricornutum

72 h NOEC

25.5


Algae

L. gibba

7 d EC50

[0.1

Brain et al. (2004)

Invertebrate

D. magna

48 h EC50

167.4

Choi et al. (2008)

Invertebrate Fish

D. magna B. Rerio

48 h EC50 72 h NOEC

123 100

Halling-Sørensen et al. (1998) Halling-Sørensen et al. (1998)

Algae

R. salina

7 d EC50

16

Holten-Lu¨tzhøft et al. (1999)

Algae

M. aeruginosa

7 d EC50

0.05


Algae

S. capricornutum

7 d EC50

3.1


Algae

L. gibba

7 d LOEC

0.300

Brain et al. (2004)

Algae

L. gibba

7 d EC10

0.069

Brain et al. (2004)

Algae

L. gibba

7 d EC10

0.65

Brain et al. (2004)

Bacteria

V. fischeri

LC50

64.50


Algae

P. subcapitata

72 h LC50

0.17

Nunes et al. (2005) Holten-Lu¨tzhøft et al. (1999) Holten-Lu¨tzhøft et al. (1999)

Chlortetracycline

Oxytetracycline

Algae

M. aeruginosa

7 d EC50

0.207

Algae

R. salina

7 d EC50

1.6

Algae

S. capricornutum

7 d EC50

4.5

Algae Algae

M. aeruginosa L. gibba

7 d EC50 7 d LOEC

0.231 1

Holten-Lu¨tzhøft et al. (1999) Holten-Lu¨tzhøft et al. (1999) Brain et al. (2004)

Algae

L. gibba

7 d EC50

1.152

Brain et al. (2004)

Algae

L. gibba

7 d EC50

4.920

Pro et al. (2003)

Algae

S. capricornutum

72 h EC50

0.342


Algae

S. capricornutum

72 h NOEC

0.183


Algae

C. vulgaris

72 h EC50

7.05


Algae

C. vulgaris

72 h NOEC

\3.58


Invertebrate

D. magna

24 h LC50

22.64


Invertebrate

C. dubia

48 h LC50

18.65


Invertebrate

C. dubia

48 h EC50

18.65

Nunes et al. (2005)

Invertebrate

C. dubia

7 d LC50

0.18


Invertebrate

D. magna

21 d EC10

7.4

Wollenberger et al. (2000)

Invertebrate

D. magna

21 d EC50

46.2

Wollenberger et al. (2000)

Fish

S. namaycush

24 h LC50

\200

Webb (2001)

Fish

M. saxatilis

24 h LC50

150

Hughes (1973)

Fish Fish

M. saxatilis M. saxatilis

48 h LC50 72 h LC50

125 100

Hughes (1973) Hughes (1973)

Fish

M. saxatilis

96 h LC50

75

Hughes (1973)

Fish

M. saxatilis

96 h LC50

62.5

Hughes (1973)

Enrofloxacin

123


533

Table 3 continued Antibiotics/Taxonomic group

Species

Endpoint/Duration

Conc. (mg/l)

Reference

Algae

M. aeruginosa

5 d EC50

0.049

Robinson et al. (2005)

Algae

P. subcapitata

72 h EC50 0

3.100


Plant

L. minor

7 d EC50

0.114


Invertebrate

D. magna

24 h EC50

[10

Bayer (1997)

Fish

Rainbow trout

96 h LC50

[10

Bayer (1997)

Fish

L. macrochirus

96 h LC50

[10

Bayer (1997)

L. gibba

7 d EC10

[1.0

Brain et al. (2004)

A. japonica

LC50

2829

US EPA (2001)

Bacteria

V. fischeri

24 h EC50

163

Backhaus and Grimme (1999)

Plant

L. gibba

7 d EC10

[1.0

Brain et al. (2004) Holten-Lu¨tzhøft et al. (1999) Holten-Lu¨tzhøft et al. (1999) Holten-Lu¨tzhøft et al. (1999) Holten-Lu¨tzhøft et al. (1999)

Neomycin Plant Ampicillin

Amoxicillin Algae

M. aeruginosa

7 d EC50

0.0037

Algae

S. capricornutum

7 d NOEC

250

Algae

R. salina

7 d EC50

3108

Algae

S. capricornutum

7 d EC50

5

Algae

C. vulgaris

72 h EC50

[1000


Algae

C. vulgaris

72 h NOEC

[1000


Algae

S. capricornutum

72 h EC50

[1000


Algae

S. capricornutum

72 h NOEC

[1000


Algae

L. gibba

7 d LOEC

[1

Brain et al. (2004)

Algae

L. gibba

7 d EC10

[1

Brain et al. (2004)

Algae

L. gibba

7 d EC10

[1

Brain et al. (2004)

Table 4 Summary of D. magna and M. macrocopa chronic toxicity test: EC50 with confidence limits (95% probability), LOEC and NOEC values, respectively, for each antibiotics NOEC (mg/l)

Sulfamethazine

D. magna

0.3–30

*

–

–

M. macrocopa

0.3–30

*

–

–

–

D. magna

0.3–35

First day of reproduction

–

35

11

Number of young per female

–

35

11

D. magna Trimethoprim

0.3–35

*

D. magna

0.2–20


–

20

6

Number of broods per female Number of young per female

– –

20 20

6 6

M. macrocopa

0.3–30

*

D. magna

0.03–0.5

Adult survival

0.09 (0.06–0.12)

0.1

0.03

D. magna

0.03–0.5


–

0.1

0.03

Adult survival

0.74 (0.39–1.08)

1.6

0.5


–

1.6

0.5

M. macrocopa

0.3–5

M. macrocopa Enrofloxacin

–

M. macrocopa D. magna D. magna Neomycin

End points

LOEC (mg/l)

Species

Sulfathiazole

Test range (mg/l)

EC50 (mg/l)

Antibiotics

D. magna

0.1–15

15

5


Adult survival

11.47 (6.25–16.71) –

15

5

Number of broods per female

–

15

5

15

5

Number of young per female M. macrocopa

0.1–15

*

* No lethal and sublethal effects were observed at the exposure levels employed in this study

123

534

S. Park, K. Choi

70

50 r

0.2

20

0.1

20

0.0 control 0.3

1.1

3.3

10

0.0

0

30

control 0.3

1

Concentration (mg/L)

R0 r

3

11

0.0

0

35

control 0.2

0.6 2 6 Concentration (mg/L)


Neomycin

80

0.1 20

R0 r

10

0

0.2 40

30

0.1

R0 r

10

0.3

60 0.2

40

r

0.3

40 30

80

0.3

60

50 R0

C

B

0.4

60

0.4

70 0.3

60

Enrofloxacin

80

D

0.4

100

r

A

Trimethoprim

0.4

80

R0

70

Sulfathiazole

0.5

R0

Sulfamethazine

80

20

0.4

E 0.3

60

0.2

40

r

r

0.2

40

R0

R0

50

30 0.1

20

0.1

20

R0 r

R0 r

10 0.0

0 control 3e-3

0.01

0.03

0.1

0.0

0

0.5

Control 0.1


0.3

1

3

15


Fig. 1 Net reproductive rates (R0) and rate of population increase (r) of D. magna after 21 d of exposure

Sulfamethazine

Sulfathiazole 1.0

A 50

50

0.8

B

50

0.8

0.2

0.0 5

15

0.4

r

20 0.2

10

R0 r 1

30

0.4 20

Control 0.3

0.6

R0

R0

r

30

0.4

0

0.8

0.6

20 10

C

40

0.6 30

1.0

60

40

40

R0

Trimethoprim

1.0

60

r

60

R0 r

R0 r 0.0

0 Control 0.3

30

0.2

10

1

3

11

35

0.0

0 Control 0.3



Neomycin

1

5

15

30


Enrofloxacin 1.0

50

D

60

40

0.8

30

0.6

20

0.4

E

1.4 1.2

50

0.8 30 0.6 20

0.2

10 R0 r

0.0

0 Control 0.03

0.1

0.5

1.6


5

r

r

R0

R0

1.0 40

10

0.4 0.2

R0 r

0.0

0 Control 0.1

0.3

1

5

15


Fig. 2 Net reproductive rates (R0) and rate of population increase (r) of M. macrocopa after 8 d of exposure

directly relate to the age at first reproduction (Sarmah et al. 2005). While many life history variables can be derived using the demographic techniques, the most common are the average lifespan, expectancy at birth, growth reproductive

123

and net reproductive rates, generation time, and r (Krebs 1985). Grist et al. (2003) reported that while majority of the life history variables are significantly influenced by the toxic substances, r is particularly more sensitive to stresses. Any chemical that affects an organism’s fitness (survival,


development, fecundity or sexual determination) is likely to have effects that transcend individual response and may affect the entire ecosystem (Kashian and Dodson 2004). The results from the chronic toxicity tests in this study showed that sensitivity of M. macrocopa was similar to that of D. magna. However it should be noted that the exposure duration for M. macrocopa was only 8 d whereas that for D. magna was 21 d. Moina shares many characteristics with D. magna (e.g., large population densities, high population growth rates, short generation time, and easiness of culture), and is often preferred for hazard evaluation because of its relatively short life span and wide geographical distribution, including Korea (Garcia et al. 2004). Chronic toxicity test with M. macrocopa have been developed in our laboratory, and the techniques have been used for testing toxicity of heavy metals (Oh 2007). This organism has rarely been tested for the toxicity of antibiotics. Therefore, this study using M. macrocopa will provide another line of information on ecological hazard of major antibiotics. Derivation of predicted no effect concentrations PNEC values for the test antibiotics were calculated as shown in Table 5. Toxicity values for neomycin and trimethoprim were collected from this study but others were derived from literature. For neomycin and trimethoprim, an AF of 100 was applied because chronic toxicity data were available.

535

Measured environmental concentrations Table 6 showed concentrations of antibiotics reported in surface water worldwide. Yang et al. (2004) observed the great influence of agriculture on the occurrence of sulfonamides such as sulfamethazine, sulfadimethoxine and sulfamethoxazole in the Poudre River (northern Colorado, USA). Also, Alder et al. (2001) reported that sulfamethazine concentrations in a lake near intensive animal husbandry were found to be higher than in the effluents of a wastewater treatment plant in the same area. Also, Kolpin et al. (2002) surveyed the concentrations of pharmaceuticals in 139 streams across 30 states in US during 1999 and 2000. In this study, sulfamethoxazole, sulfamethazine, trimethoprim, chlortetracycline and oxytetracyclines were detected in a range from 0.002 to 0.42 lg/l. Other investigators also reported occurrences of antibiotics in the surfacewater (Christian et al. 2003; Hirsh et al. 1999; Metcalfe et al. 2003; Perret et al. 2006). Choi et al. (2008) surveyed for the occurrence of three antibiotics, i.e., roxithromycin, trimethoprim and chloramphenicol, in surface water and effluents from several sewage treatment plants (STPs) in upstream and downstream Han River, Korea. The mean trimethoprim, and its 95% upper confidence limit in Table 6 Levels of antibiotics MEC in the surfacewater in other countries from literature review Antibiotics

MEC (lg/l)

Antibiotics

Sulfamethoxazole

0.066a

Sulfadimethoxine

0.028d

b

0.074d

0.030

c

Antibiotics

Lowest effect concentration (mg/l)

AF

0.034

PNEC

Trimethoprim

Chronic (LOEC/ NOEC)

Sulfamethoxazole

0.03

NA

1000

0.00003

Sulfathiazole

0.1

NA

1000

0.0001

Sulfamethazine

1.277

NA

1000

0.001277

0.035

0.013a

0.012c

0.008c

c

0.003c

c

0.012c

c

0.015 0.052c

0.004c 0.077g

0.100c

0.052g

0.019

Sulfadimethoxine

0.248

NA

1000

0.000248

Trimethoprim

–

6

Chlortetracycline

0.05

NA

1000

0.00005

Oxytetracycline

0.17

NA

1000

0.00017

Neomycin

–

0.03

100

0.0003

Enrofloxacin Ampicillin

0.049 163

NA NA

1000 1000

0.000049 0.163

Amoxicillin

0.0037

NA

1000

0.0000037

100

d

Sulfamethazine

e

0.130

Chlortetracycline

0.5j

a

0.69a

0.200 b

0.16 Enrofloxacin

NA

Ampicillin

NA

Amoxicillin

0.420a

a

0.002

0.06

NA: Not available; –: Not applicable since chronic effect concentrations were available

0.71a

0.402 Sulfathiazole

0.150a

c

0.004

Acute (EC50/ LOEC)

0.0007f

a

0.150

Table 5 PNEC values of test antibiotics derived from this study and literature review

MEC (lg/l)

0.22 Oxytetracycline

h

0.340a 0.01i

c

0.006

Neomycin

NA

NA: Not available a Kolpin et al. (2002); b Hirsh et al. (1999); c Christian et al. (2003); d Perret et al. (2006); e Metcalfe (2003); f Lissemore et al. (2006); g Choi et al. (2008); h Hamscher et al. (2000); i Roembke et al. (1996); j Meyer et al. (2000)

123

536

S. Park, K. Choi

all surface water samples, were 0.052 and 0.077 lg/l, respectively. Due to the chemically unstable beta-lactam ring, beta-lactam antibiotics are readily susceptible to hydrolysis (i.e. by beta-lactamases) and are expected to be easily eliminated (Forth et al. 1992). Antibiotics may be degraded abiotically via photodegradation and/or hydrolysis or biotically by aerobic or anaerobic organisms. The quinolones and tetracyclines are rapidly photodegraded with half-lives ranging form\1 h to 22 d (Davis et al. 1993; Halley et al. 1993; Lunestad et al. 1995; Oka et al. 1989). In contrast, trimethoprim and sulfonamides are not readily photodegradable (Lunestad et al. 1995). Hazard characterization The HQs for target compounds were derived from dividing the MEC by the PNEC. Table 7 shows the HQs of test antibiotics. HQs derived for sulfamethoxazole, sulfathiazole, chlortetracycline, oxytetracycline, and amoxicillin exceeded unity. Boxall et al. (2003) classified oxytetracycline and amoxicillin as ‘high priority’ in a prioritization study. Ferrari et al. (2003) calculated the HQs of sulfamethoxazole for France and Germany to be 11.4 and 59.3, respectively, based on its predicted environmental concentrations. Kim et al. (2007) reported the HQ of 6.3 for this compound considering its use only in human medicine. An HQ calculated based on chronic ecotoxicity data is better than the one calculated based on acute toxicity data because the former can detect subtle but meaningful ecological impacts of the test compounds (Carlsson et al. 2006). Daughton and Ternes (1999) indicated that environmental classification as well as risk assessments of pharmaceutical products should be based on knowledge on chronic toxicity following long-term exposure to low

Table 7 Hazard quotients of major veterinary antibiotics based measured environmental concentrations reported in the literature Antibiotics

MECs (lg/l)

PNECs (lg/l)

MEC/PNEC

Sulfamethoxazole

0.40

0.03

13.4

Sulfathiazole

0.13

0.10

1.30

Sulfamethazine

0.20

110.30

0.002

Sulfadimethoxine

0.07

0.248

0.282

Trimethoprim

0.71

60

0.012

Chlortetracycline

0.69

0.05

13.8

Oxytetracycline Neomycin

0.34 NA

0.17 0.30

2 NA

Enrofloxacin

NA

0.049

NA

Ampicillin

NA

163

NA

Amoxicillin

0.006

0.0037

1.62

NA: Not available

123

concentrations. In this study, we produced chronic toxicity data for several major agricultural antibiotics. However the lack of measured environmental data, often hinders understanding of real ecological consequences of these antibiotics. Therefore, to estimate potential ecological risk of veterinary antibiotics, further studies including monitoring and detailed toxicological studies are required.

Conclusion We performed acute and chronic toxicity test using microbes, invertebrates, and fish to assess ecological hazard of veterinary antibiotics, which are frequently used in Korea. Among eleven test pharmaceuticals, neomycin and enrofloxacin are the most toxic compounds to the test organisms. Using the toxicity data from this study and other literatures along with MECs reported elsewhere for the test compounds, HQs were derived. HQs for sulfamethoxazole, sulfathiazole, chlortetracycline, oxytetracycline, and amoxicillin exceeded 1, suggesting the need for further investigation for these four antibiotics including targeted monitoring and toxicological studies.

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