Plasma levels of non-steroidal anti-inflammatory drugs (NSAIDs) and - - PowerPoint PPT Presentation

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Plasma levels of non-steroidal anti-inflammatory drugs (NSAIDs) and - - PowerPoint PPT Presentation

Jul 20, 2023 213 likes •500 views

Plasma levels of non-steroidal anti-inflammatory drugs (NSAIDs) and gemfibrozil in fish exposed to treated sewage effluents: Assessing the risk of discharges to aquatic environments Jeffrey N. Brown , Nicklas Paxus*, Lars Frlin and

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SLIDE 1

Plasma levels of non-steroidal anti-inflammatory drugs (NSAIDs) and gemfibrozil in fish exposed to treated sewage effluents: Assessing the risk of discharges to aquatic environments

Jeffrey N. Brown†, Nicklas Paxéus*, Lars Förlin‡ and D.G. Joakim Larsson†

† Institute for Neuroscience and Physiology, the Sahlgrenska Academy at Göteborg University,

  • Sweden. Email: jeffrey.brown@fysiologi.gu.se

* Environmental Chemistry, Gryaab AB, Göteborg.

‡ Department of Zoology, Göteborg University.

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SLIDE 2

Introduction PHARMACEUTICALS IN AQUATIC ENVIRONMENTS

  • Widespread detection in surface waters
  • Effects on fish at environmentally relevant

concentrations

  • Environmental Risk Assessment (ERA) required

for all new pharmaceuticals in EU

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SLIDE 3

Fish Plasma Model *

* Huggett, et al. (2003) Human Ecol. Risk Assess. (9) 1789-99

The lower the ER, the higher the risk for a specific target interaction Human therapeutic plasma concentration giving known effects (HT PC) QSPR calculates bioconcentration Fish steady state plasma concentration (FSS PC) Fish exposure via water

[ ]

Effect Ratio (ER) =

[ ]

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SLIDE 4

Fish Plasma Model *

The lower the ER, the higher the risk for a specific target interaction Human therapeutic plasma concentration giving known effects (HT PC) QSPR calculates bioconcentration Fish steady state plasma concentration (FSS PC) Fish exposure via water

[ ]

Effect Ratio (ER) =

[ ]

Log BCF plasma = 0.73 log Kow – 0.88

Fitzsimmons et al. (2001) Aquatic Toxicol. (55) 23-34.

Non-polar PCBs, chloroethanes + benzene

  • Not yet well validated for pharmaceuticals (often ionic)
  • Complex environmental exposures?
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SLIDE 5

Aims

  • 1. To test the bioconcentration QSPR of

the Fish Plasma Model using fish exposed to diluted sewage effluents.

  • 2. Use the Fish Plasma Model to rank the

risks of target interactions occurring in fish.

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SLIDE 6

Non-steroidal anti-inflammatory drugs (NSAIDs)

  • 0.1 –

2 μg/l in treated sewage effluents

  • Non-ionised state

lipophilic enough to bioconcentrate

  • Reported effects in

fish

Ibuprofen

log Kow = 3.80 pKa = 4.40

Diclofenac

log Kow = 4.02 pKa = 4.15

Naproxen

log Kow = 3.10 pKa = 4.20

Ketoprofen

log Kow = 3.00 pKa = 4.60

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SLIDE 7

Gemfibrozil

  • Blood lipid lowering

agent

  • ~ 1 μg/l in treated

sewage effluents

  • In aquarium studies

bioconcentrates into goldfish blood plasma

  • Effects on fish
  • bserved

log Kow = 4.80 pKa = 4.80

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SLIDE 8

Exposure Sites

1. GRYAAB STP Göteborg ~ 600,000 people, some trade wastes, activated sludge, chemical P and biological N removal

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SLIDE 9

Exposure Sites

2. Gråbo STP ~ 4000 people, activated sludge

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SLIDE 10

Exposure Sites

3. Spenshult Rheumatic Hospital STP 180 beds + staff, activated sludge higher pharmaceutical load?

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SLIDE 11

Methods Fish Plasma

  • Juvenile rainbow trout (70g) exposed 2-3 weeks,

sacrificed, blood taken, centrifuged & plasma frozen

  • SPE column extraction, derivatisation & GC-MS

Water samples

  • Sampling every 2-3 days
  • SPE extraction, derivatisation

& GC-MS

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SLIDE 12

Results Qualitative static aquarium exposure (2 days)

Pharmaceutical Nominal exposure level (ng/ml) Measured plasma level (ng/ml) BCF Ibuprofen

520 4680 9

Naproxen

1000 3640 4

Diclofenac

520 3440 7

Ketoprofen

490 60 0.1

Gemfibrozil

510 32070 63

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SLIDE 13

Sewage exposures - pharmaceutical concentrations (ng/ml, mean ±

SD)

Pharmaceutical Exposure Site Gryaab Gråbo Spenshult Ibuprofen

0.0045 (0.0027) 0.014 (0.013) 0.048 (0.029)

Naproxen

0.25 (0.17) 0.68 (0.33) 0.043 (0.016)

Diclofenac

2.32 (0.48) 0.64 (0.28) 0.28 (0.08)

Ketoprofen

0.28 (0.18) 0.10 (0.04) 0.23 (0.08)

Gemfibrozil

1.05 (0.25) 0.54 (0.23) 1-5*

* Interfering long-chain fatty acid prevented full quantification

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SLIDE 14

Sewage exposures - Fish steady state plasma concentrations (FSS

PC) (ng/ml, mean ± SD)

Pharmaceutical Exposure Site Gryaab Gråbo Spenshult Ibuprofen

84 (62) <mdl <mdl

Naproxen

14 (9) <mdl <mdl

Diclofenac

12 (14) <mdl <mdl

Ketoprofen

<mdl <mdl <mdl

Gemfibrozil

210 (400) <mdl 8.0 (5.5)

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SLIDE 15

Sewage exposures - Fish steady state plasma concentrations (FSS

PC) (ng/ml, mean ± SD)

Pharmaceutical Exposure Site Gryaab Gråbo Spenshult Ibuprofen

84 (62) <mdl <mdl

Naproxen

14 (9) <mdl <mdl

Diclofenac

12 (14) <mdl <mdl

Ketoprofen

<mdl <mdl <mdl

Gemfibrozil

210 (400) <mdl 8.0 (5.5) Temperature oC 12 2 14

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SLIDE 16

Sewage exposures - Fish steady state plasma concentrations (FSS

PC) (ng/ml, mean ± SD)

Pharmaceutical Exposure Site Gryaab Gråbo Spenshult Ibuprofen

84 (62) <mdl <mdl

Naproxen

14 (9) <mdl <mdl

Diclofenac

12 (14) <mdl <mdl

Ketoprofen

<mdl <mdl <mdl

Gemfibrozil

210 (400) <mdl 8.0 (5.5) Temperature (oC) 12 2 14 pH 7.0 6.4 7.1

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SLIDE 17

Sewage exposures - Fish steady state plasma concentrations (FSS

PC) (ng/ml, mean ± SD)

Pharmaceutical Exposure Site Gryaab Gråbo Spenshult Ibuprofen

84 (62) <mdl <mdl

Naproxen

14 (9) <mdl <mdl

Diclofenac

12 (14) <mdl <mdl

Ketoprofen

<mdl <mdl <mdl

Gemfibrozil

210 (400) <mdl 8.0 (5.5) Temperature (oC) 12 2 14 pH 7.0 6.4 7.1 Exposure duration 2, 8, 16 days 2, 8, 16, 23 days 14 days

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SLIDE 18

Site specific differences in drug bioconcentration

  • Temperature
  • pH
  • Exposure duration
  • Particles/colloids in natural stream dilution

water limiting bioavailability at Gråbo and Spenshult?

  • Gryaab

– Surfactants enhancing bioavailability? – Factors reducing active excretion/metabolism?

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SLIDE 19

Fish Plasma Model QSPR Evaluation - Bioconcentration Factors

1 10 100 1000 10000 100000

Bioconcentration Factor (BCF)

Ibuprofen Naproxen Diclofenac Ketoprofen Gemfibrozil

Model Gryaab Gråbo Spenshult

  • Max. estimated BCF based on plasma concentration set at 3 ng/ml detection limit
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SLIDE 20

Fish Plasma Model Evaluation - Bioconcentration Factors

  • Measured BCFs generally ≤

modelled BCFs

– QSPR does not take into account special characteristics

  • f pharmaceuticals

– Active excretion/metabolism may lower plasma concentrations – Drug bioavailability may be significantly lower through partitioning to colloids or particles

  • Model greatly underestimated ibuprofen BCF at

Gryaab

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SLIDE 21

Ranking of risk of target interactions

[ ] [ ]

Effects Ratio (ER) =

Lower ER → higher risk of target interaction

Model ranking

Diclofenac > gemfibrozil > ibuprofen > naproxen - ketoprofen

Measured ranking = model ranking

Diclofenac > gemfibrozil > ibuprofen > naproxen - ketoprofen

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SLIDE 22

Measured v Modelled Effects Ratio at Gryaab

1 10 100 1000 10000 100000

Effects Ratio (ER) Ibuprofen Naproxen Diclofenac Ketoprofen Gemfibrozil Model Gryaab

Minimum estimated ER based on 3 ng/ml detection limit

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SLIDE 23

Conclusions

1. Pharmaceuticals bioconcentrated from treated sewage effluents into fish blood 2. Major bioconcentration differences between sites shows the importance of field studies 3. Diclofenac appears to present the highest risk of pharmacological effects occurring in fish 4. Fish Plasma Model looks promising with refinement of the QSPR and further validation

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SLIDE 24

Acknowledgements

Lars Förlin Joakim Larsson Jari Parkkonen Linda Samuelsson Lina Gunarsson Linda Augustsson Nicklas Paxéus

  • Spenshult Rheumatic

Hospital

  • Gråbo STP
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SLIDE 25

Acknowledgements

You!

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SLIDE 26

1 10 100 1000 10000

Effects Ratio (ER) Ibuprofen Naproxen Diclofenac Ketoprofen Gemfibrozil Gryaab Gråbo Spenshult

Minimum estimated ER based on 3 ng/ml detection limit

Risk of target interactions

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SLIDE 27

Human therapeutic plasma concentrations

Pharmaceutical HT PC (ng/ml) Ibuprofen 15,000 Naproxen 20,000 Diclofenac 420 Ketoprofen 5,000 Gemfibrozil 15,000