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What toxicants can teach us

What toxicants can teach us. about metabolic organisation …. Tjalling Jager Dept. Theoretical Biology. Contents. “There’s something rotten in the field of ecotoxicology” … Toxic effects in a DEB context ‘DEBtox’: an incomplete history and recent developments Challenges for further research.

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What toxicants can teach us

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  1. What toxicants can teach us about metabolic organisation … Tjalling Jager Dept. Theoretical Biology

  2. Contents • “There’s something rotten in the field of ecotoxicology” … • Toxic effects in a DEB context • ‘DEBtox’: an incomplete history and recent developments • Challenges for further research

  3. Talking about toxicants … Ecotoxicology: Study of effects of chemicals on organisms • In practice … • exclude humans, mice, rats, rabbits, etc. • exclude other mammals and birds • all levels of organisation (molecule to ecosystem) • stronger link to risk assessment than to science • What is “rotten” in ecotoxicology? • basic tool: the standard toxicity test

  4. Reproduction test

  5. Reproduction test

  6. Reproduction test

  7. Reproduction test wait for 21 days …

  8. Range of Concentrations

  9. EC50 Dose-response plot total offspring log concentration

  10. What use is an EC50? • The EC50 … • changes in time and differs between endpoints • time patterns are chemical-dependent • depends on test conditions (e.g., pH, temp, food) • depends on definition of response (e.g., total offspring or reproduction rate) • And therefore … • tests are highly standardised by OECD, ISO, ASTM

  11. toxic effects “Something rotten …” Ecotoxicologists are asking the wrong question • Which concentration leads to 50% effect under highly standardised test conditions? Species: Daphnia magna Age: less than 24 hours Duration: 21 days Endpoint: total # offspring Temp.: 18-22 °C Food: 0.1-0.2 mg C/ind./day OECD (1998)

  12. “Something rotten …” Ecotoxicologists are asking the wrong question • Which concentration leads to 50% effect under highly standardised test conditions? Better questions • What is the process by which a toxicant affects an organism’s life history? • How can we use test data to predict population response under field-relevant conditions?

  13. Look closer at individual

  14. Look closer at individual

  15. Look closer at individual

  16. Look closer at individual

  17. Natural role for DEB Toxic effects have energetic consequences Understanding effects on reproduction requires understanding how food is turned into offspring (start of DEB theory 30 years ago!)

  18. Natural role for DEB Toxic effects have energetic consequences Understanding effects on reproduction requires understanding how food is turned into offspring (start of DEB theory 30 years ago!) Assumptions for toxicant effects • Effects are caused by internal concentrations • Internal concentrations affect DEB parameter(s)

  19. internal concentration in time DEB parameters in time external concentration (in time) effects in time DEBtox concept ?? toxico- kinetics DEB model

  20. Potential targets food faeces assimilation reserves somatic maintenance maturity maintenance  1- maturity offspring structure

  21. TPT body length cumulative offspring time time Potential targets Jager et al. (2004)

  22. Potential targets food faeces assimilation reserves somatic maintenance maturity maintenance  1- maturity offspring structure

  23. Potential targets food faeces assimilation reserves somatic maintenance maturity maintenance  1- maturity offspring structure

  24. Pentachlorobenzene body length cumulative offspring time time Potential targets Alda Álvarez et al. (2006)

  25. Potential targets food faeces assimilation reserves somatic maintenance maturity maintenance  1- maturity offspring structure

  26. Chlorpyrifos body length cumulative offspring time time Potential targets Jager et al. (2007)

  27. internal concentration in time DEB parameters in time time-varying concentrations external concentration (in time) effects in time temperature food limitation DEBtox concept Affected DEB parameter has specific consequences for life cycle toxico- kinetics DEB model Extrapolation!

  28. A brief history of ‘DEBtox’ egg Corresponds with origin of DEB in 1979

  29. A brief history of ‘DEBtox’ egg The 80’s … • Kooijman (1981) • toxicokinetics determines survival pattern • Kooijman & Metz (1984) • toxicants affect energy budgets and thereby population response

  30. A brief history of ‘DEBtox’ egg The early 90’s … • Parallel to OECD trajectory • review test guidelines with respect to statistical analysis • 1996: “analyse time course of effects” and “study mechanistic models”

  31. A brief history of ‘DEBtox’ Birth in 1996 … • Windows software and booklet (Kooijman & Bedaux, 1996) • Series of papers • Bedaux & Kooijman (1994) • Kooijman & Bedaux (1996) • Kooijman et al (1996)

  32. A brief history of ‘DEBtox’ And 10 years later … • ISO/OECD (2006) • DEBtox next to methods for NOEC and EC50 • ECB workshop (2007) • presenting DEBtox to EU risk assessors

  33. A brief history of ‘DEBtox’ The 2000’s … • Péry et al (2002, 2003) • modifications for midges • Ducrot et al (2004, 2007) • midges and snails • Lopes et al (2005) • link to matrix models • Billoir et al (2007, 2008) • matrix models, Bayes, new derivation division

  34. A brief history of ‘DEBtox’ In our group … • Jager et al (2004), Alda Álvarez et al (2005, 2006) • multiple endpoints and ageing • population (Euler-Lotka) • Baas et al (2007, 2009) • mixtures: lethal effects • (sub-lethal subm.) division

  35. A brief history of ‘DEBtox’ Embryo division … • Klok & De Roos (1996), Klok et al (1997, 2007) • earthworm matrix model, Bayesian approach

  36. A brief history of ‘DEBtox’ The near future … ‘DEB 3’

  37. Limits of ‘DEBtox’ To work with standard test data … ‘DEBtox’ applied a simplified DEB model • constant reserve density • constant length at puberty • constant cost for an egg

  38. Constant reserve density … food faeces assimilation reserves somatic maintenance maturity maintenance  1- maturity offspring structure

  39. Constant length at puberty … food faeces assimilation reserves somatic maintenance maturity maintenance  1- maturity offspring structure

  40. Constant egg costs … food faeces assimilation reserves somatic maintenance maturity maintenance  1- maturity offspring structure

  41. ‘DEB 3’ • Explicit calculation of maturation • maturity level → hatching and onset reproduction • → maturity maintenance • Explicit calculation of egg costs • may change under (toxic) stress • Disadvantages • data requirements • computation more complex • parameter interpretation Kooijman et al (2008)

  42. Toxicants and DEB 3 Example: • Nematode Acrobeloides nanus • Data from Alda Álvarez et al (2006)

  43. 200 65 180 60 160 55 140 50 120 45 cumulative offspring per female 100 body length 40 80 35 60 30 40 25 20 20 0 0 5 10 15 20 15 0 5 10 15 20 25 30 time time Pentachlorobenzene • mode of action: decrease of ingestion rate • allows estimation of all basic parameters • somatic maint. coeff. = maturity maint. coeff.

  44. 180 65 160 60 140 55 120 50 100 cumulative offspring per female 45 80 body length 40 60 35 40 30 20 25 0 20 0 5 10 15 20 15 time 0 5 10 15 20 25 30 35 time Cadmium • MoA: increase costs for structure • decrease maturity maintenance? • .

  45. 180 65 60 160 55 140 50 120 45 100 cumulative offspring per female body length 40 80 35 60 30 40 25 20 20 0 15 0 5 10 15 20 0 5 10 15 20 25 30 35 time time Cadmium • MoA: increase costs for structure • decrease maturity maintenance? • increase ageing?

  46. 65 180 60 160 55 140 50 120 45 100 cumulative offspring per female body length 40 80 35 60 30 40 25 20 20 15 0 0 5 10 15 20 25 30 35 0 5 10 15 20 time time Cadmium • MoA: increase costs for structure • decrease maturity maintenance? • increase ageing?

  47. Lessons and questions • Using ‘DEB 3’ allows more flexibility • any parameter can be affected by toxicant • fully consistent consequences of effects • but … user-friendliness is decreased • Pentachlorobenzene: • effect through ingestion • basic parameters can be estimated

  48. Lessons and questions • Cadmium: • effect on costs for structure • and … effect on maturity maintenance and ageing? • maturity maintenance linked to structural costs? • maturity maintenance trading off with ageing?

  49. Lessons and questions • Cadmium: • effect on costs for structure • and … effect on maturity maintenance and ageing? • maturity maintenance linked to structural costs? • maturity maintenance trading off with ageing? • How to address these questions: • other endpoints, e.g., length at birth (30% reduction) • other chemicals/species with this mode of action

  50. Where do we go? DEB 3 allows to address new questions 

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