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Chemical concentration, activity, fugacity, and toxicity: dynamic implications

Chemical concentration, activity, fugacity, and toxicity: dynamic implications. Jon Arnot and Don Mackay Trent University. McKim Conference Duluth, MN September, 2007. Overview. Building on Part I by Don Mackay Four chemicals, log K OW = 2, 4, 6, 8 Two organisms, fish and mammal

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Chemical concentration, activity, fugacity, and toxicity: dynamic implications

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  1. Chemical concentration, activity, fugacity, and toxicity:dynamic implications Jon Arnot and Don Mackay Trent University McKim Conference Duluth, MN September, 2007

  2. Overview • Building on Part I by Don Mackay • Four chemicals, log KOW = 2, 4, 6, 8 • Two organisms, fish and mammal • Objectives • Reference point for acute “baseline” toxicity (narcosis) • Data quality • Assumptions vs reality • Dynamic profiles and “complicating” factors (biotransformation rates, absorption efficiency) • Internal vs external concentrations and activities

  3. Reference point for hazard identification • Lethality is “well defined” • Toxic Ratio (TR) or “excess toxicity” = CBRX (mmol.kg-1) / CBRN (mmol.kg-1) • If CBRN = 3 mmol.kg-1 and TR > ~10 then chemical “x” has greater “potency”

  4. Equilibrium partitioning (EqP) EqP = activity in exposure medium = activity in organism Complete bioavailability No biotransformation or growth dilution

  5. Series of toxicity “experiments” • Illustrations using a kinetic mass balance model • Fish • Mammal • Exposure concentrations based on EqP assumptions to exert a toxic effect at 3 mmol.kg-1 or 3 mol.m-3 whole body concentration, i.e., narcosis • Four chemicals, each with three different metabolic biotransformation rates (0, 0.1, 1.0 d-1)

  6. Metabolic biotransformation; kM Respiratory exchange; k1and k2 20% NLOM 70% water Growth dilution; kG 10% lipid Fecal egestion; kE Dietary intake; kD Two organisms – same properties and processes (air vs water) NLOM equivalent to 3.5% lipid (both 100 g)

  7. CB = ((k1•CWD ) + (kD•CD)) / (k2 + kE + kM + kG) kT kM k1 kG kD kE k2 Model steady state

  8. Equilibrium partitioning: fish Chemical

  9. Chemical A Cwater= 0.263 mol.m-3 activity in fish  activity in water  0.03 No big difference! short

  10. Chemical B Cwater= 0.0028 mol.m-3 awater= 0.04 substantial differences in activity and tsteady state

  11. Chemical B Cwater= 0.0028 mol.m-3 awater= 0.04 substantial differences in activity and tsteady state Need to increase Cwater !! activity in fish  activity in water!! Factor of 5; awater~ 0.2

  12. Chemical C Cwater= 0.028 mmol.m-3 awater= 0.056 big differences in activity and tsteady state

  13. Chemical C Cwater= 0.028 mmol.m-3 awater= 0.056 big differences in activity and tsteady state Need to increase Cwater !! BUT, exceed water solubility limits i.e., awater > 1 X

  14. Chemical D CSS = Cwater= 0.074 µmol.m-3 awater= 0.07 huge differences in activity and tsteady state

  15. Chemical D CSS = Cwater= 0.074 µmol.m-3 awater= 0.07 huge differences in activity and tsteady state No chance!

  16. Equilibrium partitioning: mammal Chemical

  17. Cair= 0.0024 mol.m-3 aair = 0.03 Chemical A Lower concentrations in air compared to water “minor” differences

  18. Chemical B Cair= 0.017 mmol.m-3 aair = 0.04

  19. Chemical B Cair= 0.017 mmol.m-3 aair = 0.04 Maximum activity in mammal  activity in air!! Need to increase Cair !! BUT, exceed air solubility limits, i.e., vapor pressure

  20. Chemical C Cair= 0.11 mol.m-3 aair = 0.056 “same story” ~ 560x ~ 5,600x ~ 56,000x

  21. Chemical D PSS = Cair= 0.22 nmol.m-3 aair = 0.07 “same story”

  22. A view to a kill (96 h LD50) Chemical C; fed 2x/d Inhalation exposure is assumed “irrelevant” not at steady state or equilibrium! BMFs are larger in the mammal

  23. A view to a kill (96 h lethal dose) Chemical C; but 0.5 * ED Have to double the dose!

  24. Summary • Uptake times can be long and can exceed standard test durations, combined exposure routes may be necessary • Exposure concentrations and activities “rarely” approximate internal concentrations and activities • Metabolites that may be toxic will further complicate interpretation of toxicity measurements • Need to measure both internal and external concentrations to identify “more potent” chemical • Need for a quality toxicity dataset • Uncertain data result in uncertain models

  25. Ferguson 1939 Careful inspection of the toxicity data can support Ferguson’s proposal that activity be used to interpret toxicity data such that “the disturbing effect of phase distribution is eliminated from the comparison of toxicities”

  26. Thank you!

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