Environmental Categorization and Screening of the DSL Substances

1. Environmental Categorization and Screening of the DSL Substances Substances on the DSL Persistent and or Inherently Toxic PHASE 1: Bioaccumulative no Categorization No further action under this Yes program PHASE 2: Is the Substance a Screening Assessment Screening level Track 1 Substance? risk assessment Add to the Priority Add to Schedule 1 No Further Action Substances List for Outcomes List of Toxic Substances for at this Time Further Assessment Possible Regulatory Actions

2. Criteria for Inherently toxic (iT) in CEPA, UNEP Proposed iT criteria for non-human organisms • aquatic acute effects levels of < 1 mg/L • above 1 mg/L professional judgment considering other factors (e.g. molecular weight, metabolism...) • log Kow > 6 (consideration of effects to wildlife)

3. “The Dose makes the Poison” Paracelcus (1567)

4. What is "Toxicity”?

9. Criteria for Inherently toxic (iT) in CEPA, UNEP Proposed iT criteria for non-human organisms • aquatic acute effects levels of < 1 mg/L • above 1 mg/L professional judgment considering other factors (e.g. molecular weight, metabolism...) • log Kow > 6 (consideration of effects to wildlife)

10. 1 mg/L

12. Potency Exposure Effect

13. Toxic Effect = f(concentration at the active site, concentration at the active site required to trigger the effect) Toxic Effect = f(EXPOSURE, POTENCY) Toxic Effect = f(EXPOSURE, TOXICITY)

14. What is the difference? • Dose makes the Poison • Toxic Effect = f(concentration at the active site, concentration at the active site required to trigger the effect)

15. What is the difference? • Dose makes the Poison • Toxic Effect = f(concentration at the active site, concentration at the active site required to trigger the effect) External Internal

16. To agree or not agree? Chemicals that cause the same effect at the same internal concentration have the same potency / toxicity

18. Internal concentrationfor acute toxicity : 5 mmol/kg Fish-water Bioconcentration Factor : 0.04 8 105.5 = 12,600 Water Concentration needed : 5 / 12,600 = 4 .10-4 mmol/L Water Solubility : 1.7 .10-5 mmol/L

19. Ferguson cut-off Chemical concentration in the water that is required to produce the internal concentration in the organism that is needed to trigger the effect exceeds the chemical’s water solubility.

23. Non-Polar Narcosis similarity with anesthetics: chloroform Lethality at an internal concentration: 3 to 6 mmol/kg All chemicals & all organisms mechanism unknown likely affect membranes: swells membranes causing a physical effect affects membrane proteins Narcosis is the most basic mode of toxic action. Chemicals will have at least this toxicity or they may have a greater toxicity.

25. Acute vs. Chronic Toxicity Water Concentration pg/L 1 0.5 0.1 Lethal Body burden

26. Mixtures of Chemicals For chemicals that share Non-Polar Narcosis Mode of Toxic Action: If Scinternal > 5 mmol/kg Then 50% lethality

27. For Chemicals Acting by Non-Polar Narcosis Mixture Toxicity Scinternal > ~ 5 mmol/kg)

29. Dioxin Toxicity in Lake Trout

30. Dose-Response Curve for TCDD

31. Substances with Dioxin-like Toxicity

32. Dioxin Toxicity + Aryl Hydrocarbon Receptor 4 Angstrom 10 Angstrom

33. Mechanism of Toxic Action

37. Cytochrome P450 Cycle

38. Phase I Reaction

39. Phase II Reaction

40. Role of Cytochrome P450 in Bioactivation

44. For Chemicals with Dioxin like mode of toxic action Dioxin-like Mixture Toxicity Toxic Equivalent Concentration (ng/kg) =  (CPCDDi × TEFi) +  (CPCDFi × TEFi) +  (CPCBi × TEFi)

46. Recipe for a Toxic Effect • Ingredients : • Exposure: • Relationship between external concentration and the concentration at the active site • Potency : • concentration at the active site required to trigger the effect • Directions: • concentration at the active site > concentration at the active site required to trigger the effect

48. FISH 1FISH 2 Volume Total (m3) 1 1 Volume Water (m3) 0.9 0.5 Volume Lipid (m3) 0.1 0.5 Concentration in water 1.10-6 1.10-6 (mol/m3) ZW 1 1 fW 1.10-6 1.10-6 fL 1.10-6 1.10-6 ZL 104 104 Cw 1.10-6 1.10-6 CL 1.10-2 1.10-2 VW.CW 0.9 . 10-6 0.5 . 10-6 VL.CL 0.1 . 10-2 0.5 . 10-2 Vi.Ci ~0.1 . 10-2 ~0.5 . 10-2 Ci ~0.1 . 10-2 ~0.5 . 10-2

50. Toxic Effect = f(fugacity at the active site, fugacity at the active site associated with the effect) f(f at the active site, f at the active site associated with the effect)