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 10 5.5 = 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. 1 0.5 0.1 Water Concentration pg/L Acute vs. Chronic Toxicity Lethal Body burden

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

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

29. Dioxin Toxicity in Lake Trout

30. Dose-Response Curve for TCDD

31. Substances with Dioxin-like Toxicity

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

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) =  (C PCDDi × TEF i ) +  (C PCDFi × TEF i ) +  (C PCBi × TEF i )

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 1 FISH 2 Volume Total (m 3 )11 Volume Water (m 3 )0.90.5 Volume Lipid (m 3 )0.10.5 Concentration in water1.10 -6 1.10 -6 (mol/m 3 ) Z W 11 f W 1.10 -6 1.10 -6 f L 1.10 -6 1.10 -6 Z L 10 4 10 4 C w 1.10 -6 1.10 -6 C L 1.10 -2 1.10 -2 V W.C W 0.9. 10 -6 0.5. 10 -6 V L.C L 0.1. 10 -2 0.5. 10 -2  V i.C i ~0.1. 10 -2 ~0.5. 10 -2 C i ~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)

51. 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)

52. Acute vs. Chronic Toxicity

54. So what?? You want to protect all aquatic life by setting a water quality criterion for chemical X, i.e. a water concentration that should not be exceeded. So, what do you do?

55. So what?? You want to protect all aquatic life by setting a water quality criterion for chemical X, i.e. a water concentration that should not be exceeded. So, what do you do? This WQC is derived from a study of LC50 or NOAEC derived in the lab, and you take the lowest LC50 divide it by a safety factor (e.g. 10), and this becomes your criterion.

56. So what?? You want to protect all aquatic life by setting a water quality criterion for chemical X, i.e. a water concentration that should not be exceeded. So, what do you do? This WQC is derived from a study of LC50 or NOAEC derived in the lab, and you take the lowest LC50 divide it by a safety factor (e.g. 10), and this becomes your criterion. Then you manage environmental quality by a monitoring program that measures water concentrations & compares them with the WQC.

57. Tissue Residue Approach for Characterizing Toxicity Merits: eliminates transport/bioaccumulation from the external environment (Exposure), including: bioavailability dietary uptake and biomagnification metabolism accumulation kinetics

58. Mixtures of Chemicals If Shared Mode of Toxic Action: Toxic Effect = f(  C internal, Potency)

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

60. Dose - Response Relationship

64. Application of Toxicity Data to conduct Hazard and Risk Assessment General Problem: The Concentration of Trichlorobenzene in River Water is: 5.10 -6 mmol/L LC50 in guppies (48 hr) : 5.10 -4 mmol/kg What is the hazard and/or risk to rainbow trout?

65. Application of Toxicity Data to conduct Hazard and Risk Assessment General Problem: The ingested dose of Trichlorobenzene by (humans or sea otters) in food items is: 5.10 -2 mg/kg/day LD50 in rats (14 days) : 50 mg/kg/day LOAEL : 5 mg/kg/day What is the hazard and/or risk to humans or sea otters?

66. Hazard : Potential for a toxicological effect occurring

67. Assessment of Hazard

68. Reference Dose Is an estimate of the daily dose to a population that is unlikely to produce an appreciable risk of adverse effect during a life time. Similar to an acceptable daily intake. Reference Concentration Is an estimate of the concentrations to a population that is unlikely to produce an appreciable risk of adverse effect during a life time. Similar to an acceptable concentration.

70. Hazard Index H = dose / Rfd < 1.0 There is no hazard > 1.0 There is a hazard

71. Hazard Index Rfd = 5 mg/kg/day(LOAEL)/1000 = 5.10 -3 H = 5.10 -2 / 5.10 -3 = 10 There is a hazard > 1.0 There is a hazard

72. Risk Probability of a toxicological effect occuring

73. Single-Point Exposure and Effects Comparison

75. Quotient-Method Cexposure / Ceffect Ceffects can be: LC50, LD50, EC50, NOAEL, LOAEL, LC5 etc. Sometimes combined with a safety-factor

76. Example: LC5 = 50 ng/L Exposure Concentration : 30 ng/L Cexposure/LC5 = 60%

77. Example: LC5 = 50 ng/L Exposure Concentration : 30  15 ng/L (normal) 8.3%

78. Example: LC5 = 50 ng/L Exposure Concentration : 30  15 ng/L (log-normal) 22%