“The Dose makes the Poison” Paracelcus (1567)

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

2. What is "Toxicity”?

8. 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

9. 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.

10. 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)

11. 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)

12. 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

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

17. 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.

19. 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

21. 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)

22. 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)

23. Acute vs. Chronic Toxicity

25. 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?

26. 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.

27. 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.

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

29. Mixtures of Chemicals If Shared Mode of Toxic Action: Toxic Effect = f(SCinternal, Potency)

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

31. Dose - Response Relationship

35. 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?

36. 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?

37. Hazard : Potential for a toxicological effect occurring

38. Assessment of Hazard

39. 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.

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

42. 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

43. Risk Probability of a toxicological effect occuring

44. Single-Point Exposure and Effects Comparison

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

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

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

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