Environmental Health

1. Environmental Health Interactions and Mixtures Week 9

2. Cumulative risks • Which mixtures are important for Public Health? • What is the nature, magnitude of cumulative exposures? • What is the mechanism of interactions? Sexton 2007 and supplement

3. Biological Chemical Physical Psychosocial Similar properties Defined (diesel) Coincidental (time, place) Types of mixtures Past and present, all routes, pathways and sources

4. High priority mixtures • Scope: large number of people exposed • Nature of exposure: magnitude, frequency • Severity of effects: unacceptable risks • Potential for interactions See: Sexton 2007 supplement

5. Total body burden over time based on exposure frequency and kinetics of a chemical See: Sexton 2007 supplement

6. Total body burden from two chemicals relative to a health benchmark See: Sexton 2007 supplement

7. Interactions among what? • Drug-drug • Environmental pollutants • Drug-environmental exposure • Diet-drug • Diet-environmental pollutant • Genes and all the above

8. When, who, how? • Exposures • Concurrent • Sequential • Order • Physiology differences • Children • Elderly • Pre-existing conditions, overall health • Genetic disposition • Route of exposure • Amount

9. Types of interactions Dose additivity - if mechanism is similar Response additivity - if acting independently

10. Putting a number to them

11. Antagonism of many kinds

12. So, what interaction is this? Q. A dose of 4 mg of an insecticide causes 20% toxicity whereas the same dose of another insecticide produces 30% toxicity. If 8 mg of a formulation containing both insecticides in equal concentrations causes 50% toxicity, the interaction is known as: Additivity Antagonism Synergism

13. …and, what about this? Q. Piperonyl butoxide added to pyrethrum insecticide results in a pyrethrum formulation having about 100 times the toxicity of pyrethrum alone. The interaction of this combination is: Additivity Antagonism Synergism

14. Main types of interactions • Physical prior to absorption • Toxicokinetic interactions • Toxicodynamic interactions

15. Toxicokinetic Interactions • One chemical affects the kinetic disposition of another: • Absorption • Distribution • Metabolism • Elimination

16. Performing in vitro CYP450 induction screens, to evaluate potential multi-chemical interactions

17. “A” increases toxicity of “B” by inhibiting a detox enzyme A B Toxic effect + Enzyme X (Phase I) B metabolite inactive Enzyme Y (Phase II) Excretion

18. “A” isprotective by inhibiting a metabolic activation reaction A B inactive + Enzyme X (Phase I) B metabolite Toxic effect Enzyme Y (Phase II) Excretion

19. “A” is protective by inducing a detox enzyme A B Toxic effect + Enzyme X (Phase I) B metabolite inactive Enzyme Y (Phase II) Excretion

20. “A” increases toxicity of “B” by inducing enzyme of metabolic activation A B inactive + Enzyme X (Phase I) B metabolite Toxic effect Enzyme Y (Phase II) Excretion

22. Toxicodynamic Interactions • One chemical’s biological activity is related to the biological activity of the other • Changing cell signaling (phosphorylation cascades) • Altering gene expression and genomic repair • Modulating cell communication • Altering cell cycle • Affecting the same biochemical pathway at a different step • Affecting a related biochemical pathway • Systemic level cross-talk interference • Autoimmune effects

23. First order Michaelis-Menten kinetics of enzyme reaction: Competitive inhibition of a enzyme reaction, transporter activity Uncompetitive inhibition of a enzyme reaction, transporter activity See: Sexton 2007 supplement

24. Change in slope as indicator of interactions See Gennings 2005

25. Slopes must be compared at the same effect regions See Gennings 2005

26. Interaction of piperonyl butoxide with malathion

27. Non-linear models Binary endpoints and probability of response A - Changing concentrations of one chemical with fixed concentration of the other B - Changing concentrations of both chemicals

28. Thyroid effects of PCBs Carpenter, 1998

29. Carpenter, 1998 PTU: propylthiouracil, known to produce hypthyroidism LTP: long term potential, electrophysiological measure indicating cognitive function EPSP: excitatory postsynaptic potential, reflects LTP

30. Parent compound and metabolite have opposite effects TrCB is also antiestrogenic by virtue of inducing the metabolism of E2 Carpenter, 1998

31. Increased estrogenic effects of combined PCBs or organochlorines Carpenter, 1998

32. Carpenter, 1998

33. Carpenter, 1998

34. Models of interactions See Groten 2001

35. Combined effects of UV filter mixtures on ER activation (yeast) B - antagonism Curve shift in-between A - synergism Curve shift to the left Kunz 2006

36. Most binary mixtures show synergism at EC25, EC50 and EC75 effect levels Kunz 2006

37. Synergism of mixtures of 4 UV filters at BC10 and NOEC effect levels Kunz 2006

38. Kunz 2006 Effect of mixture of 4 UV filters at BC10 and NOEC

39. Effect of mixtures (4 or 8) is stronger at NOEC than at BC10 Kunz 2006

40. Mixtures of 4 are as potent as the most potent one (BP1) Relative potencies are compared to E2 Kunz 2006

41. Approaches to toxicity of simple mixtures

42. Bottom-up approach Systematic studies of binary combinations of chemicals in the mixture based on mechanisms Top-down approach Start from the most complete mixture and continue with subfractions by separating components Simple mixtures toxicity testing

43. Bottom-up • Kepone’s impairment of liver regeneration will affect the toxicity of liver toxins • CCl4 • 1,1,2,2-Tetrachloroethane • Hexachloro-1,3-butadiene

44. Kepone + CCl4 • Kepone 10ppm (low environmental level) • CCl4 100ul/kg (injected) - only marginally toxic level • Combination increased lethality by 67-fold

45. Modeling of CCl4 liver toxicity +/- Kepone CCl4 only CCl4 andKepone

46. Top-Down

47. Approaches to toxicity of complex mixtures

48. Dietary factors • Red meat, processed meat, well-done meat • Vitamins and antioxidants • Trace elements, metals • Alcohol • Phytochemicals (isothiocyanates)