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James S. Smith, Jr.

OAK CREEK Toxicology & Risk Assessment Consulting. An Evaluation of the Use of Toxic Equivalency Factors to Assess Reproductive Hazards of PCBs to Wildlife. James S. Smith, Jr. Adverse Reproductive Effects Associated With PCBs. Decreased reproductive success Neurotoxic effects

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James S. Smith, Jr.

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  1. OAK CREEK Toxicology & Risk Assessment Consulting An Evaluation of the Use of Toxic Equivalency Factors to Assess Reproductive Hazards of PCBs to Wildlife James S. Smith, Jr.

  2. Adverse Reproductive Effects Associated With PCBs • Decreased reproductive success • Neurotoxic effects • Changes in reproductive behavior • Teratogenic effects • Reduced survivability OAK CREEK

  3. PCBs Cause Toxicity Through A Dioxin-Like Mechanism • Bind the aryl hydrocarbon receptor (AhR) • PCB-AhR complexes bind DNA regulatory elements to induce gene expression • Induce 3-methylcholanthrene-like enzyme activity • Species and tissue specific enzyme profile • Liver: CYP1A1 gene • Aryl hydrocarbon hydroxylase (AHH) • Ethoxyresorufin-O-deethylase (EROD) OAK CREEK

  4. Induction of CYP1A1 and EROD Induce CYP1A1 Increase EROD activity Dioxin-Like Compounds ? ? Adverse Reproductive Effects OAK CREEK

  5. Non-ortho substituted or coplanar congeners 126 (3,3’,4,4’,5-pentaCB) 169 (3,3’,4,4’,5,5’-hexaCB) Mono-ortho substituted analogues 123 (2’,3,4,4’,5-pentCB) 114 (2,3,4,4’,5-pentaCB) 105 (2,3,3’,4,4’-pentaCB) 118 (2,3’,4,4’,5-pentaCB) 156 (2,3,3’,4,4’,5-hexaCB) 167 (2,3’,4,4’,5,5’-hexaCB) 157 (2,3,3’,4,4’,5’-hexaCB) 189 (2,3,3’,4,4’,5,5’-heptaCB). Dioxin-Like PCBs OAK CREEK

  6. Compound Mammals Fish Birds 1 1 1 2,3,7,8-TCDD a,b,c,e e 3,4,4',5-TCB 81 0.0001 0.0005 0.1 3,3',4,4'-TCB 77 0.0001 0.0001 0.05 3,3',4,4',5-PeCB 126 0.1 0.005 0.1 3,3',4,4',5,5'-HxCB 169 0.01 0.00005 0.001 2,3,3',4,4'-PeCB 105 0.0001 <0.000005 0.0001 a,b,c,d b f 2,3,4,4',5-PeCB 114 0.0005 <0.000005 0.0001 2,3',4,4',5-PeCB 118 0.0001 <0.000005 0.00001 a,c,d b f 2',3,4,4',5-PeCB 123 0.0001 <0.000005 0.00001 b,c 2,3,3',4,4',5-HxCB 156 0.0005 <0.000005 0.0001 b,c,d b,c 2,3,3',4,4',5'-HxCB 157 0.0005 <0.000005 0.0001 a,d b f 2,3',4,4',5,5'-HxCB 167 0.00001 <0.000005 0.00001 a,c f 2,3,3',4,4',5,5'-HpCB 189 0.0001 <0.000005 0.00001 a Limited data set b Structural similarity c QSAR modeling prediction from CYP1A induction (monkey, pig, chicken, or fish) d No new data from 1993 review eIn vivoCYP1A induction f QSAR modeling prediction from class specific TEFs 1997 WHO TEFs OAK CREEK

  7. TEFs Used to Estimate Exposure to Dioxin-Like Compounds • Assumed that PCBs have dioxin-like toxicity • PCB “toxic” potency is determined relative to that of 2,3,7,8-TCDD • Dioxin equivalent exposure is therefore:  (TEFi x Ci)n OAK CREEK

  8. Some Problems With the Use of TEFs • TEFs do not address Non-dioxin-like toxicity • Some PCBs are antagonistic of dioxin-like toxicity • Biological relevance ? OAK CREEK

  9. Non-Dioxin-Like PCBs • Di-ortho PCBs • Do not bind AhR • Do not induce AHH/EROD • Induce phenobarbital-like enzyme activity • Associated with adverse effects: • CYP2B induction • Hypovitaminosis A • Hypothyroidism • Carcinogenic effects • Neurotoxic effects OAK CREEK

  10. Biological Relevance • Induction of CYP1A1 or EROD correlated with adverse reproductive effect? • Sure • What does it mean? • There is no mechanistic evidence that AhR binding or induction of CYP1A1 or EROD is linked to the occurrence or severity of any adverse effects. (US EPA (1995) OAK CREEK

  11. Effects of PCB Congeners OAK CREEK

  12. Dioxin-Inducible P-450s Activity Humans Rodents Birds P-450 Subclass CYP1A1 EROD/AHH +/- ++ ++ 6 B -testosterone hydroxylase ? + ? CYP1A2 MROD + + ? ACOH ? + ? Caffeine Metabolism + ? ? CYP2A1 PROD ? + ? CYP1B1 4 a -estradiol hydroxylase + + ? CYP2B1 PROD + + ? CYP2B2 PROD ? + ? CYP2H 16a-testosterone hydroxylase ? ? + 16 B -testosterone hydroxylase ? ? + CYP3A 2 B -testosterone hydroxylase ? ? + 6 B -testosterone hydroxylase ? +++ + 15 a -testosterone hydroxylase ? ? + CYP3A1 PROD ? + ? OAK CREEK

  13. Reproductive Effects Linked to Other Enzymes? • Phenobarbital is known to alter testosterone profiles and testicular function (Wani et al. 1996). • Do inducers of phenobarbital-type enzyme activity have similar effects? • Enzymes that act on estrogen may also be a potential mechanism for reproductive effect. • Effects of estrogen metabolites OAK CREEK

  14. Relative Potency of Dioxin for Reproductive Effects OAK CREEK

  15. Relative Potency for Induction OAK CREEK

  16. TEF Use Likely to Over-Estimate Reproductive Risk to Wildlife • EROD induction has not been mechanistically linked to adverse reproductive effect. • Other dioxin-induced enzyme activities may be more plausibly linked to the occurrence of adverse reproductive effect • These other enzymes are induced at dioxin concentrations that are orders of magnitude higher than required for EROD induction OAK CREEK

  17. Conclusion • Identify PCB congeners of concern for adverse reproductive effects in wildlife • Use TEFs cautiously with the knowledge that adverse reproductive effects have not been mechanistically linked to EROD induction • Explore the use of other plausible biologically-based PCB-induced enzyme activities as potential markers of exposure. OAK CREEK

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