1. OAK CREEK
Toxicology & Risk Assessment Consulting
An Evaluation of the Use of Toxic Equivalency Factors to Assess Reproductive Hazards of PCBs to Wildlife
Polycyclic Aromatic Hydrocarbons or PAHs are a large group of compounds consisting of three or more fused aromatic rings formed during the incomplete combustion of man-made and natural organic materials.
According to the Environmental Protection Agency or EPA, PAHs are found in all environmental media and as a class of compounds, PAHs are among some of the most abundant at hazardous waste sites.
As such, mixtures of PAHs at hazardous waste sites are thought to pose potential health risk to potentially exposed individuals.
The critical effect or the adverse effect to which animals are most sensitive is thought to be the ability of PAHs to cause cancer. Is exposure PAHs at hazardous waste sites causing an increase in cancer incidence? OR
ARE WE OVER-REGULATING PAHs?
James S. Smith, Jr.

2. Adverse Reproductive Effects Associated With PCBs
Decreased reproductive success
Neurotoxic effects
Changes in reproductive behavior
Teratogenic effects
Reduced survivability
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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)
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4. Induction of CYP1A1 and EROD
Dioxin-Like
Compounds
Induce
CYP1A1
Increase
EROD activity ? ?
Adverse
Reproductive
Effects
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5. Dioxin-Like PCBs 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).
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6. 1997 WHO TEFs Mammals Fish Birds Compound OAK CREEK 2,3,7,8-TCDD 1
3,4,4',5-TCB 81
0.0001
a,b,c,e
0.0005
0.1 e
3,3',4,4'-TCB 77
0.05
3,3',4,4',5-PeCB
126
0.005
3,3',4,4',5,5'-HxCB
169
0.01
0.001
2,3,3',4,4'-PeCB
105
<
2,3,4,4',5-PeCB
114
a,b,c,d b f
2,3',4,4',5-PeCB
118
2',3,4,4',5-PeCB
123
a,c,d
2,3,3',4,4',5-HxCB
156
b,c
2,3,3',4,4',5'-HxCB
157
b,c,d
2,3',4,4',5,5'-HxCB
167
a,d
2,3,3',4,4',5,5'-HpCB
189
a,c
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
e In vivo CYP1A induction
f QSAR modeling prediction from class specific TEFs
Compound
1997
WHO
TEFs
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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
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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 ?
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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
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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)
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11. Effects of PCB Congeners
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12. Dioxin-Inducible P-450s P-450 Subclass Activity Humans Rodents Birds
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 ? + ?
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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
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14. Relative Potency of Dioxin for Reproductive Effects
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15. Relative Potency for Induction
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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
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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