assessing cumulative effects of endocrine active substances…
DESCRIPTION
or What happens when I’m exposed to a whole bunch of endocrine active substances??. Assessing Cumulative Effects of Endocrine Active Substances…. Tim Pastoor, PhD, DABT September 10, 2009. Coumestrol. Ethinylestradiol (EE). Toxaphene. Dioxin. Genistein. Endrin. - PowerPoint PPT PresentationTRANSCRIPT
Tim Pastoor, PhD, DABT
September 10, 2009
Assessing Cumulative Effects of Endocrine Active Substances…
orWhat happens when I’m exposed to a whole bunch of endocrine active substances??
2
Dioxin
Lindane
Methoxychlor
Toxaphene
Endrin
ChlordaneHeptaclor
Ethinylestradiol (EE)
Estrone
Coumestrol
Genistein
Daidzein
Isobutylparaben
Butylparaben
Tim Pastoor, PhD, DABT
3
(From R. Golden)
Comparative Potency of Xenoestrogens in Rodent Uterotropic Assay
Substance
Effective dose(mg/kg/day)
Relative potencyEE=1,000,000
DES 0.0001 3,000,000
Ethinylestradiol (EE) 0.0003 1,000,000
Estrone 0.0012 250,000
Coumestrol 0.24 1250
Genistein 8 37
Daidzein 11 27
Isobutylparaben 73 4
Butylparaben 600 0.5
Benzylparaben 2500 0.12
Tim Pastoor, PhD, DABT
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Chemical MCL (mg/l) HypotheticalPotency (TEF)
Intake TEQ
Dioxin 0.00000003 0.000004 0.0000000012
Lindane 0.002 0.0038 0.00000152
Methoxychlor 0.04 0.000016 0.00000128
Atrazine 0.003 0.00005 0.0000003
PCBs 0.005 0.0000018 0.00000018
Toxaphene 0.003 0.008 0.000048
Simazine 0.1 0.0001 0.00002
Endrin 0.002 0.0009 0.000036
Chlordane 0.002 0.00001 0.000004
Heptaclor 0.0004 0.0003 0.000024
B(a)P 0.0002 0.0006 0.0000024
Total 0.00014
Hypothetical Illustration of TEF/TEQ Approach for WEEDs in Drinking Water
Tim Pastoor, PhD, DABT
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Receptor Terminology: Law of Mass Action
Drug + Receptor Drug-Receptor
ComplexResponse(s)
Tim Pastoor, PhD, DABT
• Affinity: the “tenacity” by which a drug binds to its receptor.
•Intrinsic activity: the relative maximal response caused by a drug in a tissue preparation.
•Intrinsic efficacy: a drug’s ability to affect a receptor and cause a biological response.
•Potency: the relative ability of a drug to cause a measured biological or functional change.
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The chain of events required for estrogen-induced uterine thickening
Tim Pastoor, PhD, DABT
Jonathan G. Moggs, et al. Phenotypic Anchoring of Gene Expression Changes during Estrogen-Induced Uterine Growth. Environ Health Perspect 112:1589–1606 (2004). doi:10.1289/txg.7345
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Time Course of Estrogen-Induced Uterine Growth
Tim Pastoor, PhD, DABT
Jonathan G. Moggs, et al. Phenotypic Anchoring of Gene Expression Changes during Estrogen-Induced Uterine Growth. Environ Health Perspect 112:1589–1606 (2004). doi:10.1289/txg.7345
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Receptor Terminology: Law of Mass Action
Drug + Receptor Drug-Receptor
ComplexResponse(s)
Tim Pastoor, PhD, DABT
• Affinity: the “tenacity” by which a drug binds to its receptor.
•Intrinsic activity: the relative maximal response caused by a drug in a tissue preparation.
•Intrinsic efficacy: a drug’s ability to affect a receptor and cause a biological response.
•Potency: the relative ability of a drug to cause a measured biological or functional change.
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Working Hypothesis:
Tim Pastoor, PhD, DABT
Can we state with reasonable certainty that a cumulative risk assessment of multiple week endocrine active substances is an exercise in adding zeroes??
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Dioxin
Lindane
Methoxychlor
Toxaphene
Endrin
Chlordane
Heptaclor
Ethinylestradiol (EE)
Estrone
Coumestrol
Genistein
Daidzein
Isobutylparaben
Butylparaben
Tim Pastoor, PhD, DABT
Tim Pastoor, PhD, DABT
September 10, 2009
Sneezing in a Hurricane