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

4

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

5

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.

6

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

7

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

8

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.

9

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??

10

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