Mechanism Based Carcinogenic Risk Assessment of Estrogens and Estrogen Like Compounds

Ben A. T. Willems1, Christopher J. Portier2, George W. Lucier2

1 1418 Maple St. Apt B, Santa Monica, CA 90405, USA E-mail: [email protected]

2 Laboratory of Computational Biology and Risk Analysis, National Institute of Environmental Health Sciences, Mail Drop A3-06, P.O. Box 12233, Research Triangle Park, NC 27709, USA E-mail: [email protected]

Estrogens play an important role in mammalian reproductive cycles and a disturbance of this cycle can cause adverse effects like carcinogenicity.A mechanistic modeling approach is helpful in attempting to unravel the entanglement of genomic, non-genomic, and feedback signals involved in endocrine signaling. To make more balanced decisions on possible human health risks put forth by endocrine active compounds (e.g., estrogens and estrogen-like agents), a multidisciplinary approach is necessary. Besides traditional epidemiological studies, accumulation of mechanistic data is essential for all classes of agents. Combining all available information is a positive move towards a more complete risk assessment process.

Keywords. Endocrine disruptors, Estrogen, Risk assessment, Mechanistic modeling

1 Introduction 111

2 Biological Signaling Pathways of Estrogen 112

2.1 Estrogen Metabolism and Fluctuation 112

2.2 Genomic Processes 112

2.3 Non-Genomic Processes 113

2.4 Estrogen Receptor Regulation 114

3 Endocrine Active Compounds Interactions and Adverse Endpoints 115

3.1 Adverse Endpoints 116

3.2 Agonists/Antagonists 116

3.3 Xenoestrogens 117

3.4 Phytoestrogens 118

4 Carcinogen Risk Assessment 119

4.1 Change in Perspective 119

4.2 Modes of Action 119

4.3 Change in Risk Assessment Approach 120

5 Mechanistic Model Development for Estrogens 122

5.1 Model Types 122

5.2 Estrus Cycle Model 123

5.2.1 Hypothalamus System 123

The Handbook of Environmental Chemistry Vol. 3, Part M Endocrine Disruptors, Part II (ed. by M. Metzler)

© Springer-Verlag Berlin Heidelberg 2002

5.2.2 Hypothalamus/Pituitary Portal System 125

5.2.3 Pituitary 125

5.2.4 Ovaries 125

6 Discussion 126

7 References 128

Abbreviations

AC

adenylate cyclase

cAMP

cyclic adenosine monophosphate

AP

activator protein

ATP

adenosine triphosphate

BM

benchmark dose

CL

corpora lutea

CRE

cAMP response element

DDT

dichlorodiphenyltrichloroethane

DES

diethylstilbestrol

DNA

deoxyribonucleic acid

E2

17^-estradiol

EAC

endocrine active compound

ECM

estrus cycle model

EGF

epidermal growth factor

EPA

Environmental Protection Agency

ER

estrogen receptor

ERE

estrogen response element

FSH

follicle-stimulating hormone

GnRH

gonadotropin-releasing hormone

IGF-I

insulin-like growth factor I

Inh

inhibin

LH

luteinizing hormone

LMS

linearized multistage model

MOE

margin of exposure

mRNA

messenger ribonucleic acid

NADPH

nicotinamide adenine dinucleotide phosphate, reduced form

NOAEL

no observable adverse effect level

P

progesterone

PAH

polycyclic aromatic hydrocarbon

PBPD

physiologically based pharmacodynamic

PBPK

physiologically based pharmacokinetic

PCB

polychlorinated biphenyl

PDE

phosphodiesterase

PKA

protein kinase A

QSAR

quantitative structure-activity relationship

T

testosterone

TCDD

2,3,7,8-tetrachloro dibenzo-p -dioxin

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