title: Designing Endocrine Disruption Out of the Next Generation of Chemicals.
abstract: A central goal of green chemistry is to avoid hazard in the design of new chemicals. This objective is best achieved when information about a chemical's potential hazardous effects is obtained as early in the design process as feasible. Endocrine disruption is a type of hazard that to date has been inadequately addressed by both industrial and regulatory science. To aid chemists in avoiding this hazard, we propose an endocrine disruption testing protocol for use by chemists in the design of new chemicals. The Tiered Protocol for Endocrine Disruption (TiPED) has been created under the oversight of a scientific advisory committee composed of leading representatives from both green chemistry and the environmental health sciences. TiPED is conceived as a tool for new chemical design, thus it starts with a chemist theoretically at "the drawing board." It consists of five testing tiers ranging from broadin silicoevaluation up through specific cell- and whole organism-based assays. To be effective at detecting endocrine disruption, a testing protocol must be able to measure potential hormone-like or hormone-inhibiting effects of chemicals, as well as the many possible interactions and signaling sequellae such chemicals may have with cell-based receptors. Accordingly, we have designed this protocol to broadly interrogate the endocrine system. The proposed protocol will not detect all possible mechanisms of endocrine disruption, because scientific understanding of these phenomena is advancing rapidly. To ensure that the protocol remains current, we have established a plan for incorporating new assays into the protocol as the science advances. In this paper we present the principles that should guide the science of testing new chemicals for endocrine disruption, as well as principles by which to evaluate individual assays for applicability, and laboratories for reliability. In a 'proof-of-principle' test, we ran 6 endocrine disrupting chemicals (EDCs) that act via different endocrinological mechanisms through the protocol using published literature. Each was identified as endocrine active by one or more tiers. We believe that this voluntary testing protocol will be a dynamic tool to facilitate efficient and early identification of potentially problematic chemicals, while ultimately reducing the risks to public health.
authors.forename: T T
authors.initials: TT
authors.lastname: Schug
authors.forename: R
authors.initials: R
authors.lastname: Abagyan
authors.forename: B
authors.initials: B
authors.lastname: Blumberg
authors.forename: T J
authors.initials: TJ
authors.lastname: Collins
authors.forename: D
authors.initials: D
authors.lastname: Crews
authors.forename: P L
authors.initials: PL
authors.lastname: DeFur
authors.forename: S M
authors.initials: SM
authors.lastname: Dickerson
authors.forename: T M
authors.initials: TM
authors.lastname: Edwards
authors.forename: A C
authors.initials: AC
authors.lastname: Gore
authors.forename: L J
authors.initials: LJ
authors.lastname: Guillette
authors.forename: T
authors.initials: T
authors.lastname: Hayes
authors.forename: J J
authors.initials: JJ
authors.lastname: Heindel
authors.forename: A
authors.initials: A
authors.lastname: Moores
authors.forename: H B
authors.initials: HB
authors.lastname: Patisaul
authors.forename: T L
authors.initials: TL
authors.lastname: Tal
authors.forename: K A
authors.initials: KA
authors.lastname: Thayer
authors.forename: L N
authors.initials: LN
authors.lastname: Vandenberg
authors.forename: J
authors.initials: J
authors.lastname: Warner
authors.forename: C S
authors.initials: CS
authors.lastname: Watson
authors.forename: F S Vom
authors.initials: FS
authors.lastname: Saal
authors.forename: R T
authors.initials: RT
authors.lastname: Zoeller
authors.forename: K P
authors.initials: KP
authors.lastname: O'Brien
authors.forename: J P
authors.initials: JP
authors.lastname: Myers
references.citation: Environ Health Perspect. 2006 Jan;114(1):100-5
references.pmid: 16393665
references.citation: Thyroid. 2004 Dec;14(12):1012-9
references.pmid: 15650353
references.citation: Endocrinology. 1997 Apr;138(4):1406-12
references.pmid: 9075695
references.citation: Environ Health Perspect. 2009 Jun;117(6):910-5
references.pmid: 19590682
references.citation: Toxicol Sci. 2010 May;115(1):214-24
references.pmid: 20118188
references.citation: Toxicology. 2005 Oct 1;213(3):177-93
references.pmid: 15996808
references.citation: J Comput Aided Mol Des. 2010 May;24(5):459-71
references.pmid: 20455005
references.citation: Environ Toxicol Chem. 2001 Jun;20(6):1276-90
references.pmid: 11392137
references.citation: Fundam Appl Toxicol. 1996 Apr;30(2):194-203
references.pmid: 8812265
references.citation: Gen Comp Endocrinol. 2007 Aug-Sep;153(1-3):25-9
references.pmid: 17324418
references.citation: Toxicol Sci. 2007 Jan;95(1):5-12
references.pmid: 16963515
references.citation: Toxicol Sci. 2000 Jun;55(2):433-43
references.pmid: 10828276
references.citation: Environ Health Perspect. 1994 Apr;102(4):380-3
references.pmid: 7925178
references.citation: Mol Pharmacol. 2005 Mar;67(3):766-74
references.pmid: 15611480
references.citation: Endocrinology. 2006 Jun;147(6 Suppl):S11-7
references.pmid: 16690809
references.citation: Toxicol Appl Pharmacol. 2010 Jun 1;245(2):160-70
references.pmid: 20206645
references.citation: Toxicol Sci. 2002 Mar;66(1):69-81
references.pmid: 11861974
references.citation: Chemosphere. 2011 Jun;84(3):328-35
references.pmid: 21601234
references.citation: Environ Sci Technol. 2005 Apr 15;39(8):2762-8
references.pmid: 15884374
references.citation: SAR QSAR Environ Res. 2010 Apr;21(3-4):351-67
references.pmid: 20544555
references.citation: Reprod Toxicol. 2008 Nov-Dec;26(3-4):210-9
references.pmid: 18938238
references.citation: Toxicol Sci. 2005 Feb;83(2):264-72
references.pmid: 15537743
references.citation: J Comp Neurol. 2011 Oct 15;519(15):2954-77
references.pmid: 21484804
references.citation: Nutr Res Rev. 2010 Dec;23(2):270-99
references.pmid: 20977819
references.citation: Proc Natl Acad Sci U S A. 2002 Apr 16;99(8):5476-80
references.pmid: 11960004
references.citation: Environ Health Perspect. 2004 May;112(7):773-81
references.pmid: 15159206
references.citation: Proc Natl Acad Sci U S A. 2010 Mar 9;107(10):4612-7
references.pmid: 20194757
references.citation: J Pharm Pharmacol. 2011 Jul;63(7):967-70
references.pmid: 21635263
references.citation: Arch Environ Contam Toxicol. 2003 Feb;44(2):247-56
references.pmid: 12520397
references.citation: Neurotoxicology. 1997;18(2):581-6
references.pmid: 9291506
references.citation: Dev Dyn. 2009 Oct;238(10):2641-51
references.pmid: 19718764
references.citation: J Biomol Screen. 2010 Sep;15(8):990-1000
references.pmid: 20817887
references.citation: Chem Res Toxicol. 2010 May 17;23(5):946-54
references.pmid: 20408563
references.citation: J Steroid Biochem Mol Biol. 2011 Oct;127(1-2):9-15
references.pmid: 21397693
references.citation: Aquat Toxicol. 2006 May 10;77(3):279-90
references.pmid: 16483677
references.citation: Steroids. 2010 Apr;75(4-5):314-22
references.pmid: 20096719
references.citation: Chemosphere. 2010 Jul;80(5):535-41
references.pmid: 20546840
references.citation: Toxicology. 2008 Sep 4;250(2-3):75-81
references.pmid: 18602967
references.citation: Gen Comp Endocrinol. 2003 Sep;133(2):189-98
references.pmid: 12928009
references.citation: Toxicol Appl Pharmacol. 2008 Jul 1;230(1):23-32
references.pmid: 18407306
references.citation: PLoS One. 2009;4(4):e5186
references.pmid: 19365547
references.citation: Environ Toxicol Chem. 2002 Mar;21(3):590-7
references.pmid: 11878472
references.citation: Environ Health Perspect. 2010 Sep;118(9):1243-50
references.pmid: 20488778
references.citation: BMC Genomics. 2007 Dec 06;8:453
references.pmid: 18062813
references.citation: Toxicol Appl Pharmacol. 2008 Dec 1;233(2):286-96
references.pmid: 18848953
references.citation: Endocrinology. 2006 Aug;147(8):3681-91
references.pmid: 16675520
references.citation: Mol Cell Endocrinol. 2005 Dec 1;244(1-2):31-41
references.pmid: 16221524
references.citation: Environ Sci Technol. 2005 Nov 15;39(22):9001-8
references.pmid: 16323805
references.citation: Ecotoxicol Environ Saf. 1990 Dec;20(3):246-55
references.pmid: 1708710
references.citation: Environ Toxicol Pharmacol. 2005 Feb;19(2):231-8
references.pmid: 21783481
references.citation: Endocrinology. 2011 Jul;152(7):2542-5
references.pmid: 21697454
references.citation: Water Sci Technol. 2004;50(5):125-32
references.pmid: 15497839
references.citation: Curr Opin Drug Discov Devel. 2002 Jan;5(1):104-15
references.pmid: 11865664
references.citation: Environ Health Perspect. 2006 Apr;114 Suppl 1:40-50
references.pmid: 16818245
references.citation: Toxicol Sci. 1999 Mar;48(1):55-66
references.pmid: 10330684
references.citation: SAR QSAR Environ Res. 2005 Oct;16(5):443-59
references.pmid: 16272043
references.citation: Toxicol Lett. 2008 Sep;181(1):13-8
references.pmid: 18621119
references.citation: Cancer Res. 2006 Jun 1;66(11):5624-32
references.pmid: 16740699
references.citation: Environ Health Perspect. 2009 Nov;117(11):1652-5
references.pmid: 20049113
references.citation: Toxicol Appl Pharmacol. 2005 Oct 15;208(2):127-36
references.pmid: 16183386
references.citation: J Chem Inf Comput Sci. 2001 Jan-Feb;41(1):186-95
references.pmid: 11206373
references.citation: Brain Res Dev Brain Res. 2005 Feb 8;154(2):259-63
references.pmid: 15707680
references.citation: Mar Pollut Bull. 2008;57(6-12):255-66
references.pmid: 18433798
references.citation: Toxicol Sci. 2005 Jan;83(1):136-48
references.pmid: 15483189
references.citation: Environ Toxicol Chem. 2008 Oct;27(10):2159-68
references.pmid: 18593212
references.citation: Water Res. 2003 Mar;37(6):1213-22
references.pmid: 12598185
references.citation: Gen Comp Endocrinol. 2010 Sep 1;168(2):269-74
references.pmid: 20138181
references.citation: Environ Health Perspect. 2001 Oct;109(10):1027-31
references.pmid: 11675267
references.citation: Toxicol Sci. 2002 May;67(1):121-30
references.pmid: 11961225
references.citation: PLoS One. 2011;6(9):e25448
references.pmid: 21980460
references.citation: Chem Rev. 2010 Oct 13;110(10):5845-82
references.pmid: 20873708
references.citation: Environ Toxicol Chem. 2005 Apr;24(4):926-33
references.pmid: 15839568
references.citation: Environ Toxicol. 2011 Aug;26(4):325-37
references.pmid: 20014407
references.citation: Cancer Sci. 2005 Jan;96(1):19-25
references.pmid: 15649250
references.citation: Comp Biochem Physiol C Toxicol Pharmacol. 2012 Mar;155(2):269-74
references.pmid: 21946249
references.citation: Reprod Toxicol. 2011 Jan;31(1):1-9
references.pmid: 20887781
references.citation: J Biol Chem. 2002 Aug 30;277(35):31491-8
references.pmid: 12070176
references.citation: Gen Comp Endocrinol. 1999 Aug;115(2):188-99
references.pmid: 10417232
references.citation: Int J Cancer. 2001 Jul 1;93(1):20-5
references.pmid: 11391616
references.citation: Front Neuroendocrinol. 2010 Oct;31(4):420-39
references.pmid: 20609371
references.citation: PLoS One. 2008;3(10):e3545
references.pmid: 18958157
references.citation: Biol Reprod. 2001 Oct;65(4):1215-23
references.pmid: 11566746
references.citation: Plasmid. 2010 Mar;63(2):73-8
references.pmid: 19962400
references.citation: Neurotoxicol Teratol. 2011 Nov-Dec;33(6):721-6
references.pmid: 21964161
references.citation: Steroids. 2011 Aug;76(9):921-8
references.pmid: 21291899
references.citation: Toxicol In Vitro. 1995 Jun;9(3):267-83
references.pmid: 20650088
references.citation: Proc Natl Acad Sci U S A. 2006 Aug 1;103(31):11473-8
references.pmid: 16864780
references.citation: Endocrinology. 2011 Jul;152(7):2690-703
references.pmid: 21540282
references.citation: Reprod Toxicol. 2007 Apr-May;23(3):374-82
references.pmid: 17123779
references.citation: Environ Health Perspect. 2011 Jan;119(1):104-12
references.pmid: 20870566
references.citation: Environ Health Perspect. 2011 Aug;119(8):1070-6
references.pmid: 21501981
references.citation: Environ Health. 2011 Jan 17;10(1):5
references.pmid: 21241498
references.citation: Int J Toxicol. 2008 Mar-Apr;27(2):175-82
references.pmid: 18404541
references.citation: Mol Endocrinol. 2011 Dec;25(12):2157-68
references.pmid: 22016562
references.citation: Breast Cancer Res. 2005;7(1):R130-44
references.pmid: 15642162
references.citation: Biol Reprod. 2010 Jan;82(1):112-22
references.pmid: 19741205
references.citation: Aquat Toxicol. 2011 Sep;105(1-2):13-20
references.pmid: 21684237
references.citation: Toxicol Appl Pharmacol. 2006 Nov 15;217(1):114-24
references.pmid: 16962624
references.citation: Obesity (Silver Spring). 2010 Jul;18(7):1283-8
references.pmid: 19927138
references.citation: Toxicol Appl Pharmacol. 2000 Dec 1;169(2):177-84
references.pmid: 11097870
references.citation: Endocr Rev. 2012 Jun;33(3):378-455
references.pmid: 22419778
references.citation: Obes Rev. 2010 Nov;11(11):792-807
references.pmid: 19845867
references.citation: J Med Chem. 2009 Jan 22;52(2):397-406
references.pmid: 19090659
references.citation: Environ Health Perspect. 2004 Nov;112(15):1481-7
references.pmid: 15531431
references.citation: J Toxicol Environ Health A. 2011;74(14):917-26
references.pmid: 21623536
references.citation: Toxicol Lett. 2009 Aug 25;189(1):67-77
references.pmid: 19463926
references.citation: Nanotoxicology. 2011 Mar;5(1):43-54
references.pmid: 21417687
references.citation: J Biol Chem. 2007 Jun 29;282(26):19152-66
references.pmid: 17468099
references.citation: Aquat Toxicol. 2010 Aug 15;99(2):149-59
references.pmid: 20471700
references.citation: Environ Health Perspect. 2009 Oct;117(10):1549-55
references.pmid: 20019905
references.citation: Reprod Toxicol. 2007 Apr-May;23(3):383-90
references.pmid: 17123778
references.citation: Chemosphere. 2007 Apr;67(9):S412-20
references.pmid: 17223178
references.citation: Chemosphere. 2011 Jan;82(5):764-72
references.pmid: 21111445
references.citation: Toxicology. 2012 Jan 27;291(1-3):83-92
references.pmid: 22108044
references.citation: Fertil Steril. 1982 Sep;38(3):364-71
references.pmid: 7117561
references.citation: Proc Natl Acad Sci U S A. 2009 Feb 17;106(7):2412-7
references.pmid: 19196967
references.citation: Ann N Y Acad Sci. 2009 Apr;1163:187-200
references.pmid: 19456339
references.citation: Am J Physiol Lung Cell Mol Physiol. 2009 Sep;297(3):L401-10
references.pmid: 19561139
references.citation: Environ Health Perspect. 2011 Aug;119(8):1142-8
references.pmid: 21543282
references.citation: Aquat Toxicol. 2010 Jan 21;96(1):53-61
references.pmid: 19850364
references.citation: Toxicol In Vitro. 2011 Feb;25(1):257-66
references.pmid: 20732405
references.citation: Ecotoxicology. 2010 Jan;19(1):185-95
references.pmid: 19728085
references.citation: Mol Cancer Ther. 2002 May;1(7):515-24
references.pmid: 12479269
references.citation: Environ Sci. 2007;14(5):211-33
references.pmid: 17975535
references.citation: Environ Toxicol Chem. 2004 Apr;23(4):1019-25
references.pmid: 15095900
references.citation: Environ Health Perspect. 2010 Feb;118(2):273-7
references.pmid: 20123615
references.citation: PLoS One. 2009;4(3):e4935
references.pmid: 19319186
references.citation: Environ Int. 2002 Nov;28(5):359-65
references.pmid: 12437285
references.citation: Environ Sci Technol. 2008 Nov 1;42(21):8133-9
references.pmid: 19031914
references.citation: Environ Toxicol Chem. 2003 Sep;22(9):2106-13
references.pmid: 12959538
references.citation: Anal Bioanal Chem. 2008 Apr;390(8):2031-48
references.pmid: 18327572
references.citation: Reprod Toxicol. 2007 Apr-May;23(3):290-6
references.pmid: 17321108
references.citation: Endocrinology. 2007 Feb;148(2):705-18
references.pmid: 17082257
references.citation: Ecotoxicol Environ Saf. 1999 Sep;44(1):25-39
references.pmid: 10499986
references.citation: Mol Cell Endocrinol. 2012 May 22;355(2):201-7
references.pmid: 22227557
references.citation: J Toxicol Environ Health. 1995 Nov;46(3):355-67
references.pmid: 7473863
references.citation: Environ Health Perspect. 2007 Jan;115(1):80-6
references.pmid: 17366824
references.citation: Toxicol Sci. 2005 Apr;84(2):394-407
references.pmid: 15659570
references.citation: Drug Metab Pharmacokinet. 2012;27(2):200-6
references.pmid: 22076448
references.citation: Comp Biochem Physiol C Toxicol Pharmacol. 2003 Mar;134(3):365-74
references.pmid: 12643983
references.citation: Toxicol Sci. 2006 Sep;93(1):180-8
references.pmid: 16760418
references.citation: Environ Res. 2004 Jan;94(1):102-11
references.pmid: 14643292
references.citation: Am J Physiol Endocrinol Metab. 2008 Apr;294(4):E802-6
references.pmid: 18303123
references.citation: Toxicol Lett. 2008 Feb 15;176(3):198-206
references.pmid: 18207673
references.citation: Chemosphere. 2009 May;75(9):1159-64
references.pmid: 19324393
references.citation: Endocrinology. 2010 Jun;151(6):2603-12
references.pmid: 20351315
references.citation: Toxicol Sci. 2005 Sep;87(1):255-66
references.pmid: 15933227
references.citation: Risk Anal. 2009 Apr;29(4):485-7; discussion 492-7
references.pmid: 19076321
references.citation: Environ Health Perspect. 1995 Sep;103(9):844-50
references.pmid: 7498097
references.citation: Genes Brain Behav. 2011 Jun;10(4):465-72
references.pmid: 21414140
references.citation: Horm Mol Biol Clin Investig. 2011 Mar 1;5(2):45-52
references.pmid: 21687816
references.citation: Environ Toxicol Chem. 2004 May;23(5):1305-10
references.pmid: 15180384
references.citation: J Inorg Biochem. 2008 Sep;102(9):1719-30
references.pmid: 18571240
references.citation: Toxicol In Vitro. 2006 Jun;20(4):490-8
references.pmid: 16219445
references.citation: Cancer Res. 2001 Jun 1;61(11):4325-8
references.pmid: 11389053
references.citation: Toxicol Lett. 2011 Apr 10;202(1):36-46
references.pmid: 21295121
references.citation: Neurotoxicology. 2011 Aug;32(4):400-9
references.pmid: 21396401
references.citation: Aquat Toxicol. 2009 Mar 9;91(4):346-54
references.pmid: 19157579
references.citation: Environ Health Perspect. 2003 Jun;111(8):994-1006
references.pmid: 12826473
references.citation: Environ Health. 2010 Oct 15;9:61
references.pmid: 20950447
references.citation: Comp Biochem Physiol C Toxicol Pharmacol. 2011 Jan;153(1):168-73
references.pmid: 21035564
references.citation: PLoS One. 2011 Apr 22;6(4):e19159
references.pmid: 21544203
references.citation: J Chromatogr B Analyt Technol Biomed Life Sci. 2002 Sep 25;777(1-2):269-79
references.pmid: 12270219
references.citation: Mol Endocrinol. 2006 Sep;20(9):2141-55
references.pmid: 16613991
references.citation: Toxicol Appl Pharmacol. 1999 Nov 1;160(3):297-303
references.pmid: 10544064
references.citation: Environ Health Perspect. 2002 Jun;110 Suppl 3:415-22
references.pmid: 12060838
references.citation: J Steroid Biochem Mol Biol. 2006 Nov;101(4-5):263-74
references.pmid: 17010603
references.citation: Endocrinology. 2000 May;141(5):1897-900
references.pmid: 10803601
references.citation: Environ Health Perspect. 1995 Oct;103 Suppl 7:113-22
references.pmid: 8593856
references.citation: Environ Health Perspect. 2002 Jun;110 Suppl 3:349-53
references.pmid: 12060828
references.citation: Fundam Appl Toxicol. 1996 Sep;33(1):149-60
references.pmid: 8812260
references.citation: Toxicol Lett. 2009 Aug 10;188(3):192-200
references.pmid: 19397962
references.citation: Pharmacol Biochem Behav. 2011 Nov;100(1):191-8
references.pmid: 21889525
references.citation: Neuropharmacology. 2012 Jan;62(1):436-45
references.pmid: 21884710
references.citation: Reprod Toxicol. 2000 May-Jun;14(3):207-16
references.pmid: 10838121
references.citation: Reprod Toxicol. 2010 Jun;29(3):323-31
references.pmid: 20045047
references.citation: Mol Cell Endocrinol. 2009 Nov 27;312(1-2):14-23
references.pmid: 19481582
references.citation: Drug Metab Dispos. 2011 Sep;39(9):1696-703
references.pmid: 21636669
references.citation: Comp Biochem Physiol C Toxicol Pharmacol. 2008 Jan;147(1):52-60
references.pmid: 17719278
references.citation: Toxicol In Vitro. 2004 Apr;18(2):153-63
references.pmid: 14757105
references.citation: Science. 2005 Jun 3;308(5727):1466-9
references.pmid: 15933200
references.citation: Endocrinology. 2011 Feb;152(2):581-94
references.pmid: 21190954
references.citation: Toxicology. 2010 Oct 29;276(3):198-205
references.pmid: 20708649
references.citation: Biol Pharm Bull. 2003 Aug;26(8):1219-24
references.pmid: 12913283
references.citation: Protein Pept Lett. 2008;15(3):290-6
references.pmid: 18336360
references.citation: Environ Health Perspect. 2011 Apr;119(4):547-52
references.pmid: 21126938
references.citation: Cerebellum. 2008;7(3):500-1
references.pmid: 19195072
references.citation: Endocrinology. 2012 Sep;153(9):4097-110
references.pmid: 22733974
references.citation: Environ Sci Technol. 2011 Aug 1;45(15):6567-74
references.pmid: 21678910