DSSTox Field Definition File:

NCTR Estrogen Receptor Binding Database (NCTRER)

*(last updated 15 February 2008)*

**Description:** Information in this file provides a minimum level of
annotation to the DSSTox SDF (Structure Data Format) file created for
the FDA National Center for Toxicological Research - Estrogen Receptor
(ER) Binding Database (NCTRER). For further description of experimental
details, a user is encouraged to consult the Source website and listed
references. Additional information is provided on the NCTRER SDF
Download Page
[http://www.epa.gov/ncct/dsstox/sdf_nctrer.html](http://www.epa.gov/nheerl/dsstox/sdf_nctrer.html).
A number of fields have been added to the original ER binding data
available from the NCTR Endocrine Disruptor Knowledge Base (EDKB) Source
website, most reflecting chemical class information, and qualitative
structure-activity properties and ER binding rationale reported in the
Main Citation of Fang et al. (2001). Measured ER relative binding
affinity (RBA) values from the original Source database are reported as
**LOG_ER_RBA** and in non-logarithmic form as **ER_RBA**. The
qualitative estrogen receptor binding activity measure,
**ActivityCategory_ER_RBA**, divides the NCTRER into 3 Active
categories, i.e., "active strong", "active medium", "active weak", based
on quantitative **ER_RBA** values, and 2 Inactive categories, i.e.,
"slight binder" or "inactive".

Following the designations used in Fang et al. (2001), each NCTRER
chemical is assigned to one of 6 major estrogenic structural classes or
a miscellaneous class, with the 6 major classes further divided into
subclasses to give a total of 20 class designations (**ChemClass_ERB**).
A few compounds not reported in the structure tables in Fang et al.
(2001) were assigned to the most appropriate **ChemClass_ERB** category
based on structure. Mean RBA values for activities within the 6 major
estrogenic classes are reported as **Mean_ER_RBA_ChemClass**. We include
a brief narrative structure-activity relationship (SAR) rationale
statement pertaining to ER RBA patterns observed within each of the 20
subclasses by Fang et al. (2001), and for some individual miscellaneous
compounds within the database
(**ActivityCategory_Rationale_ChemClass_ERB**). Structural templates and
descriptions of the 6 major structural classes and 20 subclasses are
provided in the Appendix following this table, along with the
corresponding field entries, **Mean_ER_RBA_ChemClass** and
**ActivityCategory_Rationale ChemClass_ERB**. Additional NCTRER
references are listed following this table that detail previous ER
modeling studies by the Source Contacts and their collaborators.

At the conclusion of their study, Fang et al. (2001) presented a
flowchart (Fig. 14) for the identification of ER ligands based on the
presence or absence of gross structural features. We approximate this
flowchart identification process for the NCTRER chemicals with 6
decision fields that take on indicator values of 1(yes) or 0 (no). These
are represented and defined in the flowchart and table below and
include: **F1_Ring,** **F2_AromaticRing**, **F3_PhenolicRing**,
**F4_Heteroatom**, **F5_Phenol3nPhenyl**, **F6_OtherKeyFeatures**. In
addition, log (octanol/water partition coefficient) values are provided
in the field, **LOGP**.

Structure of Natural Steroidal Estrogen Receptor Ligand, 17β-Estradiol
(E2):

![](media/image1.wmf)

Flowchart for Identification of ER ligands adopted from Fig. 14 of Fang
et al. (2001):

![](media/image2.wmf){width="8.875in" height="3.452777777777778in"}

Description of ***DSSTox Standard Chemical Fields*** can be found in the
Central Field Definition Table located at:

<http://www.epa.gov/ncct/dsstox/CentralFieldDef.html>

The first section of the Table below lists the ***DSSTox Standard
Toxicity Fields*** employed for this database, followed by the ***NCTRER
Source-Specific Fields*** containing the toxicity information particular
to NCTRER. The ***Field Type*** indicates the type of the field, such as
numeric, integer, defined text, memo, etc. All ***Units*** and
***Descriptions*** are extracted from Source reference materials unless
otherwise noted. ***Allowable Entries*** lists allowed field entries
occurring in NCTRER, separated by slashes for exclusive entries (i.e.,
cannot occur with another entry) and semicolons or spaces for
non-exclusive entries (i.e., can occur with other values). These are
defined and explained in the ***Description*** section.

**Source Website:** For further information on the Source NCTR ER
database and to gain relational database access to a wider body of
information on endocrine disrupting chemicals, users are encouraged to
visit the NCTR Endocrine Disruptor Knowledge Base website at
<http://edkb.fda.gov/index.html>

**Source Contacts:** Weida Tong \[email: <wtong@nctr.fda.gov>\] and Hong
Fang \[email: <hfang@nctr.fda.gov>\], National Center for Toxicological
Research, Jefferson, Arkansas.

**Main Citation:** Publications reporting use of DSSTox SDF file for the
NCTRER are asked to list the full DSSTox file name, including date
stamp, and to cite as primary references the following:

> Fang, H., W. Tong, L.M. Shi, R. Blair, R. Perkins, W. Branham, B.S.
> Hass, Q. Xie, S.L. Dial, C.L. Moland, and D.M. Sheehan (2001)
> Structure-activity relationships for a large diverse set of natural,
> synthetic, and environmental estrogens. Chem. Res. Tox. 14:280-294.
>
> Blair, R.M., H. Fang, W.S. Branham, B.S. Hass, S.L. Dial, C.L. Moland,
> W. Tong, L. Shi, R. Perkins, and D.M. Sheehan (2000) The estrogen
> receptor relative binding affinities of 188 natural and xenochemicals:
> Structural diversity of ligands. Toxicol. Sci. 54:138-153.
>
> Branham, W.S., S.L. Dial, C.L. Moland, B.S. Hass, R.M. Blair, H. Fang,
> L. Shi, W. Tong, R.G. Perkins, and D.M. Sheehan (2002) Binding of
> phytoestrogens and mycoestrogens to the rat uterine estrogen receptor.
> J. Nutr. 132:658-664.
>
> *\* For additional references, see the listing immediately following
> the table below.*

**SDF Usage Notes:**

Each DSSTox SDF file contains a single **STRUCTURE** field. For each
chemical record, the **STRUCTURE** field entry directly corresponds to
the content of the **STRUCTURE\_\...** fields. The **STRUCTURE_Shown**
field documents the relationship between what is displayed in the
**STRUCTURE** field and the actual tested chemical substance, i.e.
**TestSubstance\_\...** fields, with the latter corresponding directly
to the toxicity data field entries. Commercial chemical relational
database (CRD) applications may automatically insert one or more
structure identifier fields upon import or export of an SDF file (e.g.,
Formula, FW or Mol_ID), fields that may augment or duplicate one or more
of the DSSTox Standard Chemical Fields. Users are cautioned that fields
containing null values in the first record of the SDF will be reordered
upon import into most applications; for this reason, the word "blank"
has been inserted into null fields in Record 1 of DSSTox SDF files and
can be deleted after SDF import. Users are additionally cautioned that
some fields (**STRUCTURE_SMILES** and **STRUCTURE_InChI**, in
particular) may exceed the 200 character limit specified in the MDL
CTFiles SDF standard (see
<http://www.epa.gov/ncct/dsstox/MoreonSDF.html>), and that some CRD
applications may insert a line break or truncate these fields upon SDF
import or export. Finally, CRD application-specific molecular header
information in the SDF file is deleted in the final DSSTox SDF files;
users running CRD applications requiring a unique molecule header upon
import of the SDF can specify either **DSSTox_RID** or the
**DSSTox_FileID** be used. Upon SDF import, **DSSTox_CID** can be used
to identify and manage chemical structure duplicates and
**DSSTox_Generic_SID** can be used to identify common Test Substances
across and within DSSTox files (similar to CASRN-substance, but
available for all DSSTox substances and further distinguishes among
different purity/grade substances).

*As an MS Word document, the following table is best viewed onscreen
using either Normal or Web Layout View in Landscape page orientation.*

+-------+----+---+---+--------+---+------------------------+-----------------+
| ***   | ** | * | * |        | # |                        | ## *Comments*   |
| Field | *F | * | * |        |   |                        |                 |
| Na    | ie | * | * |        | * |                        |                 |
| me*** | ld | U | A |        | D |                        |                 |
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|       |    | * | b |        | p |                        |                 |
|       |    | * | l |        | t |                        |                 |
|       |    |   | e |        | i |                        |                 |
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|       |    |   | n |        | n |                        |                 |
|       |    |   | t |        | * |                        |                 |
|       |    |   | r |        |   |                        |                 |
|       |    |   | i |        |   |                        |                 |
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|       |    |   | s |        |   |                        |                 |
|       |    |   | * |        |   |                        |                 |
|       |    |   | * |        |   |                        |                 |
|       |    |   | * |        |   |                        |                 |
+-------+----+---+---+--------+---+------------------------+-----------------+
|       |    |   |   |        | # |                        | ##              |
|       |    |   |   |        |   |                        |                 |
|       |    |   |   |        | * |                        |                 |
|       |    |   |   |        | D |                        |                 |
|       |    |   |   |        | S |                        |                 |
|       |    |   |   |        | S |                        |                 |
|       |    |   |   |        | T |                        |                 |
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|       |    |   |   |        | d |                        |                 |
|       |    |   |   |        | s |                        |                 |
|       |    |   |   |        | * |                        |                 |
+-------+----+---+---+--------+---+------------------------+-----------------+
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| udy** | ef |   | e |        | i |                        | content are     |
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|       |    |   |   |        | . |                        |                 |
+-------+----+---+---+--------+---+------------------------+-----------------+
| # End | d  |   | E |        | F |                        | Field names and |
| point | ef |   | s |        | i |                        | content are     |
|       | in |   | t |        | e |                        | being           |
|       | ed |   | r |        | l |                        | coordinated     |
|       | te |   | o |        | d |                        | with the public |
|       | xt |   | g |        | i |                        | ToxML           |
|       |    |   | e |        | s |                        | standardization |
|       |    |   | n |        | u |                        | effort.         |
|       |    |   | R |        | s |                        |                 |
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|       |    |   |   |        | F |                        |                 |
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|       |    |   |   |        | e |                        |                 |
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|       |    |   |   |        | e |                        |                 |
|       |    |   |   |        | . |                        |                 |
+-------+----+---+---+--------+---+------------------------+-----------------+
| *     | d  |   | r |        | F |                        | Field names and |
| *Spec | ef |   | a |        | i |                        | content are     |
| ies** | in |   | t |        | e |                        | being           |
|       | ed |   |   |        | l |                        | coordinated     |
|       | te |   |   |        | d |                        | with the public |
|       | xt |   |   |        | i |                        | ToxML           |
|       |    |   |   |        | s |                        | standardization |
|       |    |   |   |        | u |                        | effort.         |
|       |    |   |   |        | s |                        |                 |
|       |    |   |   |        | e |                        |                 |
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|       |    |   |   |        | d |                        |                 |
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|       |    |   |   |        | . |                        |                 |
|       |    |   |   |        | F |                        |                 |
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|       |    |   |   |        | d |                        |                 |
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|       |    |   |   |        | t |                        |                 |
|       |    |   |   |        | h |                        |                 |
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|       |    |   |   |        | c |                        |                 |
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|       |    |   |   |        | a |                        |                 |
|       |    |   |   |        | n |                        |                 |
|       |    |   |   |        | i |                        |                 |
|       |    |   |   |        | m |                        |                 |
|       |    |   |   |        | a |                        |                 |
|       |    |   |   |        | l |                        |                 |
|       |    |   |   |        | ( |                        |                 |
|       |    |   |   |        | s |                        |                 |
|       |    |   |   |        | ) |                        |                 |
|       |    |   |   |        | u |                        |                 |
|       |    |   |   |        | s |                        |                 |
|       |    |   |   |        | e |                        |                 |
|       |    |   |   |        | d |                        |                 |
|       |    |   |   |        | i |                        |                 |
|       |    |   |   |        | n |                        |                 |
|       |    |   |   |        | t |                        |                 |
|       |    |   |   |        | h |                        |                 |
|       |    |   |   |        | e |                        |                 |
|       |    |   |   |        | t |                        |                 |
|       |    |   |   |        | o |                        |                 |
|       |    |   |   |        | x |                        |                 |
|       |    |   |   |        | i |                        |                 |
|       |    |   |   |        | c |                        |                 |
|       |    |   |   |        | i |                        |                 |
|       |    |   |   |        | t |                        |                 |
|       |    |   |   |        | y |                        |                 |
|       |    |   |   |        | s |                        |                 |
|       |    |   |   |        | t |                        |                 |
|       |    |   |   |        | u |                        |                 |
|       |    |   |   |        | d |                        |                 |
|       |    |   |   |        | y |                        |                 |
|       |    |   |   |        | . |                        |                 |
+-------+----+---+---+--------+---+------------------------+-----------------+
|       |    |   |   |        |   | ##### NCTRER           |                 |
|       |    |   |   |        |   | Source-Specific Fields |                 |
+-------+----+---+---+--------+---+------------------------+-----------------+
| **    | d  |   |   | St     |   | Six main estrogenic    | Main class and  |
| ChemC | ef |   |   | eroids |   | receptor binding (ERB) | subclass of     |
| lass_ | in |   |   |        |   | structural classes     | structures      |
| ERB** | ed |   |   | > With |   | with subclass          | listed in Figs. |
|       | te |   |   | > ar   |   | designations utilized  | 1-6 of Fang et  |
|       | xt |   |   | omatic |   | in the study of Fang   | al. (2001).     |
|       |    |   |   | > A    |   | et al. (2001).         |                 |
|       |    |   |   | >      |   |                        | Some compounds  |
|       |    |   |   |  ring/ |   | "Misc" (Miscellaneous) | not originally  |
|       |    |   |   | >      |   | category contains      | listed in Figs. |
|       |    |   |   | > W    |   | structurally diverse   | 1-7 of Fang et  |
|       |    |   |   | ithout |   | compounds that do not  | al. (2001) were |
|       |    |   |   | > ar   |   | fit into one of the    | assigned here   |
|       |    |   |   | omatic |   | six main structural    | to the most     |
|       |    |   |   | > A    |   | classes.               | appropriate     |
|       |    |   |   | >      |   |                        | main class and  |
|       |    |   |   |  ring/ |   | Main structural class  | subclass based  |
|       |    |   |   |        |   | (e.g., Phytoestrogens) | on structural   |
|       |    |   |   | DES    |   | is listed before       | features.       |
|       |    |   |   |        |   | subclass, as in, e.g., |                 |
|       |    |   |   | > DES  |   |                        | Hexestrol DL    |
|       |    |   |   | >      |   | Phytoestrogens         | isomer mixture  |
|       |    |   |   | deriva |   | Flavones               | **ER_RBA**      |
|       |    |   |   | tives/ |   |                        | value was       |
|       |    |   |   | >      |   | or                     | listed in Fang  |
|       |    |   |   | > Hex  |   |                        | et al. (2001)   |
|       |    |   |   | estrol |   | Biphenyls PCBs         | Fig. 2B but was |
|       |    |   |   | >      |   |                        | not included in |
|       |    |   |   | deriva |   |                        | original data   |
|       |    |   |   | tives/ |   |                        | listing         |
|       |    |   |   | >      |   |                        | provided by the |
|       |    |   |   | > T    |   |                        | NCTR Source     |
|       |    |   |   | riphen |   |                        | and, hence, is  |
|       |    |   |   | ylethy |   |                        | not included in |
|       |    |   |   | lenes/ |   |                        | the DSSTox      |
|       |    |   |   |        |   |                        | NCTRER SDF.     |
|       |    |   |   | Ph     |   |                        |                 |
|       |    |   |   | ytoest |   |                        | In Fang et al.  |
|       |    |   |   | rogens |   |                        | (2001),         |
|       |    |   |   |        |   |                        | incorrect       |
|       |    |   |   | > Fla  |   |                        | structure for   |
|       |    |   |   | vones/ |   |                        | Moxestrol was   |
|       |    |   |   | >      |   |                        | listed in Fig.  |
|       |    |   |   | >      |   |                        | 1A, and         |
|       |    |   |   |  Flava |   |                        | incorrect name  |
|       |    |   |   | nones/ |   |                        | of Biphenol F   |
|       |    |   |   | >      |   |                        | was listed for  |
|       |    |   |   | >      |   |                        | the shown       |
|       |    |   |   | Isofla |   |                        | structure in    |
|       |    |   |   | vones/ |   |                        | Fig 4A. Both    |
|       |    |   |   | >      |   |                        | errors were     |
|       |    |   |   | >      |   |                        | corrected in    |
|       |    |   |   |  Coume |   |                        | Source-provided |
|       |    |   |   | stans/ |   |                        | data and DSSTox |
|       |    |   |   | >      |   |                        | NCTRER SDF.     |
|       |    |   |   | >      |   |                        |                 |
|       |    |   |   | Chalco |   |                        |                 |
|       |    |   |   | noids/ |   |                        |                 |
|       |    |   |   | >      |   |                        |                 |
|       |    |   |   | > My   |   |                        |                 |
|       |    |   |   | coestr |   |                        |                 |
|       |    |   |   | ogens/ |   |                        |                 |
|       |    |   |   |        |   |                        |                 |
|       |    |   |   | Diph   |   |                        |                 |
|       |    |   |   | enylme |   |                        |                 |
|       |    |   |   | thanes |   |                        |                 |
|       |    |   |   |        |   |                        |                 |
|       |    |   |   | > Diph |   |                        |                 |
|       |    |   |   | enolal |   |                        |                 |
|       |    |   |   | kanes/ |   |                        |                 |
|       |    |   |   | >      |   |                        |                 |
|       |    |   |   | > Be   |   |                        |                 |
|       |    |   |   | nzophe |   |                        |                 |
|       |    |   |   | nones/ |   |                        |                 |
|       |    |   |   | >      |   |                        |                 |
|       |    |   |   | >      |   |                        |                 |
|       |    |   |   |  DDTs/ |   |                        |                 |
|       |    |   |   |        |   |                        |                 |
|       |    |   |   | Bip    |   |                        |                 |
|       |    |   |   | henyls |   |                        |                 |
|       |    |   |   |        |   |                        |                 |
|       |    |   |   | >      |   |                        |                 |
|       |    |   |   |  PCBs/ |   |                        |                 |
|       |    |   |   | >      |   |                        |                 |
|       |    |   |   | > Non  |   |                        |                 |
|       |    |   |   | chlori |   |                        |                 |
|       |    |   |   | nated/ |   |                        |                 |
|       |    |   |   |        |   |                        |                 |
|       |    |   |   | P      |   |                        |                 |
|       |    |   |   | henols |   |                        |                 |
|       |    |   |   |        |   |                        |                 |
|       |    |   |   | >      |   |                        |                 |
|       |    |   |   | Alkyl/ |   |                        |                 |
|       |    |   |   | >      |   |                        |                 |
|       |    |   |   | > Par  |   |                        |                 |
|       |    |   |   | abens/ |   |                        |                 |
|       |    |   |   | >      |   |                        |                 |
|       |    |   |   | > Alk  |   |                        |                 |
|       |    |   |   | yloxy/ |   |                        |                 |
|       |    |   |   |        |   |                        |                 |
|       |    |   |   | Misc/  |   |                        |                 |
+-------+----+---+---+--------+---+------------------------+-----------------+
| ## E  | n  | # |   | \#     |   | Estrogen receptor      | To create a     |
| R_RBA | um | # |   |        |   | relative binding       | purely numeric  |
|       | er | # |   |        |   | affinity is determined | DSSTox data     |
|       | ic | # |   |        |   | using a competitive    | field, the text |
|       |    |   |   |        |   | receptor binding assay | designation,    |
|       |    |   |   |        |   | as described in Blair  | NA=not active,  |
|       |    |   |   |        |   | et al. (2000).         | used in Fang et |
|       |    |   |   |        |   | Briefly, a chemical    | al. (2001), was |
|       |    |   |   |        |   | competes with          | converted to    |
|       |    |   |   |        |   | radiolabeled E2 (i.e., | the value       |
|       |    |   |   |        |   | estradiol) for binding | **ER_RBA** =0.  |
|       |    |   |   |        |   | to the ER in rat       | Chemicals       |
|       |    |   |   |        |   | uterine cytosol and    | designated      |
|       |    |   |   |        |   | the concentration of   | "slight         |
|       |    |   |   |        |   | chemical that causes   | binders" or     |
|       |    |   |   |        |   | 50% inhibition of E2   | "detectable     |
|       |    |   |   |        |   | binding (i.e., IC~50~) | activity" by    |
|       |    |   |   |        |   | is measured. The       | Fang et al.     |
|       |    |   |   |        |   | **ER_RBA** is          | (2001) are      |
|       |    |   |   |        |   | calculated by dividing | designated      |
|       |    |   |   |        |   | the IC~50~ of E2       | **ER_RBA** =0   |
|       |    |   |   |        |   | (9X10^-10^M) by the    | and             |
|       |    |   |   |        |   | IC~50~ of the          | **ActivityCa    |
|       |    |   |   |        |   | competitor and         | tegory_ER_RBA** |
|       |    |   |   |        |   | multiplying by 100 (E2 | = "slight       |
|       |    |   |   |        |   | RBA = 100). The        | binder". The    |
|       |    |   |   |        |   | validated assay tested | latter includes |
|       |    |   |   |        |   | 1nM E2 with            | chemicals that  |
|       |    |   |   |        |   | concentrations of      | exhibited       |
|       |    |   |   |        |   | competitor ranging     | binding but did |
|       |    |   |   |        |   | from 1nM to 1mM.       | not reach 50%   |
|       |    |   |   |        |   |                        | inhibition in   |
|       |    |   |   |        |   | The larger the         | the designated  |
|       |    |   |   |        |   | **ER_RBA** values, the | concentration   |
|       |    |   |   |        |   | greater the binding    | range, or       |
|       |    |   |   |        |   | affinity; **ER_RBA**   | chemicals whose |
|       |    |   |   |        |   | \> 100 means compound  | measured        |
|       |    |   |   |        |   | has greater binding    | activity was    |
|       |    |   |   |        |   | affinity than natural  | less than 1E-5. |
|       |    |   |   |        |   | ER ligand, E2.         |                 |
|       |    |   |   |        |   |                        |                 |
|       |    |   |   |        |   | **ER_RBA** = 0 when no |                 |
|       |    |   |   |        |   | activity or 50%        |                 |
|       |    |   |   |        |   | inhibition was not     |                 |
|       |    |   |   |        |   | reached (designated    |                 |
|       |    |   |   |        |   | either inactive or     |                 |
|       |    |   |   |        |   | slight binder)         |                 |
+-------+----+---+---+--------+---+------------------------+-----------------+
| ## L  | n  | # |   | \#     |   | Logarithm (base 10) of | **LOG_ER_RBA**  |
| OG_ER | um | # |   |        |   | **ER_RBA** is the      | values were     |
| _RBA  | er | # |   |        |   | measure of activity    | provided by     |
|       | ic | # |   |        |   | provided by the NCTR   | NCTR Source and |
|       |    |   |   |        |   | Source and used by     | used to         |
|       |    |   |   |        |   | Fang et al. (2001) and | generate        |
|       |    |   |   |        |   | others for QSAR        | **ER_RBA**      |
|       |    |   |   |        |   | modeling study.        | values          |
|       |    |   |   |        |   |                        | (antilog10). A  |
|       |    |   |   |        |   | For slight binders,    | few values      |
|       |    |   |   |        |   | **ER_RBA**=0 and       | differ from and |
|       |    |   |   |        |   | **LOG_ER_RBA** is      | should replace  |
|       |    |   |   |        |   | assigned the numeric   | the earlier     |
|       |    |   |   |        |   | value of -5,000.       | values reported |
|       |    |   |   |        |   |                        | in Fang et al.  |
|       |    |   |   |        |   | For inactives,         | (2001). The     |
|       |    |   |   |        |   | **ER_RBA**=0 and       | values of       |
|       |    |   |   |        |   | **LOG_ER_RBA** is      | -5,000 for      |
|       |    |   |   |        |   | assigned the numeric   | slight binders  |
|       |    |   |   |        |   | value of -10,000.      | and ‑10,000 for |
|       |    |   |   |        |   |                        | inactives were  |
|       |    |   |   |        |   |                        | used in         |
|       |    |   |   |        |   |                        | original NCTR   |
|       |    |   |   |        |   |                        | Source          |
|       |    |   |   |        |   |                        | database.       |
+-------+----+---+---+--------+---+------------------------+-----------------+
| #     | d  | # | # |        | F |                        | The qualifier   |
| # Act | ef | # | # |        | o |                        | "slight binder" |
| ivity | in | # | # |        | r |                        | has been added  |
| Categ | ed | # | # |        | p |                        | to label        |
| ory_E | te |   |   |        | u |                        | chemicals that  |
| R_RBA | xt |   | a |        | r |                        | exhibited       |
|       |    |   | c |        | p |                        | binding but     |
| *(no  |    |   | t |        | o |                        | that either did |
| spa   |    |   | i |        | s |                        | not reach 50%   |
| ces)* |    |   | v |        | e |                        | inhibition in   |
|       |    |   | e |        | s |                        | the designated  |
|       |    |   |   |        | o |                        | concentration   |
|       |    |   | s |        | f |                        | range, or had   |
|       |    |   | t |        | S |                        | barely          |
|       |    |   | r |        | A |                        | detectable      |
|       |    |   | o |        | R |                        | activity, i.e.  |
|       |    |   | n |        | a |                        | ER_RBA less     |
|       |    |   | g |        | n |                        | than 1E-5. Most |
|       |    |   | / |        | a |                        | are listed in   |
|       |    |   |   |        | l |                        | Table 13 of     |
|       |    |   | a |        | y |                        | Blair et al.    |
|       |    |   | c |        | s |                        | (2000).         |
|       |    |   | t |        | i |                        |                 |
|       |    |   | i |        | s |                        |                 |
|       |    |   | v |        | , |                        |                 |
|       |    |   | e |        | F |                        |                 |
|       |    |   | m |        | a |                        |                 |
|       |    |   | e |        | n |                        |                 |
|       |    |   | d |        | g |                        |                 |
|       |    |   | i |        | e |                        |                 |
|       |    |   | u |        | t |                        |                 |
|       |    |   | m |        | a |                        |                 |
|       |    |   | / |        | l |                        |                 |
|       |    |   |   |        | . |                        |                 |
|       |    |   | a |        | ( |                        |                 |
|       |    |   | c |        | 2 |                        |                 |
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|       |    |   |   |        | N |                        |                 |
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|       |    |   |   |        | > |                        |                 |
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|       |    |   |   |        | d |                        |                 |
|       |    |   |   |        | e |                        |                 |
|       |    |   |   |        | s |                        |                 |
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|       |    |   |   |        | g |                        |                 |
|       |    |   |   |        | n |                        |                 |
|       |    |   |   |        | a |                        |                 |
|       |    |   |   |        | t |                        |                 |
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|       |    |   |   |        | ) |                        |                 |
+-------+----+---+---+--------+---+------------------------+-----------------+
| ## Ac | d  | # | # |        | C |                        | Summary         |
| tivit | ef | # | # |        | a |                        | activity for    |
| yOutc | in | # | # |        | t |                        | use in PubChem  |
| ome_N | ed | # | # |        | e |                        | and             |
| CTRER | te |   |   |        | g |                        | str             |
|       | xt |   | a |        | o |                        | ucture-activity |
| *(no  |    |   | c |        | r |                        | relationship    |
| spa   |    |   | t |        | i |                        | studies.        |
| ces)* |    |   | i |        | c |                        |                 |
|       |    |   | v |        | a |                        | *New field      |
|       |    |   | e |        | l |                        | added to v4b.*  |
|       |    |   |   |        | a |                        |                 |
|       |    |   | / |        | c |                        |                 |
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|       |    |   |   |        | % |                        |                 |
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|       |    |   |   |        | _ |                        |                 |
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|       |    |   |   |        | B |                        |                 |
|       |    |   |   |        | A |                        |                 |
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|       |    |   |   |        | 1 |                        |                 |
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|       |    |   |   |        | 5 |                        |                 |
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|       |    |   |   |        | t |                        |                 |
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|       |    |   |   |        | > |                        |                 |
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|       |    |   |   |        | a |                        |                 |
|       |    |   |   |        | c |                        |                 |
|       |    |   |   |        | t |                        |                 |
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|       |    |   |   |        | v |                        |                 |
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|       |    |   |   |        | t |                        |                 |
|       |    |   |   |        | y |                        |                 |
|       |    |   |   |        | ) |                        |                 |
+-------+----+---+---+--------+---+------------------------+-----------------+
| ## Ac | i  | # | I |        | M |                        | Summary         |
| tivit | nt | # | N |        | a |                        | activity for    |
| yScor | eg | # | T |        | p |                        | use in PubChem  |
| e\_ N | er | # | E |        | p |                        | and             |
| CTRER |    |   | G |        | i |                        | str             |
|       |    |   | E |        | n |                        | ucture-activity |
| *(no  |    |   | R |        | g |                        | relationship    |
| spa   |    |   | \ |        | o |                        | studies.        |
| ces)* |    |   | [ |        | f |                        |                 |
|       |    |   | 0 |        | * |                        | *New field      |
|       |    |   | - |        | * |                        | added to v4b.*  |
|       |    |   | 1 |        | L |                        |                 |
|       |    |   | 0 |        | O |                        |                 |
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|       |    |   |   |        | 0 |                        |                 |
+-------+----+---+---+--------+---+------------------------+-----------------+
| #     | n  | # | # |        | V |                        | Recomputed for  |
| # Mea | um | # | # |        | a |                        | the present     |
| n_ER_ | er | # | # |        | l |                        | study based on  |
| RBA \ | ic | # | # |        | u |                        | updated         |
| _Chem |    |   |   |        | e |                        | ChemClass       |
| Class |    |   | # |        | s |                        | assignments and |
|       |    |   | / |        | a |                        | ER_RBA values.  |
| *(no  |    |   |   |        | r |                        | Values here     |
| spa   |    |   | * |        | e |                        | differ from     |
| ces)* |    |   | b |        | c |                        | those           |
|       |    |   | l |        | o |                        | originally      |
|       |    |   | a |        | m |                        | reported in     |
|       |    |   | n |        | p |                        | Fang et al.     |
|       |    |   | k |        | u |                        | (2001) Table 1, |
|       |    |   | * |        | t |                        | which were      |
|       |    |   |   |        | e |                        | based on mean   |
|       |    |   |   |        | d |                        | logRBA then     |
|       |    |   |   |        | w |                        | antilog,        |
|       |    |   |   |        | i |                        | although the    |
|       |    |   |   |        | t |                        | relative        |
|       |    |   |   |        | h |                        | ranking of      |
|       |    |   |   |        | i |                        | classes by Mean |
|       |    |   |   |        | n |                        | ER_RBA remains  |
|       |    |   |   |        | e |                        | the same.       |
|       |    |   |   |        | a |                        |                 |
|       |    |   |   |        | c |                        | Previous entry  |
|       |    |   |   |        | h |                        | "NA" for Misc   |
|       |    |   |   |        | o |                        | class has been  |
|       |    |   |   |        | f |                        | removed to      |
|       |    |   |   |        | t |                        | create pure     |
|       |    |   |   |        | h |                        | numeric field.  |
|       |    |   |   |        | e |                        |                 |
|       |    |   |   |        | s |                        |                 |
|       |    |   |   |        | i |                        |                 |
|       |    |   |   |        | x |                        |                 |
|       |    |   |   |        | m |                        |                 |
|       |    |   |   |        | a |                        |                 |
|       |    |   |   |        | i |                        |                 |
|       |    |   |   |        | n |                        |                 |
|       |    |   |   |        | s |                        |                 |
|       |    |   |   |        | t |                        |                 |
|       |    |   |   |        | r |                        |                 |
|       |    |   |   |        | u |                        |                 |
|       |    |   |   |        | c |                        |                 |
|       |    |   |   |        | t |                        |                 |
|       |    |   |   |        | u |                        |                 |
|       |    |   |   |        | r |                        |                 |
|       |    |   |   |        | a |                        |                 |
|       |    |   |   |        | l |                        |                 |
|       |    |   |   |        | c |                        |                 |
|       |    |   |   |        | l |                        |                 |
|       |    |   |   |        | a |                        |                 |
|       |    |   |   |        | s |                        |                 |
|       |    |   |   |        | s |                        |                 |
|       |    |   |   |        | e |                        |                 |
|       |    |   |   |        | s |                        |                 |
|       |    |   |   |        | a |                        |                 |
|       |    |   |   |        | s |                        |                 |
|       |    |   |   |        | t |                        |                 |
|       |    |   |   |        | h |                        |                 |
|       |    |   |   |        | e |                        |                 |
|       |    |   |   |        | g |                        |                 |
|       |    |   |   |        | e |                        |                 |
|       |    |   |   |        | o |                        |                 |
|       |    |   |   |        | m |                        |                 |
|       |    |   |   |        | e |                        |                 |
|       |    |   |   |        | t |                        |                 |
|       |    |   |   |        | r |                        |                 |
|       |    |   |   |        | i |                        |                 |
|       |    |   |   |        | c |                        |                 |
|       |    |   |   |        | m |                        |                 |
|       |    |   |   |        | e |                        |                 |
|       |    |   |   |        | a |                        |                 |
|       |    |   |   |        | n |                        |                 |
|       |    |   |   |        | o |                        |                 |
|       |    |   |   |        | f |                        |                 |
|       |    |   |   |        | E |                        |                 |
|       |    |   |   |        | R |                        |                 |
|       |    |   |   |        | _ |                        |                 |
|       |    |   |   |        | R |                        |                 |
|       |    |   |   |        | B |                        |                 |
|       |    |   |   |        | A |                        |                 |
|       |    |   |   |        | a |                        |                 |
|       |    |   |   |        | c |                        |                 |
|       |    |   |   |        | t |                        |                 |
|       |    |   |   |        | i |                        |                 |
|       |    |   |   |        | v |                        |                 |
|       |    |   |   |        | i |                        |                 |
|       |    |   |   |        | t |                        |                 |
|       |    |   |   |        | i |                        |                 |
|       |    |   |   |        | e |                        |                 |
|       |    |   |   |        | s |                        |                 |
|       |    |   |   |        | , |                        |                 |
|       |    |   |   |        | b |                        |                 |
|       |    |   |   |        | a |                        |                 |
|       |    |   |   |        | s |                        |                 |
|       |    |   |   |        | e |                        |                 |
|       |    |   |   |        | d |                        |                 |
|       |    |   |   |        | o |                        |                 |
|       |    |   |   |        | n |                        |                 |
|       |    |   |   |        | l |                        |                 |
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|       |    |   |   |        | t |                        |                 |
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|       |    |   |   |        | a |                        |                 |
|       |    |   |   |        | c |                        |                 |
|       |    |   |   |        | t |                        |                 |
|       |    |   |   |        | i |                        |                 |
|       |    |   |   |        | v |                        |                 |
|       |    |   |   |        | e |                        |                 |
|       |    |   |   |        | c |                        |                 |
|       |    |   |   |        | h |                        |                 |
|       |    |   |   |        | e |                        |                 |
|       |    |   |   |        | m |                        |                 |
|       |    |   |   |        | i |                        |                 |
|       |    |   |   |        | c |                        |                 |
|       |    |   |   |        | a |                        |                 |
|       |    |   |   |        | l |                        |                 |
|       |    |   |   |        | s |                        |                 |
|       |    |   |   |        | w |                        |                 |
|       |    |   |   |        | i |                        |                 |
|       |    |   |   |        | t |                        |                 |
|       |    |   |   |        | h |                        |                 |
|       |    |   |   |        | i |                        |                 |
|       |    |   |   |        | n |                        |                 |
|       |    |   |   |        | e |                        |                 |
|       |    |   |   |        | a |                        |                 |
|       |    |   |   |        | c |                        |                 |
|       |    |   |   |        | h |                        |                 |
|       |    |   |   |        | c |                        |                 |
|       |    |   |   |        | l |                        |                 |
|       |    |   |   |        | a |                        |                 |
|       |    |   |   |        | s |                        |                 |
|       |    |   |   |        | s |                        |                 |
|       |    |   |   |        | ; |                        |                 |
|       |    |   |   |        |   |                        |                 |
|       |    |   |   |        | * |                        |                 |
|       |    |   |   |        | " |                        |                 |
|       |    |   |   |        | b |                        |                 |
|       |    |   |   |        | l |                        |                 |
|       |    |   |   |        | a |                        |                 |
|       |    |   |   |        | n |                        |                 |
|       |    |   |   |        | k |                        |                 |
|       |    |   |   |        | " |                        |                 |
|       |    |   |   |        | * |                        |                 |
|       |    |   |   |        | o |                        |                 |
|       |    |   |   |        | r |                        |                 |
|       |    |   |   |        | n |                        |                 |
|       |    |   |   |        | u |                        |                 |
|       |    |   |   |        | l |                        |                 |
|       |    |   |   |        | l |                        |                 |
|       |    |   |   |        | e |                        |                 |
|       |    |   |   |        | n |                        |                 |
|       |    |   |   |        | t |                        |                 |
|       |    |   |   |        | r |                        |                 |
|       |    |   |   |        | y |                        |                 |
|       |    |   |   |        | i |                        |                 |
|       |    |   |   |        | n |                        |                 |
|       |    |   |   |        | d |                        |                 |
|       |    |   |   |        | i |                        |                 |
|       |    |   |   |        | c |                        |                 |
|       |    |   |   |        | a |                        |                 |
|       |    |   |   |        | t |                        |                 |
|       |    |   |   |        | e |                        |                 |
|       |    |   |   |        | s |                        |                 |
|       |    |   |   |        | c |                        |                 |
|       |    |   |   |        | a |                        |                 |
|       |    |   |   |        | l |                        |                 |
|       |    |   |   |        | c |                        |                 |
|       |    |   |   |        | u |                        |                 |
|       |    |   |   |        | l |                        |                 |
|       |    |   |   |        | a |                        |                 |
|       |    |   |   |        | t |                        |                 |
|       |    |   |   |        | i |                        |                 |
|       |    |   |   |        | o |                        |                 |
|       |    |   |   |        | n |                        |                 |
|       |    |   |   |        | n |                        |                 |
|       |    |   |   |        | o |                        |                 |
|       |    |   |   |        | t |                        |                 |
|       |    |   |   |        | a |                        |                 |
|       |    |   |   |        | p |                        |                 |
|       |    |   |   |        | p |                        |                 |
|       |    |   |   |        | l |                        |                 |
|       |    |   |   |        | i |                        |                 |
|       |    |   |   |        | c |                        |                 |
|       |    |   |   |        | a |                        |                 |
|       |    |   |   |        | b |                        |                 |
|       |    |   |   |        | l |                        |                 |
|       |    |   |   |        | e |                        |                 |
|       |    |   |   |        | t |                        |                 |
|       |    |   |   |        | o |                        |                 |
|       |    |   |   |        | c |                        |                 |
|       |    |   |   |        | h |                        |                 |
|       |    |   |   |        | e |                        |                 |
|       |    |   |   |        | m |                        |                 |
|       |    |   |   |        | i |                        |                 |
|       |    |   |   |        | c |                        |                 |
|       |    |   |   |        | a |                        |                 |
|       |    |   |   |        | l |                        |                 |
|       |    |   |   |        | s |                        |                 |
|       |    |   |   |        | i |                        |                 |
|       |    |   |   |        | n |                        |                 |
|       |    |   |   |        | t |                        |                 |
|       |    |   |   |        | h |                        |                 |
|       |    |   |   |        | e |                        |                 |
|       |    |   |   |        | " |                        |                 |
|       |    |   |   |        | M |                        |                 |
|       |    |   |   |        | i |                        |                 |
|       |    |   |   |        | s |                        |                 |
|       |    |   |   |        | c |                        |                 |
|       |    |   |   |        | " |                        |                 |
|       |    |   |   |        | c |                        |                 |
|       |    |   |   |        | l |                        |                 |
|       |    |   |   |        | a |                        |                 |
|       |    |   |   |        | s |                        |                 |
|       |    |   |   |        | s |                        |                 |
|       |    |   |   |        | . |                        |                 |
+-------+----+---+---+--------+---+------------------------+-----------------+
| #     | d  | # | # |        | Q |                        | > The same      |
| # Act | ef | # | # |        | u |                        | > general       |
| ivity | in | # | # |        | a |                        | > rationale     |
| Categ | ed | # | # |        | l |                        | > statement is  |
| ory_R | te |   | # |        | i |                        | > provided for  |
| ation | xt |   | # |        | t |                        | > all chemicals |
| ale\_ |    |   | # |        | a |                        | > within each   |
|  Chem |    |   | # |        | t |                        | > structural    |
| Class |    |   |   |        | i |                        | > subclass;     |
| _ERB  |    |   | T |        | v |                        | > these are     |
|       |    |   | e |        | e |                        | > tabulated in  |
| *(no  |    |   | x |        | s |                        | > the Appendix  |
| spa   |    |   | t |        | t |                        | > below.        |
| ces)* |    |   |   |        | r |                        | > Rationale     |
|       |    |   |   |        | u |                        | > statements    |
|       |    |   |   |        | c |                        | > are also      |
|       |    |   |   |        | t |                        | > provided for  |
|       |    |   |   |        | u |                        | > some          |
|       |    |   |   |        | r |                        | > compounds in  |
|       |    |   |   |        | e |                        | > the "Misc"    |
|       |    |   |   |        | - |                        | > category.     |
|       |    |   |   |        | a |                        |                 |
|       |    |   |   |        | c |                        |                 |
|       |    |   |   |        | t |                        |                 |
|       |    |   |   |        | i |                        |                 |
|       |    |   |   |        | v |                        |                 |
|       |    |   |   |        | i |                        |                 |
|       |    |   |   |        | t |                        |                 |
|       |    |   |   |        | y |                        |                 |
|       |    |   |   |        | r |                        |                 |
|       |    |   |   |        | a |                        |                 |
|       |    |   |   |        | t |                        |                 |
|       |    |   |   |        | i |                        |                 |
|       |    |   |   |        | o |                        |                 |
|       |    |   |   |        | n |                        |                 |
|       |    |   |   |        | a |                        |                 |
|       |    |   |   |        | l |                        |                 |
|       |    |   |   |        | e |                        |                 |
|       |    |   |   |        | r |                        |                 |
|       |    |   |   |        | e |                        |                 |
|       |    |   |   |        | l |                        |                 |
|       |    |   |   |        | a |                        |                 |
|       |    |   |   |        | t |                        |                 |
|       |    |   |   |        | i |                        |                 |
|       |    |   |   |        | n |                        |                 |
|       |    |   |   |        | g |                        |                 |
|       |    |   |   |        | w |                        |                 |
|       |    |   |   |        | h |                        |                 |
|       |    |   |   |        | a |                        |                 |
|       |    |   |   |        | t |                        |                 |
|       |    |   |   |        | i |                        |                 |
|       |    |   |   |        | s |                        |                 |
|       |    |   |   |        | k |                        |                 |
|       |    |   |   |        | n |                        |                 |
|       |    |   |   |        | o |                        |                 |
|       |    |   |   |        | w |                        |                 |
|       |    |   |   |        | n |                        |                 |
|       |    |   |   |        | o |                        |                 |
|       |    |   |   |        | r |                        |                 |
|       |    |   |   |        | i |                        |                 |
|       |    |   |   |        | n |                        |                 |
|       |    |   |   |        | f |                        |                 |
|       |    |   |   |        | e |                        |                 |
|       |    |   |   |        | r |                        |                 |
|       |    |   |   |        | r |                        |                 |
|       |    |   |   |        | e |                        |                 |
|       |    |   |   |        | d |                        |                 |
|       |    |   |   |        | c |                        |                 |
|       |    |   |   |        | o |                        |                 |
|       |    |   |   |        | n |                        |                 |
|       |    |   |   |        | c |                        |                 |
|       |    |   |   |        | e |                        |                 |
|       |    |   |   |        | r |                        |                 |
|       |    |   |   |        | n |                        |                 |
|       |    |   |   |        | i |                        |                 |
|       |    |   |   |        | n |                        |                 |
|       |    |   |   |        | g |                        |                 |
|       |    |   |   |        | t |                        |                 |
|       |    |   |   |        | h |                        |                 |
|       |    |   |   |        | e |                        |                 |
|       |    |   |   |        | s |                        |                 |
|       |    |   |   |        | t |                        |                 |
|       |    |   |   |        | r |                        |                 |
|       |    |   |   |        | u |                        |                 |
|       |    |   |   |        | c |                        |                 |
|       |    |   |   |        | t |                        |                 |
|       |    |   |   |        | u |                        |                 |
|       |    |   |   |        | r |                        |                 |
|       |    |   |   |        | a |                        |                 |
|       |    |   |   |        | l |                        |                 |
|       |    |   |   |        | b |                        |                 |
|       |    |   |   |        | a |                        |                 |
|       |    |   |   |        | s |                        |                 |
|       |    |   |   |        | i |                        |                 |
|       |    |   |   |        | s |                        |                 |
|       |    |   |   |        | f |                        |                 |
|       |    |   |   |        | o |                        |                 |
|       |    |   |   |        | r |                        |                 |
|       |    |   |   |        | e |                        |                 |
|       |    |   |   |        | s |                        |                 |
|       |    |   |   |        | t |                        |                 |
|       |    |   |   |        | r |                        |                 |
|       |    |   |   |        | o |                        |                 |
|       |    |   |   |        | g |                        |                 |
|       |    |   |   |        | e |                        |                 |
|       |    |   |   |        | n |                        |                 |
|       |    |   |   |        | i |                        |                 |
|       |    |   |   |        | c |                        |                 |
|       |    |   |   |        | a |                        |                 |
|       |    |   |   |        | c |                        |                 |
|       |    |   |   |        | t |                        |                 |
|       |    |   |   |        | i |                        |                 |
|       |    |   |   |        | v |                        |                 |
|       |    |   |   |        | i |                        |                 |
|       |    |   |   |        | t |                        |                 |
|       |    |   |   |        | y |                        |                 |
|       |    |   |   |        | w |                        |                 |
|       |    |   |   |        | i |                        |                 |
|       |    |   |   |        | t |                        |                 |
|       |    |   |   |        | h |                        |                 |
|       |    |   |   |        | i |                        |                 |
|       |    |   |   |        | n |                        |                 |
|       |    |   |   |        | e |                        |                 |
|       |    |   |   |        | a |                        |                 |
|       |    |   |   |        | c |                        |                 |
|       |    |   |   |        | h |                        |                 |
|       |    |   |   |        | o |                        |                 |
|       |    |   |   |        | f |                        |                 |
|       |    |   |   |        | t |                        |                 |
|       |    |   |   |        | h |                        |                 |
|       |    |   |   |        | e |                        |                 |
|       |    |   |   |        | 2 |                        |                 |
|       |    |   |   |        | 0 |                        |                 |
|       |    |   |   |        | s |                        |                 |
|       |    |   |   |        | t |                        |                 |
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|       |    |   |   |        | s |                        |                 |
|       |    |   |   |        | ( |                        |                 |
|       |    |   |   |        | * |                        |                 |
|       |    |   |   |        | * |                        |                 |
|       |    |   |   |        | C |                        |                 |
|       |    |   |   |        | h |                        |                 |
|       |    |   |   |        | e |                        |                 |
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|       |    |   |   |        | a |                        |                 |
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|       |    |   |   |        | s |                        |                 |
|       |    |   |   |        | _ |                        |                 |
|       |    |   |   |        | E |                        |                 |
|       |    |   |   |        | R |                        |                 |
|       |    |   |   |        | B |                        |                 |
|       |    |   |   |        | * |                        |                 |
|       |    |   |   |        | * |                        |                 |
|       |    |   |   |        | ) |                        |                 |
|       |    |   |   |        | . |                        |                 |
|       |    |   |   |        | B |                        |                 |
|       |    |   |   |        | r |                        |                 |
|       |    |   |   |        | i |                        |                 |
|       |    |   |   |        | e |                        |                 |
|       |    |   |   |        | f |                        |                 |
|       |    |   |   |        | n |                        |                 |
|       |    |   |   |        | a |                        |                 |
|       |    |   |   |        | r |                        |                 |
|       |    |   |   |        | r |                        |                 |
|       |    |   |   |        | a |                        |                 |
|       |    |   |   |        | t |                        |                 |
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|       |    |   |   |        | i |                        |                 |
|       |    |   |   |        | n |                        |                 |
|       |    |   |   |        | t |                        |                 |
|       |    |   |   |        | e |                        |                 |
|       |    |   |   |        | n |                        |                 |
|       |    |   |   |        | d |                        |                 |
|       |    |   |   |        | e |                        |                 |
|       |    |   |   |        | d |                        |                 |
|       |    |   |   |        | t |                        |                 |
|       |    |   |   |        | o |                        |                 |
|       |    |   |   |        | s |                        |                 |
|       |    |   |   |        | u |                        |                 |
|       |    |   |   |        | m |                        |                 |
|       |    |   |   |        | m |                        |                 |
|       |    |   |   |        | a |                        |                 |
|       |    |   |   |        | r |                        |                 |
|       |    |   |   |        | i |                        |                 |
|       |    |   |   |        | z |                        |                 |
|       |    |   |   |        | e |                        |                 |
|       |    |   |   |        | t |                        |                 |
|       |    |   |   |        | h |                        |                 |
|       |    |   |   |        | e |                        |                 |
|       |    |   |   |        | l |                        |                 |
|       |    |   |   |        | e |                        |                 |
|       |    |   |   |        | n |                        |                 |
|       |    |   |   |        | g |                        |                 |
|       |    |   |   |        | t |                        |                 |
|       |    |   |   |        | h |                        |                 |
|       |    |   |   |        | i |                        |                 |
|       |    |   |   |        | e |                        |                 |
|       |    |   |   |        | r |                        |                 |
|       |    |   |   |        | d |                        |                 |
|       |    |   |   |        | i |                        |                 |
|       |    |   |   |        | s |                        |                 |
|       |    |   |   |        | c |                        |                 |
|       |    |   |   |        | u |                        |                 |
|       |    |   |   |        | s |                        |                 |
|       |    |   |   |        | s |                        |                 |
|       |    |   |   |        | i |                        |                 |
|       |    |   |   |        | o |                        |                 |
|       |    |   |   |        | n |                        |                 |
|       |    |   |   |        | i |                        |                 |
|       |    |   |   |        | n |                        |                 |
|       |    |   |   |        | F |                        |                 |
|       |    |   |   |        | a |                        |                 |
|       |    |   |   |        | n |                        |                 |
|       |    |   |   |        | g |                        |                 |
|       |    |   |   |        | e |                        |                 |
|       |    |   |   |        | t |                        |                 |
|       |    |   |   |        | a |                        |                 |
|       |    |   |   |        | l |                        |                 |
|       |    |   |   |        | . |                        |                 |
|       |    |   |   |        | ( |                        |                 |
|       |    |   |   |        | 2 |                        |                 |
|       |    |   |   |        | 0 |                        |                 |
|       |    |   |   |        | 0 |                        |                 |
|       |    |   |   |        | 1 |                        |                 |
|       |    |   |   |        | ) |                        |                 |
|       |    |   |   |        | . |                        |                 |
+-------+----+---+---+--------+---+------------------------+-----------------+

+-------+----+---+--------+------------------------+-----------------+
| ## F1 | i  | # | 1/     | First decision point   | Fang et al.     |
| _Ring | nt | # |        | in Flowchart above,    | (2001) report   |
|       | eg | # | 0/     | and in Fig. 14 of Fang | that a survey   |
|       | er | # |        | et al (2001). Value    | of over 2000    |
|       |    |   |        | indicates the presence | chemicals       |
|       |    |   |        | or absence of a ring   | tested for      |
|       |    |   |        | in the chemical        | estrogenic      |
|       |    |   |        | structure, either      | activity found  |
|       |    |   |        | aromatic or not:       | no active       |
|       |    |   |        |                        | chemical        |
|       |    |   |        | > 1 = yes              | lacking a ring  |
|       |    |   |        | >                      | structure. A    |
|       |    |   |        | > 0 = no               | ring lends      |
|       |    |   |        |                        | rigidity to the |
|       |    |   |        | If a chemical contains | structure and   |
|       |    |   |        | no ring structure      | the main steric |
|       |    |   |        | (F1=0), it is unlikely | centers. A      |
|       |    |   |        | to be an ER ligand.    | total of 22     |
|       |    |   |        |                        | compounds in    |
|       |    |   |        |                        | NCTRER contain  |
|       |    |   |        |                        | only a          |
|       |    |   |        |                        | non-aromatic    |
|       |    |   |        |                        | ring; of these  |
|       |    |   |        |                        | 5 are active    |
|       |    |   |        |                        | due to H-bond   |
|       |    |   |        |                        | O,S,N           |
|       |    |   |        |                        | heteroatoms     |
|       |    |   |        |                        | (F4=1) and      |
|       |    |   |        |                        | other key       |
|       |    |   |        |                        | features        |
|       |    |   |        |                        | (F6=1).         |
|       |    |   |        |                        | Examples        |
|       |    |   |        |                        | include kepone, |
|       |    |   |        |                        | norethynodrel,  |
|       |    |   |        |                        | dihyd           |
|       |    |   |        |                        | rotestosterone, |
|       |    |   |        |                        | and 3 alpha-    |
|       |    |   |        |                        | and 3           |
|       |    |   |        |                        | beta-           |
|       |    |   |        |                        | androstanediol. |
+-------+----+---+--------+------------------------+-----------------+
| ## F  | i  | # | 1/     | Second decision point  | ## An aromatic  |
| 2_Aro | nt | # |        | in Flowchart above,    |  ring is flatte |
| matic | eg | # | 0/     | and in Fig. 14 of Fang | r and more rigi |
|  Ring | er | # |        | et al (2001). Value    | d than a non-ar |
|       |    |   |        | indicates the presence | omatic ring and |
| *(no  |    | N |        | or absence of an       |  generally bett |
| spa   |    | o |        | aromatic ring in the   | er fits the ER  |
| ces)* |    | n |        | chemical structure:    | ligand binding  |
|       |    | e |        |                        | domain. If not  |
|       |    |   |        | > 1 = yes (only if     | a phenol, howev |
|       |    |   |        | > F1=1)                | er, other key f |
|       |    |   |        | >                      | eatures are nec |
|       |    |   |        | > 0 = no               | essary for acti |
|       |    |   |        |                        | vity. Of the 67 |
|       |    |   |        |                        |  non-phenolic a |
|       |    |   |        |                        | romatics in NCT |
|       |    |   |        |                        | RER, 19 are act |
|       |    |   |        |                        | ive or slight b |
|       |    |   |        |                        | inders; each of |
|       |    |   |        |                        |  these contains |
|       |    |   |        |                        |  multiple rings |
|       |    |   |        |                        |  and all but on |
|       |    |   |        |                        | e contain eithe |
|       |    |   |        |                        | r Cl or O. Thes |
|       |    |   |        |                        | e include o,p'- |
|       |    |   |        |                        | DDT, 1,3-diphen |
|       |    |   |        |                        | yltetramethyldi |
|       |    |   |        |                        | siloxane, 3-deo |
|       |    |   |        |                        | xyl-E2, mestran |
|       |    |   |        |                        | ol, and others. |
+-------+----+---+--------+------------------------+-----------------+
| ##    | i  | # | 1/     | Third decision point   | ## I            |
| F3_Ph | nt | # |        | in Flowchart above,    | n the NCTRER, 1 |
| enoli | eg | # | 0/     | and in Fig. 14 of Fang | 12 out of 136 a |
| cRing | er | # |        | et al (2001). Value    | ctive chemicals |
|       |    |   |        | indicates the presence |  (including sli |
|       |    |   |        | or absence of a        | ght binders) co |
|       |    |   |        | phenolic ring in the   | ntain a phenoli |
|       |    |   |        | chemical structure:    | c ring, whereas |
|       |    |   |        |                        |  25 phenols are |
|       |    |   |        | > 1 = yes (only if     |  inactive. A ph |
|       |    |   |        | > F1=F2=1)             | enolic ring is  |
|       |    |   |        | >                      | usually necessa |
|       |    |   |        | > 0 = no               | ry but not suff |
|       |    |   |        |                        | icient for ER b |
|       |    |   |        |                        | inding and othe |
|       |    |   |        |                        | r key features  |
|       |    |   |        |                        | may be needed.  |
+-------+----+---+--------+------------------------+-----------------+
| #     | i  | # | 1/     | Fourth decision point  | ## Heteroat     |
| # F4_ | nt | # |        | in Flowchart above,    | oms (O,S,N) on  |
| Heter | eg | # | 0/     | and in Fig. 14 of Fang | a non-aromatic  |
| oatom | er | # |        | et al (2001), only     | ring structure  |
|       |    |   |        | reached if F1=1 and    | may confer ER b |
|       |    |   |        | F2=0. Value indicates  | inding through  |
|       |    |   |        | the presence or        | H-bonding abili |
|       |    |   |        | absence of a H-bond    | ty, but this us |
|       |    |   |        | capable heteroatom     | ually depends o |
|       |    |   |        | (O,S,N) attached to a  | n the presence  |
|       |    |   |        | non-aromatic ring      | of other key fe |
|       |    |   |        | structure:             | atures (F6=1).  |
|       |    |   |        |                        |                 |
|       |    |   |        | > 1 = yes (only if     |                 |
|       |    |   |        | > F1=1, F2=0)          |                 |
|       |    |   |        | >                      |                 |
|       |    |   |        | > 0 = no               |                 |
+-------+----+---+--------+------------------------+-----------------+
| #     | i  | # | 1/     | Fifth decision point   | ## Of 85 com    |
| # F5_ | nt | # |        | in Flowchart above,    | pounds in NCTRE |
| Pheno | eg | # | 0/     | and in Fig. 14 of Fang | R with F5=1, 63 |
| l3n P | er | # |        | et al (2001), only     |  are active (1  |
| henyl |    |   |        | reached if F1=F2=F3=1. | slight binder). |
|       |    |   |        | Value indicates the    |                 |
|       |    |   |        | presence or absence of | ## Compound     |
|       |    |   |        | a phenolic ring linked | s for which F5= |
|       |    |   |        | by 1-3 bridging atoms  | 1 occur mainly  |
|       |    |   |        | (C or O) to another    | in the Phytoest |
|       |    |   |        | aromatic ring system:  | rogens, Dipheny |
|       |    |   |        |                        | lmethanes, and  |
|       |    |   |        | > 1 = yes              | DES ChemClass_E |
|       |    |   |        | >                      | RB categories.  |
|       |    |   |        | > 0 = no               |                 |
|       |    |   |        |                        |                 |
|       |    |   |        | If F5=1, compound is   |                 |
|       |    |   |        | likely an ER ligand.   |                 |
+-------+----+---+--------+------------------------+-----------------+

+-------+----+---+--------+------------------------+-----------------+
| ## F  | i  | # | 1/     | Indicator value of     | ## Key stru     |
| 6_Oth | nt | # |        | sixth decision point   | ctural features |
| erKey | eg | # | 0/     | in Flowchart above,    |  determined by  |
|       | er | # |        | and in Fig. 14 of Fang | Fang et al. (20 |
| #     |    |   |        | et al (2001),          | 01) according t |
| # Fea |    |   |        | indicating the         | o independent c |
| tures |    |   |        | presence or absence of | alculations, in |
|       |    |   |        | a key structural       | spection, and e |
| *(no  |    |   |        | feature conferring     | xpert judgment  |
| spa   |    |   |        | activity:              | and include det |
| ces)* |    |   |        |                        | ermination of:  |
|       |    |   |        | > 1 = yes              |                 |
|       |    |   |        | >                      | > H-bonding     |
|       |    |   |        | > 0 = no               | > ability       |
|       |    |   |        | >                      | >               |
|       |    |   |        | > Decision point       | > Precise O-O   |
|       |    |   |        | > reached if F1=1 and  | > distance (11  |
|       |    |   |        | > F4=1, F3=0, or F5=0. | > angstroms)    |
|       |    |   |        | >                      | >               |
|       |    |   |        | > Definitive rules for | > Rigid         |
|       |    |   |        | > determining presence | > structure     |
|       |    |   |        | > of key structural    | >               |
|       |    |   |        | > features are not     | > Steric        |
|       |    |   |        | > provided here but    | > moieties      |
|       |    |   |        | > usually are implied  | > mimicking     |
|       |    |   |        | > by ERB activity.     | > 7alpha and    |
|       |    |   |        |                        | > 11beta        |
|       |    |   |        |                        | > position of   |
|       |    |   |        |                        | > E2            |
|       |    |   |        |                        | >               |
|       |    |   |        |                        | > Satisfactory  |
|       |    |   |        |                        | >               |
|       |    |   |        |                        |  hydrophobicity |
|       |    |   |        |                        | > (LOGP)        |
|       |    |   |        |                        |                 |
|       |    |   |        |                        | For more        |
|       |    |   |        |                        | details of ER   |
|       |    |   |        |                        | binding         |
|       |    |   |        |                        | criteria and    |
|       |    |   |        |                        | modeling        |
|       |    |   |        |                        | approaches,     |
|       |    |   |        |                        | consult         |
|       |    |   |        |                        | additional      |
|       |    |   |        |                        | NCTRER          |
|       |    |   |        |                        | references      |
|       |    |   |        |                        | listed below.   |
+-------+----+---+--------+------------------------+-----------------+
| ##    | n  | # | \#     | Logarithm of the       | Mean **LOGP**   |
|  LOGP | um | # |        | octanol/water          | values plotted  |
|       | er | # |        | partition coefficient  | for             |
|       | ic | # |        | computed by the        | **ActivityCa    |
|       |    |   |        | fragment method of     | tegory_ER_RBA** |
|       |    |   |        | Meylan and Howard      | in Fig. 13 of   |
|       |    |   |        | \[1\]. Physicochemical | Fang et al.     |
|       |    |   |        | property provides an   | (2001) show     |
|       |    |   |        | approximate measure of | positive trend  |
|       |    |   |        | hydrophobicity; values | for strong,     |
|       |    |   |        | too high or too low    | medium and weak |
|       |    |   |        | can be associated with | estrogens, but  |
|       |    |   |        | poor transport         | inactives have  |
|       |    |   |        | characteristics.       | wide range of   |
|       |    |   |        |                        | **LOGP**        |
|       |    |   |        |                        | values.         |
+-------+----+---+--------+------------------------+-----------------+
| ## N  | me | # | *Text* | Field used to provide  | Source-specific |
| ote_N | mo | # |        | supplementary          | information     |
| CTRER |    | # |        | Source-specific        | pertaining to   |
|       |    | # |        | information pertaining | the chemical    |
|       |    |   |        | to the chemical and    | record          |
|       |    |   |        | toxicity fields.       | previously      |
|       |    |   |        |                        | included in     |
|       |    |   |        |                        | *               |
|       |    |   |        |                        | *ChemicalNote** |
|       |    |   |        |                        | field has been  |
|       |    |   |        |                        | moved to this   |
|       |    |   |        |                        | field.          |
+-------+----+---+--------+------------------------+-----------------+
|       |    |   |        |                        |                 |
+-------+----+---+--------+------------------------+-----------------+

**Additional NCTRER references:**

1\. Meylan, W. and P. Howard (1995) Atom/fragment contribution method
for estimating octanol-water partition coefficients. *J. Pharm. Sci.*
84: 83-92.

2\. Tong, W., R. Perkins, R. Strelitz, E.R. Collantes, S. Keenan, W.J.
Welsh, W.S. Branham, and D.M. Sheehan (1997) Quantitative
structure-activity relationships (QSARs) for estrogen binding to the
estrogen receptor: predictions across species. *Environ. Health
Perspect.* 105: 1116-1124.

3\. Tong, W., R. Perkins, L. Xing, W.J. Welsh, and D.M. Sheehan (1997)
QSAR models for binding of estrogenic compounds to estrogen receptor
*alpha* and *beta* subtypes. *Endocrinology* 138:4022-4025.

4\. Tong, W., D.R. Lowis, R. Perkins, Y. Chen, W.J. Welsh, D.W.
Goddette, T.W. Heritage, and D.M. Sheehan (1998) Evaluation of
quantitative structure-activity relationship methods for large-scale
prediction of chemicals binding to the estrogen receptor. *J. Chem. Inf.
Comput. Sci.* 38:669-677.

5\. Xing, L., W.J. Welsh, W. Tong, R. Perkins, and D.M. Sheehan (1999)
Comparison of estrogen receptor alpha and beta subtypes based on
comparative molecular field analysis (CoMFA). *SAR QSAR Environ. Res.*
10: 215-237.

6\. Perkins, R., J. Anson, W. Branham, H. Fang, W. Tong, W. Welsh, Y.
Chen, J. Meehan, M. Jackson, R. Nossaman, L. Shi, and D. Sheehan (2000)
*The Estrogen Knowledge Base (EKB), A Prototype Toxciological Knowledge
Base for Endocrine Disrupting Compounds*, Walker J.D., Ed., SETAC.

7\. Fang, H., W. Tong, R. Perkins, A.M. Soto, N.V. Prechtl, and D.M.
Sheehan (2000) Quantitative comparisons of in vitro assays for
estrogenic activities.\
*Environ. Health Perspect.* 108: 723-729.

8\. Shi, L.M., H. Fang, W. Tong, J. Wu, R. Perkins, R.M. Blair, W.S.
Branham, S.L. Dial, C.L. Moland, and D.M. Sheehan (2001) QSAR models
using a large diverse set of estrogens. *J. Chem. Inf. Comput. Sci.*
41:186-195.

9\. Shi, L., W. Tong, H. Fang, Q. Xie, H. Hong, R. Perkins, J. Wu, M.
Tu, R.M. Blair, W.S. Branham, C. Waller, J. Walker, and D.M. Sheehan
(2002) An integrated \"4-phase\" approach for setting endocrine
disruption screening priorities\--phase I and II predictions of estrogen
receptor binding affinity.\
*SAR QSAR Environ. Res.* 13: 69-88.

10\. Hong, H., W. Tong, H. Fang, L. Shi, Q. Xie, J. Wu, R. Perkins, J.D.
Walker, W. Branham, and D.M. Sheehan (2002) Prediction of estrogen
receptor binding for 58,000 chemicals using an integrated system of a
tree-based model with structural alerts. *Environ. Health Perspect*.
110: 29-36.

**Appendix: Description of ChemClass_ERB Structural Assignments and
Corresponding ActivityCategory_Rationale_ChemClass_ERB Field Entries.**

+-----------+----------+----------------------+-----------------------+
| ***Che    | *        | #########            | #########             |
| mClass*** | **Common |                      |                       |
|           | St       | ######### *ChemCl    | ########              |
| Mean      | ructural | ass_ERB Description* | # ActivityCategory_Ra |
| ER_RBA of | Frame*** |                      | tionale_ChemClass_ERB |
| class     |          |                      |                       |
|           |          |                      |                       |
| (#        |          |                      |                       |
| chemicals |          |                      |                       |
| in        |          |                      |                       |
| subclass) |          |                      |                       |
+-----------+----------+----------------------+-----------------------+
| **S       |          | Steroidal framework  |                       |
| teroids** |          | shared by natural    |                       |
|           |          | ligands of estrogen  |                       |
| Me        |          | and androgen         |                       |
| an_ER_RBA |          | receptors.           |                       |
| = 1.24    |          |                      |                       |
+-----------+----------+----------------------+-----------------------+
| With      | ![](m    | Steroidal backbone   | For steroids with     |
| aromatic  | edia/ima | of 17β-estradiol     | phenolic A ring, 3OH  |
| A ring    | ge3.wmf) | (E2) shown at left.  | and 17β OH H-bond     |
|           |          | Most common          | centers optimal; 3OH  |
| \(18\)    |          | substitutions at 2,  | loss gives greatest   |
|           |          | 3, 4, 6, 11α, 16β,   | RBA reduction, steric |
|           |          | 17β positions.       | bulk at 7α or 11β     |
|           |          |                      | also leads to reduced |
|           |          |                      | RBA.                  |
+-----------+----------+----------------------+-----------------------+
| Without   | ![](m    | Steroidal backbone   | Steroids lacking      |
| aromatic  | edia/ima | of androgenic        | phenolic A ring have  |
| A ring    | ge4.wmf) | compounds shown at   | significant reduction |
|           |          | left. All class      | in RBA relative to    |
| \(13\)    |          | members have H-bond  | E2; weak activity     |
|           |          | group at 3 position  | only when framework   |
|           |          | (OH or =O) and more  | and H-bond centers    |
|           |          | diverse substitution | most similar to E2.   |
|           |          | patterns than E2     |                       |
|           |          | analogs,             |                       |
|           |          | particularly around  |                       |
|           |          | 17β position; can    |                       |
|           |          | have A and B ring    |                       |
|           |          | unsaturation.        |                       |
+-----------+----------+----------------------+-----------------------+
| **DES**   |          | Two aromatic rings   |                       |
| (d        |          | separated by 2       |                       |
| iethylsti |          | carbons; 2 para      |                       |
| lbestrol) |          | phenols in DES.      |                       |
|           |          |                      |                       |
| Me        |          |                      |                       |
| an_ER_RBA |          |                      |                       |
| = 2.14    |          |                      |                       |
+-----------+----------+----------------------+-----------------------+
| DES       | ![](m    | Two aromatic rings,  | DES is one of highest |
| de        | edia/ima | one para substituted | affinity synthetic    |
| rivatives | ge5.wmf) | with OH or OR,       | estrogens, loss of    |
|           |          | separated by 2       | one or both OH or     |
| \(6\)     |          | carbon ethenyl       | loss of ethyl         |
|           |          | bridge; ethyl or     | substituents          |
|           |          | methyl substitutions | decreases RBA         |
|           |          | on each ethenyl      | significantly.        |
|           |          | bridge carbon mimic  |                       |
|           |          | steric framework of  |                       |
|           |          | E2.                  |                       |
+-----------+----------+----------------------+-----------------------+
| Hexestrol | ![](m    | Two aromatic rings,  | Hexestrols are less   |
| de        | edia/ima | one para substituted | rigid than DES, less  |
| rivatives | ge6.wmf) | with OH or OR,       | optimal when two OH   |
|           |          | separated by 2       | binding sites but     |
| \(9\)     |          | carbon ethyl bridge; | greater flexibility   |
|           |          | ethyl substitutions  | preferred when single |
|           |          | on each ethyl bridge | OH binding site.      |
|           |          | carbon mimic steric  |                       |
|           |          | framework of E2.     |                       |
+-----------+----------+----------------------+-----------------------+
| Triphenyl | ![](m    | DES derivative       | Triphenylethylenes    |
| ethylenes | edia/ima | framework with third | act as antiestrogens; |
|           | ge7.wmf) | aromatic ring off    | the more structurally |
| \(7\)     |          | ethenyl bridge       | similar to DES the    |
|           |          | carbon. Ethyl and    | greater the RBA, with |
|           |          | alkoxyamine          | 4-OH-tamoxofen having |
|           |          | substituents most    | the greatest RBA,     |
|           |          | common.              | half of DES and       |
|           |          |                      | greater than E2.      |
+-----------+----------+----------------------+-----------------------+
| **Phytoes |          | Plant estrogens with |                       |
| trogens** |          | less than full       |                       |
|           |          | steroidal frame.     |                       |
| Me        |          |                      |                       |
| an_ER_RBA |          |                      |                       |
| = 0.019   |          |                      |                       |
+-----------+----------+----------------------+-----------------------+
| Flavones  | ![](m    | Includes flavone     | Flavones are weak     |
|           | edia/ima | framework as shown   | binders, RBA          |
| \(15\)    | ge8.wmf) | at left; most class  | optimized when OH     |
|           |          | members have OH      | groups in 6,4\'       |
|           |          | substitutions on one | positions             |
|           |          | or more rings.       | approximately         |
|           |          |                      | correspond to 4,4\'   |
|           |          |                      | OH positions in DES   |
|           |          |                      | as in                 |
|           |          |                      | 3,6,4                 |
|           |          |                      | \'-trihydroxyflavone. |
+-----------+----------+----------------------+-----------------------+
| F         | ![](m    | Includes flavanone   | Flavanones are weak   |
| lavanones | edia/ima | framework as shown   | binders, RBA          |
|           | ge9.wmf) | at left, differs     | optimized when OH     |
| \(10\)    |          | from flavones by     | groups in 6,4\'       |
|           |          | single bond on       | positions approx      |
|           |          | C2-C3; most class    | correspond to 4,4\'   |
|           |          | members have OH      | OH positions in DES;  |
|           |          | substitutions on one | less rigid flat       |
|           |          | or more rings.       | structure than        |
|           |          |                      | flavones leads to     |
|           |          |                      | slightly lowered      |
|           |          |                      | RBAs.                 |
+-----------+----------+----------------------+-----------------------+
| Is        | ![](me   | Includes framework   | Isoflavones are       |
| oflavones | dia/imag | shown on left with   | relatively weak       |
|           | e10.wmf) | keto group on C4 and | binders, RBA          |
| \(9\)     |          | one or more OH or OR | optimized when OH     |
|           |          | substitutions on one | groups in 7,4\'       |
|           |          | or more rings.       | positions approx      |
|           |          |                      | correspond to 4,4\'   |
|           |          |                      | OH positions in DES,  |
|           |          |                      | a more frequent       |
|           |          |                      | coincidence than in   |
|           |          |                      | flavones and          |
|           |          |                      | flavanones.           |
+-----------+----------+----------------------+-----------------------+
| C         | ![](me   | Includes framework   | RBA of coumestans     |
| oumestans | dia/imag | shown at left with   | approx 100-fold less  |
|           | e11.wmf) | additional C4 ethyl  | than E2; coumestrol   |
| \(2\)     |          | substitution or oxo  | has similar framework |
|           |          | bridge from C4 to    | to E2, whereas other  |
|           |          | C2'; OH or OCH~3~ on | class member has      |
|           |          | C4'.                 | ethyl group           |
|           |          |                      | functionally similar  |
|           |          |                      | to DES.               |
+-----------+----------+----------------------+-----------------------+
| Ch        | ![](me   | Two aromatic rings   | Chalconoids are weak  |
| alconoids | dia/imag | separated by propyl- | binders; OH groups at |
|           | e12.wmf) | or propenyl-one      | 4,4' positions approx |
| \(5\)     |          | bridge; most class   | d~o-o~ in DES and E2, |
|           |          | members have OH      | but flexibility       |
|           |          | substitutions on     | reduces RBA           |
|           |          | either C4 or C4'.    | 1000-fold; single OH  |
|           |          |                      | reduces RBA 20-fold   |
|           |          |                      | further.              |
+-----------+----------+----------------------+-----------------------+
| Myco      | ![](me   | Includes framework   | Mycoestrogens are     |
| estrogens | dia/imag | shown at left; some  | most active           |
|           | e13.wmf) | class members have   | phytoestrogens; for   |
| \(5\)     |          | double bond on       | same framework with   |
|           |          | C11-C12 carbons and  | 7-OH, RBAs are        |
|           |          | hydroxyl or oxo      | 100-fold higher for   |
|           |          | substitution at C7.  | α isomers (d~o-o~     |
|           |          |                      | approx 11A) , as in   |
|           |          |                      | E2 and DES, than for  |
|           |          |                      | β isomers (d~o-o~     |
|           |          |                      | approx 10A).          |
+-----------+----------+----------------------+-----------------------+
| **        |          | Includes two         |                       |
| Diphenylm |          | aromatic rings       |                       |
| ethanes** |          | separated by a       |                       |
|           |          | single bridging      |                       |
| (Me       |          | atom, varying in     |                       |
| an_ER_RBA |          | substituents on      |                       |
| = 0.0087) |          | bridge atom and      |                       |
|           |          | phenyls.             |                       |
+-----------+----------+----------------------+-----------------------+
| Diphen    | ![](me   | Two phenolic rings   | Diphenolalkanes are   |
| olalkanes | dia/imag | separated single     | relatively weak       |
|           | e14.wmf) | bridge C, with       | binders, 4-OH         |
| \(12\)    |          | possible third ring  | critical for binding, |
|           |          | and various          | RBA inhibited by      |
|           |          | substituents on      | steric bulk as in     |
|           |          | phenols and bridge   | 2,                    |
|           |          | carbon.              | 6-di-tertbutylphenol, |
|           |          |                      | bulk at bridge atom   |
|           |          |                      | increases RBA similar |
|           |          |                      | to 7a substitution on |
|           |          |                      | E2.                   |
+-----------+----------+----------------------+-----------------------+
| Benz      | ![](me   | Two phenyl rings, at | Benzophenones are     |
| ophenones | dia/imag | least one phenolic,  | weaker binders than   |
|           | e15.wmf) | separated by         | diphenolalkanes, 4-OH |
| \(6\)     |          | carbonyl (although   | critical for binding. |
|           |          | in one case a        |                       |
|           |          | sulfonyl) varying in |                       |
|           |          | OH and OCH~3~        |                       |
|           |          | substitutions.       |                       |
+-----------+----------+----------------------+-----------------------+
| DDTs      | ![](me   | DDT framework with   | DDTs are strongest    |
|           | dia/imag | di or                | binders in class,     |
| \(12\)    | e16.wmf) | trichloromethyl      | 4-OH or o,p'-Cl       |
|           |          | group single or      | critical; highest RBA |
|           |          | double bonded to     | with dichloroethenyl  |
|           |          | bridge carbon        | substitution at       |
|           |          | between two phenyl   | bridge atom adding    |
|           |          | groups with OH,      | rigidity, mimicking   |
|           |          | OCH~3~, or Cl        | 7α substitution on E2 |
|           |          | substituents.        | and enhancing         |
|           |          |                      | H-bonding.            |
+-----------+----------+----------------------+-----------------------+
| **Bi      |          | Two aromatic rings   |                       |
| phenyls** |          | attached by a single |                       |
|           |          | bond, with Cl or OH  |                       |
| (Me       |          | groups.              |                       |
| an_ER_RBA |          |                      |                       |
| = 0.0028) |          |                      |                       |
+-----------+----------+----------------------+-----------------------+
| PCBs      | ![](me   | Two aromatic rings   | PCBs are weak         |
|           | dia/imag | attached by a single | binders; 4-OH or      |
| polych    | e17.wmf) | bond with one or     | o,p'-Cl critical      |
| lorinated |          | more Cl              | although o,o\',p,p\'  |
| biphenyls |          | substituents; some   | inactive; increased   |
|           |          | also have OH groups. | RBA with increased Cl |
| \(9\)     |          |                      | substitution on B     |
|           |          |                      | ring due to           |
|           |          |                      | polarization of 4-OH. |
+-----------+----------+----------------------+-----------------------+
| Nonch     | ![](me   | Two aromatic rings,  | Nonchlorinated        |
| lorinated | dia/imag | one a phenol,        | biphenyls are weak    |
|           | e18.wmf) | attached by a single | binders; RBA          |
| \(3\)     |          | bond; one a phenol.  | decreases 2-fold from |
|           |          |                      | 4-OH to 3-OH and      |
|           |          |                      | eliminated for 2-OH,  |
|           |          |                      | weak binding for 3-OH |
|           |          |                      | indicates less        |
|           |          |                      | optimal but confers   |
|           |          |                      | some binding          |
|           |          |                      | activity.             |
+-----------+----------+----------------------+-----------------------+
| **        |          | Contains a phenol.   |                       |
| Phenols** |          |                      |                       |
|           |          |                      |                       |
| (Me       |          |                      |                       |
| an_ER_RBA |          |                      |                       |
| =         |          |                      |                       |
| 0.00088)  |          |                      |                       |
+-----------+----------+----------------------+-----------------------+
| Alkyl     | ![](me   | Phenol or with       | Alkyl phenols are     |
|           | dia/imag | various alkyl or     | very weak binders,    |
| \(17\)    | e19.wmf) | chloro substituents. | log RBA correlates    |
|           |          |                      | with log P for para   |
|           |          |                      | substituted phenols;  |
|           |          |                      | RBA increases with    |
|           |          |                      | chain length to       |
|           |          |                      | maximum value of      |
|           |          |                      | 0.031 in              |
|           |          |                      | 4-nonylphenol.        |
+-----------+----------+----------------------+-----------------------+
| Parabens  | ![](me   | Phenol with para     | Parabens are very     |
|           | dia/imag | alkoxycarbonyl group | weak binders, log RBA |
| \(7\)     | e20.wmf) | having various R     | approx correlates     |
|           |          | groups.              | with log P for para   |
|           |          |                      | substituted phenols,  |
|           |          |                      | with 2-ethylhexyl     |
|           |          |                      | paraben having        |
|           |          |                      | highest RBA (0.018)   |
|           |          |                      | in subclass.          |
+-----------+----------+----------------------+-----------------------+
| Alkyloxy  | ![](me   | Phenol with alkyloxy | Alkoxy phenols are    |
|           | dia/imag | substituents.        | very weak binders,    |
| \(5\)     | e21.wmf) |                      | RBA increases approx  |
|           |          |                      | with chain length to  |
|           |          |                      | maximum value of      |
|           |          |                      | 0.0013 for            |
|           |          |                      | 4-heptyloxyphenol.    |
+-----------+----------+----------------------+-----------------------+
| **Misc**  |          |                      |                       |
+-----------+----------+----------------------+-----------------------+
| (62       |          |                      |                       |
| total) 5  |          |                      |                       |
| active,   |          |                      |                       |
| 57        |          |                      |                       |
| inactive  |          |                      |                       |
+-----------+----------+----------------------+-----------------------+
|           |          |                      |                       |
+-----------+----------+----------------------+-----------------------+