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Speciation and Metabolism. Molecular Initiating Events. Measurable System Effects. Adverse Outcomes. Parent Chemical. IQF Framework for QSAR. Systems Biology. Chemistry/ Biochemistry. QSAR. 1. Identify Plausible Molecular Initiating Events

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Speciation

and

Metabolism

Molecular

Initiating

Events

Measurable

System

Effects

Adverse

Outcomes

Parent

Chemical

IQF Framework for QSAR

Systems

Biology

Chemistry/

Biochemistry

QSAR

1. Identify Plausible Molecular Initiating Events

2. Design Database for Abiotic Binding Affinity/Rates

3. Explore Linkages in Pathways to Downstream Effects

4. Develop QSARs to Predict Initiating Event from Structure


Estrogen Receptor (ER) Toxicity Pathway

Chemical interacts with Receptor at Molecular Level,

Initiates a Series of events, and leads to Adverse Outcome

In vitroAssays

QSAR

In vivo Assays

Inert/Antimicrobial Chemical

INDIVIDUAL

POPULATION

CELLULAR

Response

TISSUE/ORGAN

MOLECULAR

Initiating Event

Skewed

Sex Ratios;

Yr Class

Sex reversal;

Altered behavior;

Repro.

Altered proteins, hormones;

Ova-testis

Altered

Protein

Expression

ER Binding

Toxicological

Understanding

Risk Assessment

Relevance


Er toxicity pathway

INDIVIDUAL

Response

POPULATION

Response

TISSUE/ORGAN

Response

CELLULAR

Respopse

MOLECULAR

Initiating Event

Skewed

Sex Ratios,

Altered

Repro.

Chg 2ndry

Sex Char

Altered

Repro.

Altered proteins (VTG),

Ova-testis

Altered

Protein

Expression

ER Binding

In vitro

Assay

Endpts

Trout

cyto rtER

Binding

MaleTrout

Liver Slice Vtg Induction

ER Toxicity Pathway

Male Medaka

Chg in 2ndary sex characteristic; behavior?

Papillary Processes

Male Medaka

Liver

Vtg Induction

In vivo

Assay

Endpts

Sex Reversal

Genetic Males to Phenotypic Females

Female Medaka

Liver

Vtg decr.

Female Medaka

Fecundity

Hatch

Male Medaka

Gonad

Complete conversion to ovary


No

Yes

ChemicalUniverse

Yes

No

No

  • Alkylbenzsulfonic Acids

  • Sulfonic Acid Dyes

  • p-Alkyl Fluorobenzenes

  • Bis–anilines

  • Alkoxy Anilines

  • Imidazolidines

  • Isothiazolines

  • Alkyl Benzthiols

  • Pyrrolidiones

Non binder(RBA<0.00001)

Contains at least one possible H-bonding site

Yes

Log Kow <1.3

  • Oxazoles

  • Benzamide

  • Furans

  • Sorbitans

  • Triazines

Possible Low Affinity

Binder

No

Yes

Type “A”

Contains Phenol

Fragment

Belongs to

known Active

class

II

Yes

  • DDT-Like

  • Tamoxifen-Like

  • Multi-Cyclohydrocarbons

  • Alkyl Chlorobenzenes

Yes

Special Rule Classes

IV

No

No

Type “B”

Contains identif. Type B

Fragment

Belongs to

known Inactive

class

No

III

Yes

Yes

III

  • Alkyl Phenols

  • Alkoxy Phenols

  • Parabens

  • Salicylates

Potency

Rules / Equations

No

No

Belong to untested class

Non binder(RBA<0.00001)

Yes

Belongs to

known Active

class

  • Fully-hindered Alkyl Phenols

Needs testing

Belong to untested class

with possible

Type A low affinity

Yes

  • Mixed Phenols

  • Alkyl Anilines

  • Phthalates

  • Branched Phenones

  • Cyclo Phenones

  • p-subst Cyclohexanols

  • p-subst Cyclohexanones

  • ring subst (o-CH3,

  • tri-CH3) Benzoates

No

Needs testing

  • N-alkyl Phenones

  • Non ring subst Benzoates

Belongs to

known Inactive

class

Yes

Non binder(RBA<0.00001)

  • ring subst p-CH3 Benzoates

  • Thiophosphate Esters

  • Mixed Organics

  • Cyclic Alcohols (not

  • p-subst hexanols)

  • Cyclic Pentanones/Others

  • Br, I halobenzenes

No

Needs testing

Belongs to class

with possible

Type B low affinity

under investigation

Potency

Rules / Equations

Contains Cycle

Belongs to

known Inactive

class

Contains 2 OH,

or OH and =0, at

Spec. Dist

Possible High Affinity,

“A-B”; “A-C”; or

“A-B-C” type binder

Yes

V

No

Contains some

attenuating feature

steric?; other?

Yes

No

High Binding Affinity

“A-B”;“A-C” or “A-B-C” type

Assess strength

of attenuation steric?;

other?

Some

Complete

Non binder

Ex: Progesterone

Corticossterone

(RBA<0.00001)

No

Low Affinity Binder

“A-B”,“A-C” or “A-B-C” type


No

Yes

ChemicalUniverse

Yes

No

No

  • Alkylbenzsulfonic Acids

  • Sulfonic Acid Dyes

  • p-Alkyl Fluorobenzenes

  • Bis–anilines

  • Alkoxy Anilines

  • Imidazolidines

  • Isothiazolines

  • Alkyl Benzthiols

  • Pyrrolidiones

Non binder(RBA<0.00001)

Contains at least one possible H-bonding site

INDIVIDUAL

Response

POPULATION

Response

Yes

Skewed

Sex Ratios,

Altered

Repro.

TISSUE/ORGAN

Response

CELLULAR

Respopse

Chg 2ndry

Sex Char

Altered

Repro.

MOLECULAR

Initiating Event

Altered proteins (VTG),

Ova-testis

Log Kow <1.3

Altered

Protein

Expression

ER Binding

  • Oxazoles

  • Benzamide

  • Furans

  • Sorbitans

  • Triazines

Possible Low Affinity

Binder

No

Speciation

and

Metabolism

Molecular

Initiating

Events

Measurable

System

Effects

Yes

Adverse

Outcomes

Parent

Chemical

Type “A”

Contains Phenol

Fragment

Belongs to

known Active

class

II

Yes

  • DDT-Like

  • Tamoxifen-Like

  • Multi-Cyclohydrocarbons

  • Alkyl Chlorobenzenes

Yes

Special Rule Classes

IV

No

No

No

Type “B”

Contains identif. Type B

Fragment

Belongs to

known Inactive

class

III

Yes

Yes

III

  • Alkyl Phenols

  • Alkoxy Phenols

  • Parabens

  • Salicylates

Potency

Rules / Equations

No

No

Systems

Biology

Chemistry/

Biochemistry

QSAR

Belong to untested class

Non binder(RBA<0.00001)

Yes

Belongs to

known Active

class

  • Fully-hindered Alkyl Phenols

Needs testing

Belong to untested class

with possible

Type A low affinity

Yes

  • Mixed Phenols

  • Alkyl Anilines

  • Phthalates

  • Branched Phenones

  • Cyclo Phenones

  • p-subst Cyclohexanols

  • p-subst Cyclohexanones

  • ring subst (o-CH3,

  • tri-CH3) Benzoates

No

Needs testing

  • N-alkyl Phenones

  • Non ring subst Benzoates

Belongs to

known Inactive

class

Yes

Non binder(RBA<0.00001)

  • ring subst p-CH3 Benzoates

  • Thiophosphate Esters

  • Mixed Organics

  • Cyclic Alcohols (not

  • p-subst hexanols)

  • Cyclic Pentanones/Others

  • Br, I halobenzenes

No

Needs testing

Belongs to class

with possible

Type B low affinity

under investigation

Potency

Rules / Equations


Speciation

and

Metabolism

Speciation

and

Metabolism

Molecular

Initiating

Events

Molecular

Initiating

Events

Measurable

System

Effects

Adverse

Outcomes

Parent

Chemical

Parent

Chemical

Circulating LH, FSH

LDL R

HDL R

LH R

FSH R

Cholesterol

Outer mitochondrial membrane

Activin

StAR

VTG

Inhibin

Fecundity

Population

Fecundity

Population

Fecundity

Population

Fecundity

Population

Inner mitochondrial membrane

P450scc

pregnenolone

3bHSD

17α-hydroxyprogesterone

progesterone

Systems

Biology

Chemistry/

Biochemistry

QSAR

P450c17

20βHSD

androstenedione

17βHSD

17α,20β-P (MIS)

testosterone

P450arom

P45011β

(steroidogenic cells)

11βHSD

11-ketotestosterone

estradiol

VTG

VTG

VTG

Circulating Sex Steroids / Steroid Hormone Binding Globlulin

AR

Estradiol

+

Vtg

ER

ER ( -)

AR (+)

Aromatase (CYP 19)

Fenarimol

17α-trenbolone

17β-trenbolone

Fadrozole

Prochloraz

CYP17


  • Risk Assessment Applications

  • Prioritization

    • -Systematic testing with a “well-defined” endpoint

    • -QSAR Decision Support System for ER molecular initiating event

    • - diverse chemical structures

    • Same approach can be taken for other molecular initiating events

    • AR – diverse structures – extent may be same of less than ER

    • systematic testing needed to develop model for defined chemical list

    • - assays available; may need to be optimized for anticipated

    • low affinity chemicals (EPA problem); EU application?

    • aromatase – diversity of structures causing enz inhib?

    • systematic testing needed to develop model for defined chemical list

    • - assays available; need optimization??

    • other steroidogenic enzymes – (same approach as above)

  • Higher Tier Assessment

    • HPG Systems Models assist data interpretation?


Developmental Endpoints

HPT Systems Model

Identify molecular initiating events

NIS

TPO ( in vitro assays optimized for QSAR approach)

CYP induction – T4 kinetics (gluc)


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