t. w. schultz presented at the mckim conference september 17, 2008
TRANSCRIPT
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T. W. Schultz
Presented at the McKim Conference
September 17, 2008
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MolecularInitiating Events
Speciation,MetabolismReactivity
Etc.
In Vitro and
System Effects
In VivoAdverse
Outcomes
ParentChemical
The Toxicity Pathway The Toxicity Pathway Framework for Predicting Framework for Predicting
HazardHazard
Up-Stream Down-Stream CHEMISTRY BIOLOGY Structure-Activity Levels of Organization
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Human Health Hazards Sensitization - skin and respiratory Acute toxicity - inhalation gas or vapors Chromosomal aberrations Developmental toxicity Selected organ-specific effects
Aquatic Toxicity Excess toxicity for aquatic organisms
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No consensus in number > 25 < 50 (40)Vary in target moiety
Typically 45% -SH and 45% -NH2
Vary in structural domain Simple: isothiocyanate RN=C=S More complex: Michael addition Most complex: SNAr addition
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Michaeladdition
SN2
SNAr
Reactive Potency
In vitroeffects
Mechanisms of
ProteinBinding
In vivosensitization
HazardAssessme
nt Endpoints
In silicomodeling
In ChemicoMeasurem
ent
In VitroMeasureme
nts
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CH2=CH- k(thiol) K(amine) ______________________________________________________
C(=O)OMe 0.011 0.00076
C#N 0.0027 0.00020
C(=O)NH2 0.00046 0.000026
Different nucleophiles can differ in their absolute reactivity towards a given
electrophile, but relative reactivity is well correlated over a range of nucleophiles
within the same mechanism.
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In silico; qualitative, pre-screen 1000’s of compounds
In chemico; depletion-based quantitative, screen 100’s of compounds
Adduct identification; LC-MS-MS, 10’s of compounds
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Use in a similar context to in vitro or in silico
Quantitative, rapid, inexpensive experiments with model nucleophiles
Verify mechanism-based rules of reactivity
Define the applicability domain of a reactive mechanism
Provides a measure of relative potency
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Protocol (Schultz et al., 2005) is quantitative, rapid, inexpensive, abiotic, and spectrophotometric-based
Depletion method; measures % free thiol with GSH as the model nucleophile
Endpoint is RC50 (50% reactive concentration; mM) is calculated by probit analysis of concentrations-response data after 2-hrs
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RC50 (mM) Date Lot Operator_____________________________________________________________
0.094 02-10-05 1 A 0.081 02-18-05 1 A 0.085 02-18-05 1 B 0.086 02-19-05 1 B 0.092 03-03-05 1 A 0.074 03-06-05 1 A 0.084 03-14-05 1 A 0.085 03-21-05 1 A 0.088 12-21-06 2 C 0.068 01-03-07 2 D 0.100 01-05-07 2 D
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Readily available
Concentration can be analyzed by simple methods
Odorless, non-hazardous
Water soluble but NOT readily soluble in organic solvents
Does not lead itself to HPLC
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Depletion of reactant or formation of product
Full Kinetics- measured at several time intervals with several initial concentrations of electrophile (100 chemicals)
Partial Kinetics- measured at several time intervals with one initial concentrations of electrophile
Concentration giving 50% reaction in a fixed time- measured at one time with several initial concentrations of electrophile (1000 chemicals)
Extent of reaction after a fixed time- measured at one time with one initial concentrations of electrophile
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highly relevant with complex domains1) Michael Addition,2) Nucleophilic substitution (N-sub) of
haloaliphatics,3) N-sub of haloaromatics (SNAr).
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Base Structure and Special Features
X = -CHO, -COR,
-CN, etc.
XC=CXC#C
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GSH & LLNA DATA
O
OO
ClO
OO
O
OO
O
RC50 = 0.05
RC50 = 0.05 RC50 = 0.03
RC50 = 0.09 RC50 = 0.02
EC3 = 0.01
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TYPE STRUCTURE RC50 (mM)
Acetylenedicarboxylates RC(=O)C#CC(=O)R 0.025
Propiolates C#CC(=O)OR 0.1
trans-Vinylene dicarboxylates RC(=O)C=CC(=O)R 0.2
Acrylates C=CC(=O)CR 0.8
cis-Vinylene dicarboxylates RC(=O)C=CC(=O)R 2.0
Methacrylates C=C(C)C(=O)CR 30.0
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Base Structure and Special Features
R1C(X)YR2
Y = C6H5 > C#C > C=C, etc
X = I > Br > Cl > F
R1 = H > CnH(2n +1)
R2 no effect
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Base Structure and Special Features
XC6H3Y2
Y = NO2, > in-ring-N > CHO > CN
X = F > Cl > Br > IPosition of leaving group in relationship to activity groups effects potency
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Substance RC50 (mM) Sensitizer_______________________________________________1-F-2,4-dinitrobenzene 0.07 +1-Cl-2,4-dinitrobenzene 1.5 +1-Br-2,4-dinitrobenzene 1.2 +1,3-Cl-4,6-dinitrobenzene 0.24 +1,5-Cl-2,3-dinitrobenzene 0.20 +1,2-dinitrobenzene NRAS -2,4-F-1-nitrobenzene NRAS -2,4-Cl-1-nitrobenzene NRAS -1-Br-4-Cl-2-nitrobenzene NRAS -1,2,3-Cl-5-nitrobenzene NRAS -
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F
NO2
NO2
F
NO2
F
F
NO2
F
FF
NO2
F F
F
1.4 0.6 3.40.07
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1) Michael Addition (largely completed),
2) Pre-Michael Addition (nearly completed),
3) N-sub of Haloaliphatics (largely completed),
4) N-sub of Haloaromatics (just started).
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relevant with simple domains
1) disulfide exchange; 2) disulfide formation, 3) O-heterocyclic ring opening, 4) N-sub of alkyl sulfates &
sulfonates, 5) nitroso-binding.
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1) disulfide exchange, (5 compounds) 2) disulfide formation, (5 compounds) 3) O-heterocyclic ring opening, (5 compounds) 4) N-sub of alkyl sulfates, (3 compounds) 5) N-sub of alkyl sulfonates, (3 compounds) 6) nitroso-binding (3 compounds). All demonstrate GSH reactivity and
are related to sensitization
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less relevant
1) arycarboxylate aminolysis,2) electrostatic interactions,3) mercury thiolate formation,4) oxime group condensation,5) others.
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Applies computational methods to filling data gaps
By facilitating the selection of chemical analogues and grouping chemicals into categories
Integrates (among other things) mechanisms of action with categories
Among the best characterized method, which integrates mechanisms of action into grouping chemicals is the profiler bases on Protein-binding.
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Currently covers 38 different mechanismVary in specificityVary in completenessStructural Alerts for mechanisms tend to be
qualitative in nature Michael addition alerts include the extreme
sensitizer p=benzoquinone, the moderate sensitizer ethyl acrylate, and the very weak sensitizer methyl methacrylate.
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Extremely fast: quinones, propiolates , 1-alken-3-ones
Fast: acrylates, 2-alkenals, 3-alken-2-ones
Moderately Fast: alkyl 2-alkynoates
Slow: tiglates
Very Slow: methacryates
Non-Reactive: non-,-unsaturated
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≈ 1500 substances on the List of Flavor and Fragrance Related Substances
≈1300 discrete substances of which: 79 Fast- to moderate-reacting Michael-acceptors; 19 Slow-reacting Michael-acceptors; 57 Schiff-base aldehydes; 29 Acetals; 15 Disulfide formers; 11 Cyclic addition diones; 9 Disulfide exchangers; 3 O-heterocyclic ring openers.
>40 pro-electrophiles
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Thank you.