Dow's Predictive Toxicology Program and the LCSA
Sue Marty, PhD, DABT TERC Science Director August 16, 2017
ED 002061 00042950-00001
Agenda
An Introduction to TERC - W hy does Dow need a Predictive Toxicology Program? Dow's Predictive Tox Program - Five Science Pillars TSCA/LCSA - An Integrated Approach - Opportunities to Partner?
TE RC- loxicology and Environmental Research and Consulting
A Toxicology testing and consulting expertise center within Dow An industry leader in applying the best science and technology to:
^Support sustainable product development (guide decision making) ^Support product registrations to speed time to market ^Address complex product safety questions
Mdian
Seneffe. Belgium
Horg-'n Switres !,3hd
Shanghai. Beijing and Taipei
6.
Health Canada
Protecting human health and the environment
Mumbai, india
-200 people globally * Full-service Toxicology Lab in Midland Michigan Expert Internal Toxicology Consultants- Globally
> 70 advanced degrees in Toxicology or related disciplines (Ph.D, M.Sc., DVM, DABT) World Class Expertise in Traditional and 21st Century Toxicology tesiingapproachps
CECHA
KUaOPEAN CH6MCAI.S ASSNCY
CM* KMCH
Ths Rt
j ..
ED 002061 00042950-00003
TERC: Complete Toxicology Support for Product Safety Assessment
ED 002061 00042950-00004
W hy Does Dow Need a Predictive Tox Program ?
PT applications in modern chem ical product safety assessm ent - Design and select more sustainable products - Tailor regulatory testing based on alerts - Save time, money and animals
Ja
Increase confidence in chemical technology (2025)
- More attention to front end = less effort defending commercialized molecules
Integrated testing strategy - Predictive approaches + conventional animal testing
ED 002061 00042950-00005
Dow's Predictive Toxicology Program
Cheminformatics Bioprofiling
Toxicokinetics Environ Chem/Tox
Exposure
m
Cheminfor
Sensitivity
Specificity Predictive Negative Value Accuracy
Nicotinic ACh Receptor 96.44% 82.35%
98.12%
86.68%
Muscarinic ACh Receptor 99.33%
50.49%
Acetvlcholinest
erase
98.91% 23.94%
98.93%
96.57%
72.49%
56.78%
Rt T h e
Form ula
ED 002061 00042950-00007
TERC Cheminformatics: Mechanisms of Acute Toxicity
Reactivity
Blood
~ Acids/bases - protein dnaturation - Non-specific protein-binding via reactivity
Metabolism to reactive protein-binder
Anticoagulation - Heme biosynthesis inhibit
Vasoactive/blood pressure
Alkylation
Histamine activation - inhibit ligand-gated Cl- channel
Radiation poisoning - DNA/tissue destruction PhysChem properties subject to precipitation
Non-specific iipid membrane disruption
m G-Protein coupled receptors
5-Hydroxytryptamine) receptor a-p Adrenergic receptor agonist
Chelation
* Mitotic spindle poison by binding tubulin
* Energy
is
Mitochondria inhibition
Phosphorylation of glucose inhibition
Hexokinase (glycolysis) inhibition
- Transketolase (glycolysis) inhibition
Inhibit pyruvate dehydrogenase (glycolysis)
is
Bcr-Abltyrosine kinase inhibition
Inhibit aconitase (TCA cycle)
Vitamin interference
GABA receptor Dopamine receptor Adenosine receptor CNS p-, d-, K-opioid receptors
Cys-loop ligand gaited ion channels
Nicotinic acetylcholine receptor GABA receptor Glycine receptor 5-HT3 (5-Hydroxytryptamine) receptor
Neuro/lon Channel Signaling
Acetylcholinesterase inhibit Voltage-gaited channels Sodium/potassium ATPase
Vit B6: Pyridoxine phosphokinase
Block synthesis of neurotransmitter glutamate
Ubiquinone analogs Folate analogs
Protein synthesis inhibit
Nucleotide synthesis inhibit
GMP synthetase inhibit - purine biosyn G6PD inhibition
Norepinephrine reuptake inhibitor NMDA receptors Ether-a-go-go (ERG) voltage-gated K+ channel
i Aryl hydrocarbon receptor Beta2-macroglobulin binding kidney Nuclear receptors; Transcription
IMP dehydrogenase inhibit - purine biosyn Adenyisuccinate synthetase inhibit - purine biosyn
factors
Adenylsuccinassyfl^bif - purine biosyn
Rt the
for-myti
ED 002061 00042950-00008
Bioprofiling: Current in vitro Capabilities
Dermal corrosion & irritation
Corrositex
EpiDerm corrosion
EpiDerm irritation
Ocular corrosion & irritation
BCOP NRR
EpiOcular
Skin sensitization
KeratinoSens
DPRA SENS-iS (2017)
Dust Gun Aerosol Generator
Phototoxicity
3T3 NRU
Respiratory irritation
EpiAirway MucilAirway
Cancer MOA
NR expression in hepatocytes
Genomics
Rt
Acute oral/dermal/inhalation
No good in vitro assays
Basal cytotoxicity Calculation method for formulations Endocrine
- ER/AR binding
ER/AR transactivation Aromatase Steroidogenesis
DART WEC
Zebrafish embryo Genomics Genetic Toxicity
RLCAT
In vitro MNT Hgprt
Oxidative stress
ROS, Mt activity, cytotoxicity
ihe Rt
ED 002061 00042950-00009
Integrated Approaches to Testing and Assessment: Sensitization
1 silicei methods
Sufficient information::
i-$ensitizer
information:
Insufficient information
Stop testing
sufficient rency unto
Stop testing
No Potency inf
LINA for potency
Non "sensitizer
Stop testing
KeratiiioSeris - OPRA
in consistent results
h-CLAT Non-sensitizer <WoE) Stop testing
Sensitizer in both
U N A for potency
ED 002061 00042950-00010
In Silico Toxicokinetics: GastroPlus Modeling
GastroPlus to predict:
* Systemic exposure/Bioavailability * Absorption rates, M etabolic clearance, Plasma protein binding and
Tissue distribution Parent compound and m etabolite(s) In vitro-to-in vivo extrapolations (IV IV E) Support for multiple exposure routes (oral, inhalation, dermal) Supports various species (hum an, rat) and life stages
ED 002061 00042950-00011
Environmental Chemistry and Toxicology
Predictions of the persistence and environmental fate of chemicals in the environm ent as well as their effects on taxa in the environment
(e.g., Biodegradation, persistence fate, bioconcentration factor, acute/aquatic toxicity)
Exposure: HEAT Model
Using in silico models as a high-throughput approach to predict human
exposures to environmental chemicals, particularly consumer products.
Application: HEAT Case Study with Cleaning Solvent
35
Aggregate exposure to one chemical Solvent use in household cleaners; 3 exposure routes Ten most frequently used groups of cleaners One from each group with average percentage of chemical in formulation "Spring cleaning" scenario
10
Hand Glass cleaner Floor cleaning: Furniture Bathroom liquid cteaner Abrasive
dishwashing
liquid leather spray cleaning
powder
liquid
liquid
Detergent liquid
Carpet Spray cleaner Aggregate REACH DUEL cleaning
liquid
mi.
fhfe fe rm a li..... :...14,,
ED 002061 00042950-00014
TSCA/LCSA APPLICATIONS
ED 002061 00042950-00015
Current EPA PM N Assessment Process
With insufficient tox data, the New Chemicals Program may:
- Run the `Sustainable Futures' tools - Use read-across, possibly based on CBI (PMN)
information - Issue consent orders and SNURs
Health or environmental hazard concerns
- Often leads directly to in vivo testing - Extensive hazard characterization - limited consideration
of exposure
ED 002061 00042950-00016
A Proposed Approach to PM N s
Exposure-driven and Risk-based for reasonably foreseen uses Greater use of non-animal methods for hazard screening - EPA guidance: Incorporate alternative approaches in risk
assessment Integrated approach to evaluate `Sustainable Futures' endpoints - Take into account existing data from other jurisdictions
(ECHA, Canada, other programs)
- Use in silico methods (i.e., read-across, categories, QSAR) - Use in vitro approaches
- Margins of safety determine need for animal testing
ED 002061 00042950-00017
Hazard Identification with Exposure Consideration
Risk matrix exposure categories
1 - industrial intermediate 2 - industrial use 3 - professional use 4 - consumer use
Cat 1,2 - classify Cat 3,4 - in vivo
IVIVE 0
Yes
Yes
Rt The
forfliylii
J::S.
ED 002061 00042950-00018
Dow Proposed Process
Incorporate lATAs for Sustainable Futures endpoints
- Mutagenicity - Sensitization - Irritation - Aquatic toxicity - Biodegradation - Bioaccumulation - Others as they become available
ED 002061 00042950-00019
Exposure Assessment
industrial
Phys-Chem PPTIES (measured) - Log Kow - Vapor pressure - W ater solubility - Particle size dist'n - Others, as needed
Consumer
ED 002061 00042950-00020
Outcome Evaluation of potential RISK for intended conditions of use Determine if additional refinement is needed
(animal testing, measure exposures, etc...) Risk informs decisions, i.e., whether to support
certain applications, require engineering controls or PPE, C&L, etc...
ED 002061 00042950-00021
Next Steps:
Desire to partner with EPA
- With the program office to improve registration process - With ORD/research groups to incorporate alternative
approaches for regulatory use
Dow to submit a case study for PMN review Visit TERC Laboratory
- Coincide with ACC LRI discussions
EPA development of a strategic plan for incorporating alternative approaches
ED 002061 00042950-00022
I
2
ED 002061 00042950-00023