A Path Forward for 1,4-Dioxane: Opportunity for Increasing Remediation Goals Mark Lafranconi, PhD, DABT Principal Toxicologist ERM

Body text What’s this layout for? This slide forms the base of the majority of slides – a text box with bullets are included ready for you to type into. 1,4-Dioxane Background

•  Fate and Transport §  Water soluble §  Mobile in ground water

• Reported Health Effects (EPA 2010, 2013) §  EPA-designated as “Likely carcinogenic to humans” §  Readily absorbed when ingested or inhaled

Body text What’s this layout for? This slide forms the base of the majority of slides – a text box with bullets are included ready for you to type into. IRIS Conclusions for 1,4-Dioxane

• The EPA applied a linear, low-dose extrapolation method to assess cancer risks from ingestion of 1,4-dioxane.

• One in a million lifetime excess risk - 0.35 µg/L (ppb)

• Available data (at the time) inadequate to establish threshold Mode of Action (MOA) •  Limited evidence of early events •  Incomplete characterization of metabolism

•  Incomplete evidence that cytotoxicity preceded tumors •  Lack of evidence of proliferative response

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Low-Dose Extrapolation Assumptions used by EPA in IRIS assessment: Linear vs Threshold

Body text What’s this layout for? This slide forms the base of the majority of slides – a text box with bullets are included ready for you to type into. Mode of Action

KE 1 Initial Molecular Event

KE 2 Biochemical Response

KE 3 Cellular Response

KE 4 Organ Level Response

KE 5 Adverse Outcome

KE 1 DNA Reactivity

KE 2 Mutations

KE 3 Mutation incorporation

KE 4 Clonal expansion

KE 5 Tumor formation

KE 1 Saturable Metabolism

KE 2 Cytotoxicity

KE 3 Repair/regeneration

KE 4 Clonal expansion

KE 5 Tumor formation

Mutagenic Cytotoxic

Progress since 2013

§  Paper published in 2014

§  Cytotoxicity and proliferative lesions present in NCI study

§  Paper published in 2017

§  Toxicokinetics correlated with early key events

§  Data evaluated across all studies

Graphics What’s this layout for? Plain slide without a text box – used for inserting graphics e.g. pies, bars or images Metabolism

HEAA

CYPB1/2 and CYP2E1

Graphics What’s this layout for? Plain slide without a text box – used for inserting graphics e.g. pies, bars or images Toxicokinetics

Young et al 1978

§  Metabolism is limited (saturable)

§ 30-100 mg/kg (Rats) § 200 mg/kg (mice)

§  Metabolite (HEAA) has lower cytotoxic potential than parent

§  Metabolism enhances excretion and reduces exposure

Key Events from Rat Studies

0

100

200

300

400

500

600

Metabolism Liver Enzymes Necrosis Proliferation Tumor

LOEL (mg/kg/d)

Dourson et al. 2017

Results from NTP Mouse Study

Dourson et al, 2017

Quantitative Weight of Evidence to Assess Confidence in Potential Modes of Action (Becker et al., 2017)

Regul Toxicol Pharmacol. 86: 205-220, 2017

KE 1 Initial Molecular Event

KE 2 Biochemical Response

KE 3 Cellular Response

KE 4 Organ Level Response

KE 5 Adverse Outcome

Information on each event graded against;

1.  Essentiality 2.  Empirical support 3. Consistency 4. Analogy

Quantitative WOE Comparison

Mutagenic MOA Cytotoxic MOA

KE 1 Event – DNA Reactivity KE 1 Event – Metabolic Saturation

Confidence Score = -45 Confidence Score = +57

KE 1 Initial Molecular Event

KE 2 Biochemical Response

KE 3 Cellular Response

KE 4 Organ Level Response

KE 5 Adverse Outcome

Calculation of Risk - Threshold MOA

§  The RfD calculated from rat liver necrosis data

50 µg/kg/d

§  The corresponding Maximum Contaminant Goal 350 µg/L (ppb)

Path Forward

1.  EPA will be re-evaluating toxicity of 1,4-dioxane as part of the TSCA Priority Chemicals process

2.  State water authorities are revisiting water quality standards for 1,4-dioxane

3.  Publish findings and analysis as they develop

4.  Participate in discussions as opportunities arise