# Overview of Risk Assessment U nder TSCA - Tala Henry Ph.D. Director Risk Assessment Division Office of Pollution Prevention & Toxics 1

# O UTLINE • Introduction: Assessment Paradigm under TSCA • TSCA Work Plan Chemicals Assessments • OPPT’s Risk Assessment Process • More Information TSCA Work Plan Chemicals | 2

# Risk Assessment Paradigm under TSCA

3

# R ISK 

# ASSESSMENT 

# P ARADIGM UNDER 

# TSCA Under TSCA, OPPT evaluates and regulates, as appropriate, the full life cycle, i.e., manufacture (import), distribution in commerce, use and disposal, of industrial chemicals

− Safety Evaluation for a Wide Array of Industrial Chemicals:

− Existing and New Industrial Chemicals

− Data Availability/Quality Varies, but generally limited/incomplete

− New Risk Assessment/Management Challenges Continually Arise as New Chemistries and New Uses Emerge 45 

### Food Additives, Drugs & Cosmetics ~2,000 AI Federal Food, Drug, and Cosmetic Act By OPP & FDA FFDCA requires experimental data 

## Industrial Chemicals ~ 84,000 Chemicals Regulated under Toxic Substances Control Act (TSCA) By Office of Pollution, Prevention, and Toxics (OPPT)  New Chemical Submissions do not require “ new” data  NO mandate to assess existing chemicals 

# Assessment Paradigm: How is TSCA Different? U.S. Chemical Universe 

## Pesticides ~2000 Chemicals (Active Ingredients) Reviewed and Regulated under FIFRA By Office of Pesticides (OPP)

FIFRA requires experimental data6 

# DATA FOR 

# ASSESSMENT UNDER 

# TSCA • New Chemicals

− Computational approaches used extensively • QSAR and Expert Systems • Read -Across from Analogs/Categories



### − Tiered -Testing Approach: requests for higher tiered testing contingent on screening results • Existing Chemicals

− Established Test Guidelines; most testing for toxicity is in vivo

− Read -Across from Analogs/Categories used extensively in screening programs (e.g., HPV)

− Categories/Clusters used some in TSCA Work Plan Assessments 6

# Existing Chemicals Assessment under TSCA: TSCA Work Plan

7| 8

# TSCA W ORK 

# P LAN • Criteria for Selecting Chemicals for Assessment

− Hazard • Potentially of concern to children’s health (reproductive or developmental effects) • Neurotoxic effects • Probable or known carcinogens • Aquatic toxicity

− Exposure • Used in products to which children might be exposed • Detected in biomonitoring • Data reported to Toxic Release Inventory & under Chemical Data Reporting Rule

− Persistence & Bioaccumulation | 9

# TSCA W ORK 

# P LAN

Sum of Hazard, Exposure and

P/B scores 7 to 9: High (Work Plan)

4 to 6: Moderate 1 to 3: Low 

## • Work Plan published with methodology in 2012 • Work Plan scores updated in 2014 • Of the 345 chemicals, 90 currently scored high and are considered Work Plan chemicals https://www.epa.gov/assessing - and- managing - chemicals - undertsca/tsca - work-plan - chemicals | 10

# TSCA W ORK 

# P LAN 

# : ASSESSMENTS Assessing Chemicals for Safety Work Plan Chemicals Risk Action (Voluntary, Regulatory) 

## No Risk No Action https://www.epa.gov/assessing - and- managing - chemicals - undertsca/tsca - work-plan - chemicals | 11https://www.epa.gov/assessing - and- managing - chemicals - under- tsca/assessments - tsca - work-plan - chemicals 12

### • Five Final Risk Assessments

− Three final assessments indicated risks • Trichloroethylene (TCE) – degreaser, spray fixative, stain remover • Methylene Chloride (MC) or Dichloromethane – paint remover • NMP – paint remover

− Two final assessments did not indicate risks • 1,3,4,6,7,8 - Hexahydro - 4,6,6,7,8,8, - hexamethylcyclopenta - [ γ] - 2 - benzopyran (HHCB) – fragrance in products • Antimony Trioxide (ATO) – synergist in halogenated flame retardants 

### • Risk reduction actions, both voluntary and regulatory, are underway for TCE, MC and NMP 

# Completed Assessments 

# TSCA WORK 

# P LAN 

# : ASSESSMENTS

| 13

# Trichloroethylene (TCE) EPA identified risks associated with commercial and consumer uses of TCE in vapor and aerosol degreasers, and with use as a spotting agent in dry cleaning

− Acute exposure can affect developing fetus; high acute exposure can irritate the respiratory system and skin, and induce central nervous system effects

− Chronic exposure is associated with adverse effects in liver, kidneys, immune system, reproductive system, and developing fetuses. Also carcinogenic in humans
14 https:// www.epa.gov/assessing - and- managing - chemicals - undertsca/tsca - work-plan - chemical- risk- assessment 

# TSCA WORK 

# P LAN 

# : ASSESSMENTS

# NMP and Methylene Chloride EPA identified risks associated with commercial and consumer paint and varnish remover uses

− NMP - Developmental toxicity effects including low birthweight, growth retardation and fetal death are associated with certain uses

− Methylene chloride - A volatile organic compound that has acute effects including confusion, incapacitation and death. Also classified as a likely human carcinogen
15 https:// www.epa.gov/assessing - and- managing - chemicals - under- tsca/tsca - work-plan - chemicalrisk- assessment- n - 0 https://www.epa.gov/assessing - and - managing - chemicals - under -tsca/tsca - work- plan - chemical risk- assessment - methylene 

# TSCA WORK 

# P LAN 

# : ASSESSMENTS

# DRAFT Risk Assessment for Work Plan Chemical: 1 - Bromopropane • released for public comment & peer review March 2016 • Occupational uses in spray adhesives, dry- cleaning & degreasing operations • Occupational and Consumers • Effects on human health only • https://www.epa.gov/assessing - and - managing - chemicals - undertsca/tsca - work - plan - chemical - risk - assessment - peer - review • Public Comments accepted until May 8, 2016 @ EPA Docket: EPA HQ- OPPT- 2015 - 0084 • Public Comments accepted until May 10 @ EPA Docket : EPA - HQOPPT- 2015 - 0805 or by submission to Designated Federal Official 

# TSCA WORK 

# P LAN 

# : ASSESSMENTS

| 16

## Completed Work Plan Chemical Problem Formulation & Initial Assessments • 1,4 - Dioxane

− Problem formulation on uses as a solvent & effects on human health 

### • Flame Retardants

− Brominated Phthalates Cluster (TBB & TBPH) • Data Needs Assessment: polyurethane foams

− Tetrabromo Bisphenol A Cluster (TBBPA) • Problem Formulation: plastics/printed circuit boards for electronics

− Cyclic Aliphatic Bromides Cluster (HBCD) • Problem Formulation: extruded and expanded polystyrene foam and polystyrene products

− Chlorinated Phosphate Esters Cluster (TCEP) • Problem Formulation: furniture foams and textiles 

# TSCA WORK 

# P LAN 

# : ASSESSMENTS

https://www.epa.gov/assessing - and - managing - chemicals - undertsca/assessments -tsca - work- plan - chemicals | 17

## • Problem Formulation & Initial Assessments in FY16 - 17

− Pigments

− Chlorinated Solvents • 1,1 - Dichloroethane • 1,2 - Dichloroethane • 1,2 - Dichloropropane • Trans - 1,2 - Dichloroethylene • 1,1,2 -Trichloroethane • Carbon Tetrachloride • Tetrachloroethylene (PERC) 

# TSCA WORK 

# P LAN 

# : ASSESSMENTS

| 18

# OPPT’s Risk Assessment Process

1920

## S COPING OF 

## DATA 

## & I NFORMATION FOR 

## R ISK 

## ASSESSMENT 

### • Gather , review and organize data and information on chemical uses, exposure: frequency, duration, & magnitude, ecological and health hazard data to be

− Sources: Manufacture/Import and Uses

− Exposure Pathways and Receptors

− Hazard Data: Hazard Values, Dose - Response 

# Hazard | 21

# N OT 

# A LL 

# ASSESSMENTS 

# A RE 

# C REATED 

# E QUAL • “Fit for Purpose” • Manufacture, Process & Uses Assessed • Chemical - Specific Uses define:

− Exposure Pathways/Routes • Air, Water, Sediment, Soil, Fish • Inhalation, Oral, Dermal

− Receptors/Populations • Occupational • General population • Consumer exposures • Environment/Ecological 

### • Only Existing/Available Data are used • Problem Formulation is critical first step | 22• 1983: NAS “Red Book*” frame the Risk Assessment Paradigm:

– Risk Assessment = Haz ID + Dose - Response and Exposure Assessment • 1992/1998: EPA’s Guidelines for Ecological Risk Assessment explicitly incorporated Problem Formulation into the Risk Assessment Paradigm

– 1992 : Framework

– 1998: Final Publication • 2011 : NRC “Silver Book” recognized/affirmed the Importance of Problem Formulation and recommended to be integrated into Human Health risk Assessment paradigm in 2011 • 2014: EPA Incorporated into Framework for Human Health Risk Assessment 

# P ROBLEM FORMULATION

23

# P ROBLEM 

# F ORMULATION Problem Formulation • EPA uses problem formulation to determine the extent to which data and tools are available to support the analysis • Outcomes of Problem Formulation:

− Conceptual Model – including a visual representation and written description of actual or predicted relationships between chemicals and human or wildlife, and

− Analysis Plan – describing the intentions regarding the technical aspects of the risk assessment | 24Planning (Risk Assessor/

Risk Manager Dialogue) PROBLEM FORMULATION Integrate Available Information Source and

Exposure Characteristics Populations Potentially at Risk Effects Assessment

Endpoints Conceptual Model Analysis Plan ANALYSIS PROBLEM FORMULATION ANALYSIS RISK CHARACTERIZATIONAs Necessary: AcquireData, Iterate Process,Monitor Results

2526Example of a Generalized Conceptual Model With Examples of Possible Dimensions and Linkages

27Combined Commercial and Residential Uses of HHCB*

Wastewater Treatment Plant HHCB in Surface Water • Streams at Outfall Sites • Lakes • Estuaries, Marine HHCB in Sediment

HHCB in Biosolids for Land Application HHCB in Soil HHCB in Effluent
HHCB in Sludge Soil Toxicity • Soil Invertebrates • Plants Aquatic Toxicity (acute and chronic) • Fish • Invertebrates • Plants Sediment Toxicity (chronic) • Benthic Invertebrates *Includes all fragranced products such as soaps, detergents, fabric softeners, shampoos, cosmetics, and cleaners. EXPOSURES HAZARDS 

# Conceptual Model from Problem Formulation Example from HHCB Assessment

28LEGEND • Solid lines = Pathway can be quantified • Dashed lines = Pathway out of scope, not quantified • Shaded boxes/ovals = Elements proposed for inclusion in risk assessment; exposure and toxicity can be quantified SOURCES

Consumer: Paint Strippers EXPOSURE PATHWAYS HUMAN RECEPTORS Dose EFFECTS

Consumers Inhalation , Dermal Occupational: Paint Strippers
Air/Vapor, Direct Contact Air/Vapor,

Direct Contact Workers Occupational: Coatings, Electronics, Petrochemical, Process Solvents

Agricultural Crops Food Crops Ingestion General Population Consumer: Cleaning Products Air/Vapor, Direct Contact Inhalation , Dermal
Air/Vapor,

Direct Contact Inhalation , Dermal Inhalation , Dermal Chronic Risks

Developmental Toxicity: Fetal Mortality Acute Risks Body Weight Reductions Liver/ Kidney Effects

Clinical Chemistry Neurotoxicity Developmental Toxicity: Reduced Fetal Body Weight/Mortality

Reproductive

Toxicity 

# Conceptual Model from Problem Formulation

Example from N - methylpyrrolidone Assessment 29

# Conceptual Model from Problem Formulation Example from HBCD Assessment

## OCSPP SYSTEMATIC 

## R EVIEW 

## F RAMEWORK 

## - OVERVIEW

| 31

# DATA 

# E VALUATION When determining or evaluating the strengths and limitations of toxicity, clinical and epidemiological studies, numerous criteria are considered, including but not limited to the following: • adequacy of study design (Fit - for- Purpose) • test substance identification (e.g., purity, analytical confirmation of stability and concentration), • information about test animals (e.g., species, source, sex, age/ lifestage/embryonic stage) and relevance to the endpoint(s) of interest, • number of subjects in each dose/concentration group, • dosing regimen (e.g., dose/concentration levels and controls including solvent controls), • timing and duration of exposure, and relevance to the endpoint(s) of interest, • route/type of exposure, • test conditions (e.g., husbandry, culture medium), • endpoints evaluated (e.g., schedule of observations, randomization and blinding procedures, assessment methods), • reporting (quality and completeness) | 32

# C ONSIDERATIONS FOR REVIEWING DATA QUALITY IN EPIDEMIOLOGICAL DATA Study Population - Recruitment Strategy, inclusion/exclusion criteria

- Number, time period, age/sex/other distribution, geographic area

- Participation rates (at each stage), eligibility, comparison group selection, attrition rate

- Follow up

- Comparability (exposed and non - exposed) Exposure - Specific substance measured, analytical methods

-Types of samples collected (matrix)

- Exposure groups defined, methods to assign

- Limit of detection or level of quantitation, number of samples above/below

- Exposure distribution (central tendency, range, etc)

- Potential for exposure misclassification

- Use of TWAs for occupational studies

- Empirical, estimated, or modeled exposures

-Timing of collection

-Validation of biomarkers Statistical Analysis - Power

-Appropriateness of methods used

- Reliable, consistent

-Treatment of non - detects or < LOQ

-Adjustment of variables

- Explicit presentation of results

- Significance levels clearly defined Outcome - Novel or validated assessment tools, appropriateness for study population

- Blinding

- Explicit, complete presentation of results

-Timing

- Confounding

- Concordance of text with data results in tables

- Potential bias | 33

# E XPOSURE 

# ASSESSMENT Chemical Specific Factors • Physical chemical properties

− Solubility in water (log kow)

− Volatility/vapor pressure @ 20 o C

− Melting point 

### • Environmental Fate

− 1⁄2 life in environmental media 

### • Persistence

− Abiotic and Biotic breakdown 

### • Bioconcentration and Bioaccumulation | 34

# E XPOSURE 

# ASSESSMENT Exposure Scenarios and Populations Assessed

− Occupational: manufacturing and processing; chemical specific

− General population

− Consumer exposures: use specific 

### Exposure Characterization

− Duration

− Pattern

− Route of Exposure | 35

# E XPOSURE 

# ASSESSMENT

# : F IT FOR 

# P URPOSE Fit for purpose hazard or risk?

− E mergency response guidance e.g., AEGLs

− National assessment

− Site specific assessment 

### Acute typically time weighted average (TWA)

− Occupational 8 hr TWA

− Consumer 24 h r TWA

− General population 1 - 24 h r TWA (e.g., fence line, drinking water, fish consumption)? 

### Chronic scenarios typically for occupational but may include general population and consumers

− Average daily dose

− Life -time average daily dose | 36

# E XPOSURE 

# CALCULATION 

# : ACUTE Acute exposures are estimated as follows: AC = C × ED AT where:

− AC = acute concentration (8 - hr TWA)

− C = contaminant concentration in air ( 8 - hr TWA)

− ED = exposure duration (8 - hr/day )

− AT = averaging time (8 - hr/day) | 37Average Daily C oncentration (ADC) and Lifetime Average D aily C oncentration (LADC) are used to estimate workplace exposures for non - cancer and cancer risks, respectively, as follows: ADC or LADC = C × ED × EF × WY AT where:

− ADC = average daily concentration (8 - hr TWA) used for chronic non - cancer risk calculations

− LADC = lifetime average daily concentration (8 - hr TWA) used for chronic cancer risk calculations

− C = contaminant concentration in air (8 - hr TWA)

− ED = exposure duration (8 hr/day)

− EF = exposure frequency (260 days/yr)

− WY = working years per lifetime (40 yr)

− AT = averaging time (LT × 260 days/yr × 8 hrs/day; where LT = lifetime; LT = 40 yr for non - cancer risks; LT=70 yr for cancer risks ) • Parameters adjusted for consumers and general population exposures 

# E XPOSURE 

# CALCULATIONS 

# : C HRONIC

| 38

# E XPOSURE 

# : D ESCRIPTIVE 

# M EASURES

Consumer/general population high end Occupational high end
| 39

# AGGREGATING 

# E XPOSURES

• Data permitting, OPPT strives to aggregate exposures:

− Multiple Sources/Uses: • multiple occupational use scenarios • m ultiple consumer products



## − Multiple pathways: dust is aggregate of uses; plus water ingestion and fish consumption

− Multiple routes: dermal and inhalation • Aggregate exposure assessments evaluate continued exposures to single chemical entity across multiple pathways and routes

| 40

# E FFECTS 

# ASSESSMENT

# : E XPOSURE 

# R ELEVANCE • Exposure Factors: e.g., Sex and Life - Stage Dependent • Biological Factors: Life - Stage Dependent

− Pharmacokinetic

− Pharmacodynamics • Acute Effects – Exposure Considerations

− Developmental • Reversible (e.g., hypoxia, narcosis) • Irreversible (e.g., lethality, terata ) • Latent expression

− Adult • Reversible (e.g., hypoxia, narcosis) • Irreversible (e.g., lethality) • Latent expression • Chronic Exposures – Exposure Considerations

− Cancer and non - cancer | 41

# H AZARD AND 

# D OSE 

# R ESPONSE • Choice of less than lifetime exposure studies (< 1/10 the of lifespan) for chronic health effects P oint o f D eparture ( POD )/Uncertainty Factors (UFs)= RfV

− Typical of IRIS and PPRTV assessments

− Use developmental endpoints – resulting from short durations of exposure for chronic POD. • Development of RfV’s or PODs for different durations

− EPA RfC/ RfD Guidance Document

− EPA Children's Risk A ssessment Framework | 42

# H AZARD 

# V ALUE 

# R ELEVANT 

# F OR 

# E XPOSURE 

# S CENARIO • A range of MOEs for acute and chronic risk estimates for respective exposure scenarios. • For chronic exposure scenarios: a relatively low dose and short term/sub - chronic exposure can result in long -term adverse consequences. • For acute exposure scenarios: most sensitive endpoints are often development and/or reproductive endpoints (e.g., TCE and NMP developmental toxicity).

− Supported by EPA policy.

− Science - based policy based on the presumption that a single exposure of a chemical at a critical window of development can be adverse (EPA’s 1991 Guidelines for Developmental Toxicity Risk Assessment (pg. 38) and 1996 Guidelines for Reproductive Toxicity Risk Assessment (pg. 83 )). | 43

# N ON 

# - CANCER 

# D OSE 

# - R ESPONSE 

# S UMMARY

| 44

# S CREENING 

# L EVEL 

# R ISK 

# E STIMATION Q UANTIFYING 

## N ON 

## - C ARCINOGENIC 

## H AZARD for HEALTH AND ECOLOGICAL RECEPTORS The hazard or risk quotient ( HQ/RQ) is the ratio of the exposure level at a site to the reference dose



### HEALTH HQ/RQ = Acute or Chronic Exposure (i.e., ADD/C ) Reference Value (POD/UFs) 

### ECO HQ/RQ = Acute or Chronic Exposure Concentration of Concern (NOAEL or LOAEL (POD/UFs )) • HQ/RQ values are variable, with values less than and equal to 1 generally considered indicative of acceptable hazard | 45

# R ISK 

# CALCULATION Non -

Cancer MOE compared to benchmark MOE (UF)s MMMMMM aaaaaaaaaa oooo cc cccc 

### = NN − CC HH HH HH VV aaaaaaaa (PP PP ) HH HH EEEE EE Where:

− MOE = Margin of exposure (unitless)

− Hazard value (POD) = HEC or HED (ppm )

− Risk estimate compared to Benchmark MOE (UFs) which is unacceptable risk level 

### Risk No Risk | 46

# R ISK 

# CALCULATION Cancer RR RR = HH HH EEEE EE × IIII Where:

− Risk = Cancer risk (unitless)

− Human exposure = Exposure estimate (LADC in ppm) from occupational exposure assessment

− IUR = Inhalation unit risk ( a x 10 -x per ppm)

| 47

# Assessing Chemicals for Safety Work Plan Chemicals Risk Action (Voluntary, Regulatory) 

## No Risk No Action 

# Risk Assessment & Reduction

| 48

# S ELECTED 

# G UIDANCE WITH 

# R ELEVANCE TO 

# WORK 

# P LAN 

# R ISK 

# ASSESSMENTS • 2014 Framework for Human Health Risk Assessment to Inform Decision Making

− 2011 Recommended Use of Body Weight 3/4 as the Default Method in Derivation of the Oral Reference Dose

− 2006 A Framework for Assessing Health Risk of Environmental Exposures to Children

− 2005 Guidelines for Carcinogen Risk Assessment -

− 2005 Supplemental Guidance for Assessing Susceptibility from Early - Life Exposure to Carcinogens

− 2002 A Review of the Reference Dose and Reference Concentration Processes

− 1998 Guidelines for Neurotoxicity Risk Assessment -

− 1996 Guidelines for Reproductive Toxicity Risk Assessment

− 1991 Guidelines for Developmental Toxicity Risk Assessment • 1992 Guidelines for Exposure Assessment

− 2011 Exposure Factors Handbook

− 2009 Guidance Document on the Development, Evaluation and Application of Environmental Models

− 2001 Summary Report of the Technical Workshop on Issues Associated with Considering Developmental Changes in Behavior and Anatomy When Assessing Exposure to Children • 1998 Guidelines for Ecological Risk Assessment • 2000 Risk Characterization Handbook • 2015 Peer Review Handbook - 4th Edition https://www.epa.gov/risk/risk - assessment - guidelines | 49

# R ESOURCES
To learn more about TSCA Work Plan Chemicals & Assessments: http://www2.epa.gov/assessing - and- managing - chemicals - undertsca/tsca - work-plan - chemicals | 50