Incorporating Exposure Science into

(U.S.) Regulatory Decision Making

Nicole Kleinstreuer, Ph.D.

Deputy Director, NICEATM

NC3Rs/Unilever Workshop

February 16, 2017

Agency for Toxic Substances and Disease Registry • Consumer Product Safety Commission • Department of Agriculture

Department of Defense • Department of Energy • Department of the Interior • Department of Transportation Environmental

Protection Agency • Food and Drug Administration • National Institute for Occupational Safety and Health National

Institutes of Health • National Cancer Institute • National Institute of Environmental Health Sciences National Library of Medicine • Occupational Safety and Health Administration

1

National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM), organized as an office under the NTP Division, part of NIEHS

ICCVAM Agency Activities: Examples of Exposure Science in

Regulation and Research

• EPA OPP (HED)

• FDA CFSAN (TDS)

• CPSC (FRs)

• EPA OPP (LD50s)

• EPA ORD/EDSP (IBER)

• NICEATM ICE (IVIVE)

The Health Effects Division

• Responsible for reviewing and validating data on effects of pesticides, as well as characterizing and assessing exposure and risks to humans

• Assess new pesticide uses, new pesticides,

and reevaluation of existing uses (e.g., registration review)

EPA/OPP:

• Mosquitocide

• Home Lawn

• Food use

Assessment Process -- Examples

Basic Assessment Process

• Define the exposure scenario(s)

– Dietary

– Residential

– Occupational

• Population of concern: who may be potentially exposed?

• Route of exposure: how are they going to be exposed?

• Exposure Duration: how long might they be exposed?

Exposure Scenarios

Type of Exposure Scenarios

Dietary Food + Water

Residential (non-dietary)

Handler: Homeowner that mixes/loads/applies

pesticide

Post-application: reentry after application (e.g., playing on

treated lawn, playing on treated floor,

playing with treated pet)

Occupational

Handler:

Professional that mixes/loads/applies

pesticide (agricultural or commercial)

Post-application: reentry after application (e.g., pickers,

thinners)

Human-Health Risk Assessment

• NAS (National Academy of Sciences) four-step risk assessment process†

• Takes into consideration the toxicity of a chemical, the exposure to that chemical, and any uncertainty factors (UF)

Risk = Toxicity * Exposure (*UF)

† From the National Research Council’s Risk Assessment in the Federal Government: Managing the Process, 1983.

Residential (Dietary and Non-Dietary) And Occupational

Hazard Identification

Dose-Response Assessment

Exposure Assessment

Risk Characterization

Toxicokinetic Data

• TK data support smarter testing strategies

• By better understanding TK properties, EPA can tailor required toxicity data for a particular pesticide or group.

• Many potential uses:

– Dose selection: avoid excessively toxic doses & characterization of doses closer to human exposures

– Lifestage sensitivity: Characterization of how metabolism & tissue

dosimetry differs/changes among lifestages

– Incorporation in MOA/AOP evaluation

– Animal to human extrapolation (PBPK models, Derivation of Data Derived Extrapolation Factors)

– Refinement of data requirements

– Read across approaches

FDA/CFSAN

Total Diet Studies (TDS) • Major objectives:

• Measure levels of substances (e.g. nutrients, contaminants) in major dietary components

• Estimate total dietary intakes of these substances (using food consumption data)

• Estimate total dietary exposure and contributions from each TDS food

• Track changes in exposure over time

• Provide information for prioritizing risks and targeting resources of other FDA monitoring/compliance programs

FDA’s TDS

Conducted continuously since 1961; initiated due to concern about radioactive fallout.

Current study design:

280 foods & beverages

4 regional sample collections “market baskets” per year (West, North Central, South, North East)

Foods analyzed for ~ 800 analytes

(pesticide residues, industrial contaminants, toxic & nutrient elements)

Design currently being evaluated as part of TDS modernization program

FDA’s TDS: Elements and Years of Analysis

Toxic Elements

19

62

19

70

19

80

19

90

20

00

20

14

20

15

20

16

Arsenic

Cadmium

Chromium

Lead

Mercury

Nickel

Element analyzed in TDS foods

Analyzed in TDS foods and speciated in juice samples above 10 ppb total arsenic

FDA’s TDS: Elements and Years of Analysis

Nutrient Elements

19

66

19

70

19

80

19

90

20

00

20

10

20

14

2

01

5

20

16

Calcium

Copper

Iodine

Iron

Magnesium

Manganese

Phosphorus

Potassium

Selenium

Sodium

Zinc

Element analyzed in TDS foods

Element analyzed in bottled drinking water only

Sources of food consumption data

Most recent published TDS exposure estimates: • USDA 1994-96, 1998 Continuing Survey of Food Intakes by

Individuals (CSFII).

Current food consumption data: • What We Eat In America (WWEIA), the food consumption

portion of the National Health and Examination Survey

(NHANES) - 1999 to present.

• Two year cycles; most current data are from 2011-2012

• About 8000 dietary respondents per cycle

• Per capita or per consumer intake of foods/food

constituents

Dietary Exposure

Exposure to Food Constituent =

(Concentration in each food consumed * Consumption)

Regulatory action based on margin between

exposure and acceptable daily intake

U.S. Consumer Product Safety

Commission

• Independent regulatory agency (1973)

• Products in and around the home

• Includes child-resistant packaging for household chemicals, drugs, & cosmetics

• Generally, food, drugs, cosmetics, medical devices, pesticides, automobiles not included

Federal Hazardous Substances Act (FHSA)

• Risk-based

– Considers toxicity, exposure, and bioavailability

– Includes acute and chronic effects

• Does not require specific testing for chronic hazards

• No pre-market approval

– Consumer Product Safety Improvement Act (CPSIA) requires 3rd party certification for children’s products

• Requires manufacturers to ensure that their products either are not hazardous or are properly labeled

– Children’s products that are hazardous are banned

Chronic Hazards in Consumer Products

• Asbestos - plaster patch, artificial embers

• Arsenic - Playground equipment made with pressure-treated lumber

• Formaldehyde - urea-formaldehyde foam insulation, pressed wood products

• Flame retardants - children’s sleepwear, upholstered furniture, mattresses

• Methylene chloride - paint strippers

• Phthalates - children’s products

Schematic for Migration Tests

l nteragency Coordinating Committee on the Validati on of Alternative Methods

Exposure Assumptions

• Lifetime exposure (75 years)

• 3-Piece suite of furniture

• Particles released over 15 years

• 4 (0.5—16) hours/day adult exposure

• Wearing short sleeves & short pants

• Hand-to-mouth (adults & children)

• Mouthing for small children

• Two-zone mass-balance model

– Breathing zone plus living/family room

Estimated Exposure to Adults a

TDCP TPP b PIP b TBB/TBPH

ADD (µg/kg-d) 9.5 1.8 0.18 0.20

Percent from:

Dermal 1.7 3.6 35.3 2.9

Oral 0.5 0.9 8.5 7.7

Inhalation, vapor 97.7 95.6 56.2 89.4

Inhalation, particles <0.1 <0.1 <0.1 <0.1

ADI (µg/kg-d) 5 ND c ND c ND

Cancer risk / million 300 NA NA NA

a ADD, average daily dose; ADI, acceptable daily intake; ND, not determined; NA, not applicable.

b Dermal, oral, and inhaled particle exposures are based on data for TBB/TBPH. c Related compounds have ADI’s from 10 to 1,000 µg/kg-d.

Estimated Exposure to Children 3 Years Old a

TDCP TPP b PIP b TBB/TBPH

ADD (µg/kg-d) 26 4.8 0.4 0.55

Percent from:

Dermal 0.7 1.4 17.4 1.1

Oral 0.6 1.0 12.4 9.1

Inhalation, vapor 98.7 97.5 70.1 89.8

Inhalation, particles <0.1 <0.1 <0.1 <0.1

ADI (µg/kg-d) 5 ND c ND c ND

a ADD, average daily dose; ADI, acceptable daily intake; ND, not determined; NA, not applicable.

b Dermal, oral, and inhaled particle exposures are based on data for TBB/TBPH. c Related compounds have ADI’s from 10 to 1,000 µg/kg-d.

Conclusions—Upholstered Furniture

• Triaryl phosphates nominated to NTP

– Testing underway

• Need additional exposure data

– Vapor phase exposure

• Proposed upholstered furniture standard

– Performance standard

– Does not require FR-treated fabrics or foam

– Inherently flame resistant interior barriers can be used

EPA/OPP: Acute Toxicity

Excerpt for Letter to Stakeholders on OPP’s Goal to Reduce Animal Testing:

“OPP's immediate goal is to significantly reduce the use of animals in acute effects testing (the "6-pack" studies). Over 50 animals are used for a complete set of 6-pack studies. Annually, we receive over 500 acute toxicity 6-pack submissions.”

25 https://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPP-2016-0093-0003

Systemic Acute Toxicity (LD50s)

• Compare route of exposure: oral vs. dermal

• Acute Dermal Pesticide Formulation Toxicity Testing

– Collaboration between EPA & NICEATM

– Analyze the relative contribution of data from acute oral and dermal toxicity tests to pesticide hazard classification and labelling

– Collected acute lethality dermal and oral toxicity data from rat

studies on pesticide formulations

• Dataset ~600 different formulations across >200 active ingredients.

• >99% of cases: Oral LD50 < Dermal LD50

https://www.epa.gov/pesticides/new-epa-guidance-testing-pesticides-will-reduce-animal-testing

Draft for Public Comment March 11, 2016

Retrospective Analysis & Guidance for Waiving Acute Dermal

Toxicity Tests for Pesticide Formulations

28

Submitted Acute 6-Pack Studies

Guideline 2012 2013 2014 2015

Acute oral 870.1100 324 248 328 268

Acute dermal 870.1200 292 257 313 255

Acute inhalation

870.1300 264 217 248 254

Eye irritation 870.2400 291 261 273 251

Skin irritation 870.2500 270 254 268 258

Skin sensitization

870.2600 247 237 262 267

Tox21/ToxCast HTS

Tox21: Examining ~10,000 chemicals using ~60 assays intended to identify interactions with biological pathways (Tice et al. EHP 2013)

EPA Toxicity

Forecaster

(ToxCast):

For a subset

(~3000) of Tox21

chemicals run

~1000 additional

assay endpoints

(Kavlock et al. CRT 2012)

High-Throughput Bioactivity

▪ Most assays conducted in dose-response format (identify 50% activity concentration – AC50 – and efficacy, described by a Hill function)

▪ All data is public: http://actor.epa.gov/dashboard2/

▪ New datasets being added continuously

▪ Uncertainty included via R package: toxboot (CRAN)

Assay AC50

with Uncertainty

Concentration (M)

In vitro Assay AC50

Concentration

Re

spo

nse

IBER – Integrated Bioactivity Exposure

Ranking

Wetmore et al. Tox Sci 2015

Wambaugh et al. ES&T 2014

IBER in Practice: EDSP Estrogenic Activity

ToxCast Chemicals

ToxCast-derived

ER Bioactivity

Converted to

mg/kg/day with

HTTK

ExpoCast Exposure Predictions

Near Field Far Field

EPA EDSP: December, 2014 SAP:

“Scientific Issues Associated with Integrated Endocrine Bioactivity and Exposure-

Based Prioritization and Screening“

Exposure Data/Predictions: https://comptox.epa.gov/

NICEATM web resource

ICE: Coming March 2017…….

Bell at al. 2017 EHP doi: 10.1289/EHP1759

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Chang et al 2017 submitted

Range of Injection doses (mg/kg/day) estimated from in vitro HTS assays compared to range of in vivo uterotrophic injection LELs (mg/kg/day)

ICE Functionality

Acknowledgments

• EPA/OCSPP/OPP: Anna Lowit, Kelly Lowe

• FDA/CFSAN: Suzy Fitzpatrick, Judith Spungen

• CPSC: Joanna Matheson, Michael Babich

• EPA/ORD/NCCT: John Wambaugh

• EPA/ORD/NERL: Barbara Wetmore

• NTP/NICEATM

• ILS/NICEATM (Xiaoqing Chang)

• Sciome

• ICCVAM

Questions?