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
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Incorporating Exposure Science into (U.S.) Regulatory ... · Systemic Acute Toxicity (LD50s) • Compare route of exposure: oral vs. dermal • Acute Dermal Pesticide Formulation
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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)
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.”