Advancing New Approach Methodologies (NAMs) for Tobacco Harm Reduction: Synopsis from the 2021 CORESTA SSPT—NAMs Symposium
Abstract
:1. NAM-00: Introduction
2. NAM-01: U.S. Federal Efforts to Develop and Implement Alternatives to Animal Testing
2.1. Case Example: Alternatives to the Acute Toxicity “6-Pack” In Vivo Testing
2.1.1. Waiver for 6-Pack: Acute Lethality Tests
2.1.2. Opportunities: Addressing the Variability of In Vivo Data When Developing NAMS
2.1.3. Case Example: Defined Approach (DA) for Skin Sensitization
2.2. Tools for NAM-Based Computational Toxicological Assessment
3. NAM-02: Applications of Biokinetic Modeling for In Vivo to In Vitro Extrapolation in Chemical Risk Assessment
- Provide recommendations and procedures for characterizing, reporting, and evaluating PBPK models intended for regulatory decision making;
- Address challenges to developing and evaluating PBPK models for chemicals without in vivo kinetic data;
- Promote use of PBPK models in regulatory risk assessment and facilitate dialogue between model developers and users.
4. NAM-03: Inhalation Exposure Modeling for Assessment of Aerosols and Vapors
4.1. Case Example: Multiscale CFD/PBPK Modeling for Aldehydes
4.2. Case Example: Waiver of Sub Chronic 90-Day In Vivo Inhalation Study for Pesticide Reregistration
5. NAM-04: Assessing Respiratory Toxicity of Chemicals in Two Human Bronchial In Vitro Systems
- What chemical or substance? The chemical or substance to test will dictate an appropriate study design. The physicochemical properties determine how the substance is inhaled and which region of the respiratory tract will be most affected—in silico aerosol models (e.g., CFD models as discussed in NAM 03) can be helpful for identification. Whether the substance is locally metabolized will further influence the choice of cells to use. If these properties are unknown, a structurally similar compound (i.e., a read-across approach) may give some insight.
- What in vitro exposure system? When selecting the in vitro exposure systems, considerations to balance include the ease of conducting the experiment with physiological relevance in inhalation exposures. Pipetting and air–liquid interface (ALI) exposures are the two most common exposure routes to a test chemical for an in vitro system. While aerosol or gas exposure using an ALI exposure system would require specialized equipment and training, it may be more human-relevant than pipetting. No matter what exposure system is used, the robustness of the in vitro test method should be assessed to identify and account for any potential variability [72].
- Which in vitro/ex vivo test system? Various test systems exist ranging from relatively simple monocultures to more complex organotypic micro-physiological systems and precision-cut lung slices. The choice of test system depends on the goals of the study. Table 2 highlights some advantages and disadvantages of representative test systems.
- What kinds of cells? The human respiratory tract is composed of more than 40 cell types. The cells used should be from the region(s) of the respiratory tract that is most affected by the test chemical (in silico model predictions should help with the identification of the area). However, while there are a wide range of cells from the proximal respiratory tract available (cell lines and primary cells), the choice for distal respiratory tract cells is currently more limited.
- What endpoints/readouts? Assay endpoint and readouts selections will depend on the properties of the chemical as well as the goal of the study. Using AOPs can be helpful in linking assay readouts to the steps (key events) along the pathway and identifying adverse outcomes of interest.
Case Example: Silanes in 2D Monoculture and 3D Human Tissue Models
6. NAM-05: In Silico Toxicology as a New Approach Method in Tobacco Regulatory Science
7. NAM-06: Applications of Mechanistic Data in Risk Assessment: Exposure Alignment and Evidence Integration
7.1. Case Example: Assessing New Chemical Substances for TSCA Using an AOP-Inspired IATA
7.2. Additional Considerations in the Use of NAMs
8. Panel Discussion and Closing Remarks
- Expanded use of NAMs in toxicological assessment applications requires a shift in paradigm from screening and hazard identification to hazard characterization and, ultimately, quantitative risk assessments for regulatory applications and with that a shift from the apical in vivo endpoints to mechanistic NAM-based endpoints. This means changing the question, for example, from testing that seeks an “in vivo no effect level” to one generating a “POD for a mechanistic cellular event that leads to adverse outcomes”.
- In vitro testing needs to be designed considering a variety of factors including properties of the test substance, test system, and the desired endpoints under the intended use. There is likely more than one set of NAM assay data to answer toxicological questions typically addressed by in vivo testing. Computational kinetic models allow for extrapolation of dosimetry data across test systems to provide human relevance and simulate different exposure scenarios for qualitative and quantitative exposure and risk assessment.
- IATAs provide a structure to combine mechanistic information and data from different NAMs in a weight of evidence-based toxicological assessment.
- To fully recognize the potential of NAMs for risk assessment, criteria for establishing confidence in fit for purpose, reliable, and relevant NAMs are necessary. For example, in vitro inhalation testing is not yet standardized for longer-term exposures. Addressing these deficiencies will help new methods’ scientific confidence and traction.
- For tobacco products, including novel smoke-free products, there are increasing human data available from volunteers from clinical trials or consumers in addition to historical epidemiological data from cigarettes. This availability of human data is unique and can help substantially in gaining scientific confidence in an application of NAMs for PRR products and for enhancing tobacco regulatory sciences.
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
Abbreviations
ADME | Absorptions, distribution, metabolism, and elimination |
AEP | Aggregate exposure pathway |
AOP | Adverse outcome pathway |
BMD | Benchmark dose |
CFD | Computational fluid dynamics |
CFPD | Computational fluid particle dynamics |
CORESTA | Cooperation Centre for Scientific Research Relative to Tobacco |
DA | Defined approach |
ENDS | Electronic nicotine delivery system |
GRAS | Generally recognized as safe |
HEC | Human equivalent concentration |
IATA | Integrated approaches to testing and assessment |
IVIVE | In vitro to in vivo extrapolation |
KE | Key event |
LADD | Lifetime average daily dose |
LD/LC50 | Lethal dose/concentration at 50% |
NAMs | New approach methodologies |
NGO | Non-governmental organization |
NOAEL | No observable adverse effect level |
PBPK | Physiologically based pharmacokinetic |
PSLT | Poorly soluble low toxicity |
QRA | Quantitative risk assessment |
SME | Subject matter expert |
SSPT | Smoke-Science and Product Technology |
TSE | Target site exposure |
TSCA | Toxic Substances Control Act |
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Speaker | Title |
---|---|
NAM-00: K Monica Lee, Altria; S Bell, ILS | Advancing New Alternative Methods for Tobacco Harm Reduction: Introduction |
NAM-01: Nicole Kleinstreuer, U.S. NIEHS | U.S. Federal Efforts to Develop and Implement Alternatives to Animal Testing |
NAM-02: Alicia Paini and Andrew Worth, EC JRC 1 | Application of Biokinetic Modeling for IVIVE in Chemical Risk Assessment |
NAM-03: Richard Corley, GCTC LLC | Inhalation Exposure Modeling for Assessing Health Risks of Toxic Aerosols and Vapors |
NAM-04: Andreas O. Stucki, PETA Science Consortium International | Assessing Respiratory Toxicity of Chemicals in Two Human Bronchial In Vitro Systems |
NAM-05: Luis Valerio Jr., U.S. FDA/CTP | In Silico Toxicology as a New Approach Methodology in Tobacco Regulatory Science |
NAM-06: Annie Jarabek, U.S. EPA | Application of Mechanistic Data in Risk Assessment: Exposure Alignment and Evidence Integration |
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Precision cut lung slices |
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Lee, K.M.; Corley, R.; Jarabek, A.M.; Kleinstreuer, N.; Paini, A.; Stucki, A.O.; Bell, S. Advancing New Approach Methodologies (NAMs) for Tobacco Harm Reduction: Synopsis from the 2021 CORESTA SSPT—NAMs Symposium. Toxics 2022, 10, 760. https://doi.org/10.3390/toxics10120760
Lee KM, Corley R, Jarabek AM, Kleinstreuer N, Paini A, Stucki AO, Bell S. Advancing New Approach Methodologies (NAMs) for Tobacco Harm Reduction: Synopsis from the 2021 CORESTA SSPT—NAMs Symposium. Toxics. 2022; 10(12):760. https://doi.org/10.3390/toxics10120760
Chicago/Turabian StyleLee, Kyeonghee Monica, Richard Corley, Annie M. Jarabek, Nicole Kleinstreuer, Alicia Paini, Andreas O. Stucki, and Shannon Bell. 2022. "Advancing New Approach Methodologies (NAMs) for Tobacco Harm Reduction: Synopsis from the 2021 CORESTA SSPT—NAMs Symposium" Toxics 10, no. 12: 760. https://doi.org/10.3390/toxics10120760