Identification, prioritization and conduct of applied research and analyses impacting policy development
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The document outlines the National Toxicology Program's (NTP) approaches and methodologies for evaluating public health hazards, emphasizing the process of identifying and analyzing toxic substances impacting policy development. It includes case studies, such as chromium VI and bisphenol-A, and highlights new testing methods and research approaches like Tox21 and the response to chemical spills. The NTP aims to enhance toxicological understanding and inform regulatory decision-making through a collaborative framework involving various stakeholders.
![Proposed NTP Studies
Studies
Test Article [Abbreviation, CAS Number]
RatPrenatalToxicity
MouseDermalIrritationand
Hypersensitivity
5-DayRatToxicogenomic
BacterialMutagenicity
ZebrafishDevelopmental
NematodeToxicity
HighThroughputScreening
StructureActivity
Relationship(SAR)Analysis
4-Methylcyclohexanemethanol [MCHM, 34885-03-5] X X X X X X X X
Dipropylene glycol phenyl ether [DiPPH, 51730-94-0] X X X X X
Propylene glycol phenyl ether [PPH, 770-35-4] X X X X X X
1,4-Cyclohexanedimethanol (CHDM; 105-08-8) X X X X X
2-Methylcyclohexanemethanol [2MCHM, 2105-40-0] X X X X
4-(Methoxymethyl)cyclohexanemethanol [MMCHM, 98955-27-2] X X X X
4-Methylcyclohexanecarboxylic acid [4331-54-8] X X X
Cyclohexanemethanol, 4-[(ethenyloxy)methyl]- [114651-37-5] X X X X
Cyclohexanemethanol, alpha,alpha,4-trimethyl- [498-81-7] X X X
Dimethyl 1,4-cyclohexanedicarboxylate [DMCHDC, 94-60-0] X X X X X
Methyl 4-methylcyclohexanecarboxylate [MMCHC, 51181-40-9] X X X X
Phenoxyisopropanol [4169-04-4] X X X X
Technical product [“crude MCHM”] X X X X X](https://image.slidesharecdn.com/1601143walker-161012150120/85/Identification-prioritization-and-conduct-of-applied-research-and-analyses-impacting-policy-development-34-320.jpg)
Identification, prioritization and conduct of applied research and analyses impacting policy development
- 1. Identification, prioritization and conduct of applied research and analyses impacting policy development: lessons learned from the U.S. National Toxicology Program (NTP) Nigel Walker, PhD, DABT National Institute of Environmental Health Sciences (NIEHS) National Institutes of Health, North Carolina, USA EFSA Scientific Conference Milan, 14-16 October 2015
- 2. Outline • Overview of the National Toxicology Program – Scientific approach – Operational approach • Case examples of NTP projects – Chromium VI – Bisphenol-A • New approaches • Tox 21 • Elk River Spill • Reflections
- 3. “Evaluate agents of public health concern by developing and applying tools of modern toxicology and molecular biology.”
- 4. Safety = lack of risk Risk = hazard x exposure • Exposure assessment • Hazard identification • Hazard characterisation • Dose-response
- 5. NTP Approaches • Hazard Characterization (“Testing Program”) – Carcinogenicity and toxicity and evaluations – Primarily via in vivo GLP-studies • New testing methods development and approaches – Quantitative high throughput screening/in vitro testing (Tox21) – Non-mammalian systems – Validation of alternative models (NICEATM/ICCVAM) • Toxicology/Pathology Research – Molecular pathogenesis, informatics, genetics variability, cancer stem cells, • Human health Hazard Assessments (literature-based analyses) – Report on Carcinogens (RoC) – Non-cancer Health Assessments (OHAT) and systematic reviews • Exposure assessments – Via interagency agreements
- 6. Food safety related areas of emphasis for the NTP • Botanicals and Dietary supplements • Endocrine active compounds • Flame retardants • Food derived carcinogens • Dinking water contaminants • Mixtures/Combined exposures • Nanoscale materials • Occupational exposures • Polycyclic aromatic compounds • Persistent environmental contaminants • Personal care products • Radiofrequency radiation • Sunscreen constituents
- 7. Operational framework Problems Solutions Needs Capabilities Nominations Hypotheses Ideas etc Concepts Strategies Study designs Endpoints Assays Procedures Contracts Core labs IAGs Services
- 8. Review Process for Nominations to NTP Nominations from: • Federal and state agencies • Public • Labor groups • Academia • Industry • Advocacy and other organizations • NIEHS/NTP Agency NTP staff develop research/testing or literature-analysis concepts NTP Office of Nomination and Selection (NIEHS) NTP Director Agency Point of Contact •Coordinates agency input on nominations and draft concepts Select substances for study or evaluation based on resources and priorities NTP Executive Committee review NTP Board of Scientific Counselors review (public meeting) Solicit public comment on nominations and draft concepts NTP Director Research/testing and OHAT or RoC literature-analysis activities
- 9. Nominations Reviewed 1998-2009 • 180 single agent nominations • 41 ‘complex’ nominations – Mixed occupational exposures – Structural classes – Functional categories • Sources – NIH/NIEHS-21% – NIH/NCI-23% – Private individuals- 14% – FDA-11% – NIOSH- 8% – USEPA-8% – CPSC/OSHA/NCEH/ATSDR-8% – Other- 8%
- 10. Prioritization: principles considered • Being responsive to “nominators” question • GLP-compliance (defensibility for regulatory decision-making) • Transparency • Personnel capabilities • Operational capabilities • Comprehensiveness needed • Fiscal constraints • Timeframe of data needs • Scientific creativity
- 11. Team science model • Some groups are self contained with the organizational structure • Many projects operate across the administrative structure • Not “collaborations”
- 12. DNTP Operational Workflow • Project-centered, centrally funded, research model • NOT a Principal Investigator group centered research model – Not a specific or specific person or project – Not a single contract for a specific study • Projects proceed primarily through consensus-based decision making • Research primarily conducted in the context of NTP projects, NTP review processes and uses shared DNTP resources • Research teams span across the administrative structure and are flexible
- 13. Design Protocol COR Contract #1 COR COR Contract #2 Contract #3 Tasks Contract #4 Team How work gets done Project Leader Team Project Leader Not a single contract per project
- 14. Logic Model for NTP Studies OUTPUTS OUTCOMES (Impacts) Activities & Products Proximal Intermediate Distal Number and dates of milestones of what NTP did and produced Number of downloads and requests for NTP products Number and nature of citations in science publications, grants, and reports from stakeholder groups* Citations in documents that led to a change or action in legislation, lawsuit, policy, etc. *Stakeholder groups include academia, industry, federal regulatory and non-regulatory agencies, state agencies, non-government groups, and international agencies. MoneyMoney TimeTime StaffStaff INPUTS OUTPUTS OUTCOMES Nomination, concept, studies, peer review, etc. Nomination, concept, studies, peer review, etc. Awareness of NTP products Awareness of NTP products Inform science in stakeholder groups* Inform science in stakeholder groups* NTP reports, journal publications, etc. NTP reports, journal publications, etc. Proximal Intermediate DistalActivities Products Inform decision- making to effect a change Improve public health External Factors
- 15. Outline • Overview of the National Toxicology Program – Scientific approach – Operational approach • Case examples of NTP projects – Chromium VI – Bisphenol-A • New approaches • Tox 21 • Elk River Spill • Reflections
- 16. Hexavalent Chromium (VI) • Cr VI is a drinking water contaminant – Cr(III) is an essential nutrient and is relatively nontoxic • Lots of Public/media attention • Nominated for study – California Congressional Delegation, the California Environmental Protection Agency, and the California Department of Health Services • Human carcinogen by inhalation • Lack of adequate data on the toxicity and carcinogenicity of hexavalent chromium ingested orally
- 17. Outcome of the CrVI Program • Carcinogenic in both sexes of rats and mice • Extensive evaluation of kinetics showed systemic exposure to CrVI based on the tissue distribution data. • Multiple reports and publications • Report on Carcinogens evaluation and conclusion as known human carcinogen
- 18. Impact of the NTP study and use of the data • Basis for California’s Public Health Goal for Cr(VI) in drinking water – dose-related increase of tumors of the small intestine in male mice – PHG are non-mandatory goals used for establishing drinking water standards • NTP data used in a risk assessment conducted by the New Jersey Department of Environmental Protection in 2009 – human cancer potency estimate for Cr(VI) by ingestion and an associated Soil Cleanup Standard of 1
- 19. CrVI: an example of the need for new approaches • Clearly addressed the issue of carcinogenic hazard by the oral route • Project was given “front of the line status” in the various places in the NTP pipeline. • Time from nomination to regulatory impact was over 10 years
- 20. Bisphenol-A • Chemical widely used to make polycarbonate plastics & epoxy resins. • Widespread low exposure from migration of small amounts into foods from food contact materials • Considerable debate over risk posed by “low level” exposure. • GLP guideline studies show no effects of concern at low doses – Basis for FDA regulatory decision making • Academic “investigative/exploratory” studies show that BPA induces a variety of dysfunctions in a variety of model systems at low exposures.
- 21. CLARITY-BPA • Consortium Linking Academic and Regulatory Insights on the Toxicity of BPA (CLARITY-BPA) • Goal: Address scientific uncertainties about BPA toxicity, optimize BPA- focused research investments, and to generate additional data for risk assessment. – New collaborative research model that draws upon the strengths of academic investigation and guideline-compliant research. • Brings together academic researchers with federal scientists and regulators to answer critical research questions. – NIEHS/NTP and NIEHS/Extramural Training program – FDA/NCTR and CFSAN – 13 NIEHS-funded academic grantees
- 22. BPA-CLARITY • Guideline-compliant 2-year chronic study conducted under GLP – Includes perinatal exposure by direct dosing of F1 pups – 1 year interim sacrifice (histopathology, clinical chemistry, sperm parameters) and 2 year terminal sacrifice (histopathology) • 13 Academic grantees studies – Focus on a range of molecular, structural, and functional endpoints – Focus on reported BPA effects in animal models but not usually assessed in guideline-compliant studies
- 23. BPA-CLARITY
- 24. BPA-CLARITY Outcomes • Project still ongoing • Clear differences in culture between academic science and regulatory science – Scientific freedom – Innovation • Building/maintaining trust has been critical – Involvement in study design – Sample blinding – Use of independent NTP CEBS database for deposition and decoding – Clear “articles of collaboration” – Constant communication
- 25. Outline • Overview of the National Toxicology Program – Scientific approach – Operational approach • Case examples of NTP projects – Chromium VI – Bisphenol-A • New approaches • Tox 21 • Elk River Spill • Reflections
- 26. Fundamental challenge for hazard evaluation
- 28. Suspicion of being a hazard “Exposure” (magnitude/prevalance) No- brainers Challenging Justifiable Lower priority
- 29. A National Toxicology Program for the 21st Century • Roadmap to Achieve the NTP Vision – Released November 2004 – http://ntp.niehs.nih.gov/go/vision • “To support the evolution of toxicology from a predominantly observational science at the level of disease-specific models to a predominantly predictive science focused upon a broad inclusion of target specific, mechanism- based, biological observations.”
- 30. Tox21 Quantitative High Throughput Screening • Phase I - Proof of Principle (2005-2010) – Robotic screens of 2700 chemcials in 15 concentrations in 140 qHTS assays representing 77 predominantly cell-based reporter gene endpoints. – Data made public via PubChem and CEBS • Phase II – Expanded Screening (2010-2014) – 10K compound library screened 3 x at 15 concentrations in qHTS assays that focused on: • Nuclear receptor activation or inhibition • Induction of cellular stress response pathways • Phase III (2014-onwards) – Incorporation of metabolic capability into screens – Use of high throughput genomics – Alternative model systems
- 31. Connectivity Network map of Tox21 Assay data 31
- 32. West Virginia Chemical Spill: NTP Research Response • Jan 2014; Residents of Charleston, West Virginia began to notice a “sweet smell” (like licorice) in the air and reported it to the WV Department of Environmental Protection. • 10,000 gallons of chemicals used to process coal spilled from a storage tank – Mixture of multiple chemicals including 4- methylcyclohexanemethanol (MCHM), propylene glycol phenyl ether (PPH) • CDC issues a 1 ppm screening level based on limited information • NTP was asked to evaluate the point of departure used in the risk assessment, determine if there are life stage specific hazards and screen minor components of the mixture.
- 33. In silico SAR In vitro HTS Bacterial mutagenicity Nematode Toxicity Zebrafish Embryotoxicity Mouse Dermal Irritancy/Hypersensitivity Rat repeat dose Toxicogenomics Rat Prenatal Developmental Toxicity BiologicalComplexity #Compoudnsevaluated
- 34. Proposed NTP Studies Studies Test Article [Abbreviation, CAS Number] RatPrenatalToxicity MouseDermalIrritationand Hypersensitivity 5-DayRatToxicogenomic BacterialMutagenicity ZebrafishDevelopmental NematodeToxicity HighThroughputScreening StructureActivity Relationship(SAR)Analysis 4-Methylcyclohexanemethanol [MCHM, 34885-03-5] X X X X X X X X Dipropylene glycol phenyl ether [DiPPH, 51730-94-0] X X X X X Propylene glycol phenyl ether [PPH, 770-35-4] X X X X X X 1,4-Cyclohexanedimethanol (CHDM; 105-08-8) X X X X X 2-Methylcyclohexanemethanol [2MCHM, 2105-40-0] X X X X 4-(Methoxymethyl)cyclohexanemethanol [MMCHM, 98955-27-2] X X X X 4-Methylcyclohexanecarboxylic acid [4331-54-8] X X X Cyclohexanemethanol, 4-[(ethenyloxy)methyl]- [114651-37-5] X X X X Cyclohexanemethanol, alpha,alpha,4-trimethyl- [498-81-7] X X X Dimethyl 1,4-cyclohexanedicarboxylate [DMCHDC, 94-60-0] X X X X X Methyl 4-methylcyclohexanecarboxylate [MMCHC, 51181-40-9] X X X X Phenoxyisopropanol [4169-04-4] X X X X Technical product [“crude MCHM”] X X X X X
- 35. Summary findings • MCHM and most of the spill chemicals were inactive in the “screening studies” • MCHM was a mild irritant but not a sensitizer and crude MCHM was a mild irritant and weak sensitizer. • MCHM and crude MCHM produced changes in biological activity at doses of approximately 100 mg/kg/day (approximates 1000 ppm in drinking water). – PPH produced changes in biological activity at doses in the range of 1 mg/kg/day (approximates 30 ppm in drinking water). • At doses well in excess of the drinking water advisory level MCHM was toxic to developing rats. Toxicity in the developing rats was observed at dose levels where there was no maternal toxicity. The most sensitive effect in the Rat Developmental Toxicity Study of MCHM was decreased fetal weight.
- 36. 5-Day Rat Toxicogenomics for MCHM • Rat liver microarray • Identification of BMDs for biological processes Median BMD (mg/kg/d) 0.10 1.00 10.00 100.00 1000.00 130 120 110 100 90 80 70 60 50 40 30 20 10 0 MolecularBiologicalProceses mitochondrion localization Carbon fixation serotonin secretion regulation of microtubule depolymerization negative regulation of microtubule depolymerization NADPH regeneration pentose-phosphate shunt hypothalamus development beta-Alanine metabolism response to caffeine negative regulation of protein complex disassembly ER-associated ubiquitin-dependent protein catabolic process Alzheimer's disease negative regulation of actin filament depolymerization Propanoate metabolism negative regulation of TOR signaling actin filament capping positive regulation of bone remodeling positive regulation of bone resorption positive regulation of tissue remodeling regulation of plasma lipoprotein particle levels Citrate cycle (TCA cycle) Alanine and aspartate metabolismpositive regulation of BMP signaling pathway microtubule anchoring regulation of tyrosine phosphorylation of Stat3 protein tyrosine phosphorylation of Stat3 protein positive regulation of osteoclast differentiation vitamin biosynthetic process cell surface receptor signaling pathway involved in heart developmentresponse to mercury ion regulation of vesicle fusionattachment of spindle microtubules to kinetochore phagocytosis, engulfment membrane invagination acute-phase response positive regulation of steroid metabolic process regulation of insulin-like growth factor receptor signaling pathway regulation of Cdc42 protein signal transductionregulation of triglyceride biosynthetic process establishment of endothelial barrier Proteasome hydrogen peroxide catabolic processregulation of chromosome segregation fever generation heat generation arachidonic acid metabolic process regulation of triglyceride metabolic process positive regulation of triglyceride metabolic process regulation of protein localization to cell surface regulation of humoral immune response tricarboxylic acid cycle regulation of fatty acid biosynthetic process triglyceride catabolic processplasma lipoprotein particle organization Complement and coagulation cascades positive regulation of lipid storage temperature homeostasis organ regeneration negative regulation of cytokine secretionTyrosine metabolism regulation of transcription regulatory region DNA binding cellular aldehyde metabolic processnucleus localization synaptic vesicle endocytosis prostaglandin transport negative regulation of transforming growth factor beta receptor signaling pathway endoderm formation Biosynthesis of unsaturated fatty acids response to glucagon acylglycerol catabolic processneutral lipid catabolic process plasma lipoprotein particle remodeling protein-lipid complex remodeling macromolecular complex remodeling regulation of acute inflammatory response 2-oxoglutarate metabolic process inclusion body assembly response to cadmium ion positive regulation of multicellular organism growth regulation of glycolytic process negative regulation of bone mineralization negative regulation of biomineral tissue development negative regulation of response to nutrient levels negative regulation of response to extracellular stimulus localization within membrane histone mRNA metabolic process anion homeostasis lipid storage regulation of T cell apoptotic process regulation of cell proliferation involved in heart morphogenesis embryonic hindlimb morphogenesis negative regulation of antigen receptor-mediated signaling pathway positive regulation of insulin secretion involved in cellular response to glucose stimulus positive regulation of mRNA 3'-end processing complement activation humoral immune response mediated by circulating immunoglobulin cellular response to dexamethasone stimulus regulation of transforming growth factor beta production transforming growth factor beta production apoptotic cell clearance regulation of lipid storage regulation of macrophage derived foam cell differentiation macrophage derived foam cell differentiation foam cell differentiation mitotic spindle organization negative regulation of leukocyte apoptotic process hindlimb morphogenesis negative regulation of lymphocyte apoptotic process regulation of osteoclast differentiation Urea cycle and metabolism of amino groups negative regulation of lipid catabolic process negative regulation of mRNA splicing, via spliceosome positive regulation of fatty acid metabolic process regulation of cellular carbohydrate catabolic process regulation of carbohydrate catabolic process homeostasis of number of cells within a tissue complement activation, classical pathway response to selenium ion tricarboxylic acid metabolic process ectoderm development midgut development negative regulation of T cell apoptotic process retina layer formation forelimb morphogenesisHistidine metabolism regulation of DNA-templated transcription in response to stress receptor biosynthetic process protein activation cascade regulation of receptor biosynthetic process mitochondrial DNA metabolic process negative regulation of innate immune response
- 37. Outcome • Data produced by NTP to date supports a focus on MCHM in determining the health risks associated with the spill and the selection of 100 mg/kg/day as a point of departure on which to base a drinking water advisory level. • A focus on “dose”, as opposed to a focus on a comprehensive assessment of hazard, was a pragmatic solution to the question and afforded a more rapid evaluation.
- 38. Outline • Overview of the National Toxicology Program – Scientific approach – Operational approach • Case examples of NTP projects – Chromium VI – Bisphenol-A • New approaches • Tox 21 • Elk River Spill • Reflections
- 39. Lessons learned from a program like NTP • Mission driven – Team science/project centric model vs “Investigator-group” model • Centralized operational funding – Flexibility with “capabilities” – Adapts multi year programs/studies within a 1 yr-cycle funding NIH budget system • Pipeline management – Diverse drivers make it hard to manage priorities within such an operationally driven pipeline • Headquartered within NIH – A biomedical applied research organization not a specific regulatory agency – Freedom to push the boundaries of what data could be used vs data that is asked for within confines of current regulatory framework
- 40. Transparency • CEBS; all data available to individual level – Anyone can use ALL the data – People can it use it disagree with our conclusions – Open peer review of reports • Literature analyses: – OHAT systematic review – Public review of PECO statements/protocol review • Open access tools for data visualization – User interrogation of data – HAWK • ICCVAM – Public forums for direct engagement – New approaches for more rapid ”fit for purpose” validation.
- 41. “NTP exists to develop the information and the tools that both agencies of government and industry need so that we can all live together safely in the same world.” David P. Rall, 1981 NIEHS Director 1971-1990 NTP Director 1978-1990
- 42. walker3@niehs.nih.gov The contents reflect the opinions and views of the author and do not represent the official views of NIEHS, NIH, NTP or DHHS. The mention of trade names or commercial products does not constitute endorsement or recommendation for use.