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Exposure Science at the NIEHS
Linda S. Birnbaum, PhD, DABT, ATSDirector
National Institute of Environmental Health Sciences and
National Toxicology ProgramResearch Triangle Park, NC, USA
National Institutes of Health• NIH is the steward of medical and behavioral research
for the Nation. Its mission is science in pursuit of fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to extend healthy life and reduce the burdens of illness and disability.
• NIH statistics– Annual Funding ~$30 Billion
– ~80% of the NIH’s funding is awarded extramurally
– ~50,000 competitive grants supporting more than 200,000 researchers
– ~2,800 universities, medical schools, and other research institutions in every state and several foreign countries.
– ~10% of the NIH’s budget supports intramural research projects conducted by nearly 6,000 scientists
• 27 Institutes and Centers
What makes NIEHS Different?• 1. NOT in Bethesda area
– Research Triangle Park, NC
• 2. Translation is to Public Health
– Bench to Bedside, Policy, and Public Health
• 3. Funding from 3 Congressional Committees
– Health – Regular NIH appropriation
– Interior - Superfund Research Program and Worker Training
– Energy - Worker Training Program
• 4. Home of the National Toxicology Program
– NIEHS, FDA (NCTR), and CDC (NIOSH)
We All Know That Exposures Are Bad For Us. But What Makes Them Bad - And What Can We Do About It?
Pesticides and Toxics
UV Radiation Lead
Biologicals
Indoor Air
Mercury
Particulate Matter
Ozone
Asbestos
Exposure Science is an Integrating principle • Crosses all scientific disciplines • Relates fate and transport of hazardous substances • To internal doses to tissues and organs• To Disease Processes
EnvironmentalMatrix
Environment -Individual Interface
Internal -Disease
We are building exposure science through Partnerships• With EPA on ambient exposure, fate and transport• With CDC on Biomonitoring• With other NIH Institutes on Health Effects
NIEHS Efforts in Exposure Science• Improve the Characterization of Exposure
– The NIH Genes Environment and Health Initiative
• Tool Demonstrations Thursday AM
• Improve our Understanding of Susceptibility
– Epigenetics
• Presentation Session This Morning
• Improve the Translation and Relevance of our efforts
– Community Engagement
• Presentation Session Thursday AM
Changing The Way We Think About –And Measure –
‘Environment’ and ‘Exposure’
The NIHGenes, Environment, and Health
Initiative
What Makes Environmental Chemicals Hazardous?
• Persistence
• Bioaccumulation
• Toxicity
• Dose
• Timing
Dose?
• The "dose makes the poison" …
– Different effects occur at different doses
• “Low” dose may just mean “lower” than usually studied
– The most common definition: Below previously identified “adverse” dose level; environmental exposure levels; in the physiological range…
Timing?
• Acute, chronic, periodic?
• Developmental staging including both early life-stages and older life stages?
• External factors including co-morbid disease and lifestyle?
• Humans are always exposed to multiple chemicals
• It is difficult to decipher how exposure to many chemicals will influence the effects of each one – both in time and space
• There is no such thing as being unexposed
• What does the CDC “report card” mean?
Chemical Mixtures
What Causes Disease?• Gene-Centric Approach
– Single mutation alters
– Single protein alters
– Single activity causes
– Single disease
• Environment-Centric Approach– Exposure to a single analyte alters
– Single Gene or Protein directly alters
– Single activity causes
– Single disease
Both – Too Simple
Development and Age
Other Diseases
Nutrition Social Factors
Drugs
Healthy Diseased
Genetic Vulnerability
Need to View the Role of Environment in Disease as a Complex Process
Environmental Toxicants
Identify genetic variants
GENETICS PROGRAM
• GWA Studies• Data Analysis• Replication• Sequencing
• Database• Function• Translation
GXE
EXPOSURE BIOLOGY PROGRAM
Develop technology and biomarkers
• Diet• Physical Activity• Environmental Exposures• Psychosocial Stress and
Addictive Substances
Genes, Environment and Health Initiative
External contact
Internal dose
Biological response
Early markers of
Disease
Clinical disease
Environment
Exposure Biology Program
Link personal exposures to biology to disease
Body burden measures of
exposure
• Chemical Exposures• Diet and Lifestyle• Psychosocial Stress• Drug Abuse
Personalized Environmental
Sensors
• Oxidative stress• Inflammation• DNA damage/repair
Biomarkers and Biosensors
Overt diseaseand phenotypiccharacterization
Environmental exposure
assessment
Genes, Environment and Health Initiative
Goal Of Changing the View of ExposureIn 2007…
• Indirect
– Environmental monitoring
– Surrogate biomarkers
– Questionnaire
• Limited
– Single definition of exposure
– Little temporal/spatial information
• Obtrusive
In 2011…
• Direct
– Individual Exposure Metric
– Breathing zone/Point of Contact
• More Comprehensive
– Integrated across measures of exposure
– Multiplex sensing
– Near real-time spatially resolved
• Minimally Intrusive
– Lightweight
– ‘Easy to use’
Genes, Environment and Health InitiativeExposure Biology Program
Genes, Environment and Health InitiativeSensors for Personal Exposure Assessment
External contact
Internal dose
Biological response
Early markers of
Disease
Clinical disease
Environment
• Volatile Organics
• Particulates
• Molecular Gases
• Pesticides
Genes, Environment and Health InitiativeSensors for Personal Exposure Assessment
Chemical Sensors Program
Genes, Environment and Health InitiativeSensors for Personal Exposure Assessment
• Chemical sensors grantees:– Particulate Matter and Molecular Gases:
• PM2.5, CO, O3, Steven Chillrud, Columbia University• PM10, PM2.5, Charles Rodes, Research Triangle Institute• PM1, Sang Young Son, University of Cincinnati
– Pesticides• Esterase Inhibition, Markus Erbildinger, ICx Agentase
– Allergens• Cat, mouse, cockroach, dust mite, Kenneth Shepard, Columbia University
– Volatile Organics• Gasoline and Diesel Exhaust, Ashok Mulchandani, UC Riverside• Toxic Industrial Compounds, Kenneth Suslick, University of Illinois• Aromatic hydrocarbons, Nongjian Tao, Arizona State University
External contact
Internal dose
Biological response
Early markers of
Disease
Clinical disease
Environment
• Camera based Intake analysis
•Improved Recall
•Accelerometers
•GPS
Genes, Environment and Health InitiativeSensors for Personal Exposure Assessment
Diet and Physical Activity Program
NIH Genes, Environment and Health InitiativeExposure Biology Program
Improved Measures of Diet and Physical Activity Grantees:
Diet• Improved EMA Recall, Tom Baranowski, PhD., Baylor College of Medicine, • Cell Phone Image Analysis, Carol Boushey, Ph.D., Purdue University• Cell Phone Image Analysis, Rick Weiss, M.S., Princeton Multimedia Technologies
Corporation
Physical Activity• Activity and Ventilation, Patty Freedson, Ph.D., University of Massachusetts• Sensors and cell phone analysis, Stephen Intille, Ph.D., Massachusetts Institute of
Technology• Geospatial Analysis of Activity, Kevin Patrick, M.D., University of California
Both Diet and Physical Activity• Necklace based Camera and Accelerometer, Mingui Sun, Ph.D., University of
Pittsburgh
Improved Measures of Diet and Physical Activity for the Genes and Environment Initiative (GEI) (U01) RFA CA-07-032
External contact
Internal dose
Biological response
Early markers of
Disease
Clinical disease
Environment
•Improved Questionnaire
•Circadian Rhythm
•Alcohol and Other Drug Use
•Stress marker assessment
Genes, Environment and Health InitiativeSensors for Personal Exposure Assessment
Psychosocial Stress Program
Psychosocial Stress and Addictive Substances Program Awards:
• Stress measurement and perception:• Salivary alpha-amylase, Vivek Shetty; UCLA• Circadian rhythm disruption, Dr. Mark Rea; Rensselaer Polytechnic Institute• Computer-Assisted Stress Assessment, Dr. Thomas Kamarck; U Pittsburgh
• Drug Use and Stress• EMA of drugs and stress, Drs. Gregory Kirk [Johns Hopkins U] & Kenzie Preston
[NIDA]• Simultaneous detection of alcohol and physiological markers of stress, Dr.
Santosh Kumar; U Memphis
NIH Genes and Environment InitiativeExposure Biology Program
External contact
Internal dose
Biological response
Early markers of
Disease
Clinical disease
Environment
Biology Response Indicators Program
Body burden measures of
exposure
• Oxidative stress• Inflammation• DNA damage/repair
Biomarkers and Biosensors
NIH Genes and Environment InitiativeExposure Biology Program
• Env. Chemicals• Tobacco Smoke• Diet• Alcohol• Stress
Stressors MarkersApproachesTobacco smoke
Alcohol
Diet/Obesity
Chemicals –PAHs, PCBs, EDC, OPs
Stress
Gene expression patterns
Proteomics
Metabolomics
Epigenetic changes
DNA and Protein Adducts (LC/MS)
mRNA/miRNA profiles in blood/ buccal/nasal cells
Protein profiles/ modifications in serum/saliva
Metabolite profiles in serum
methylation/ miRNA profiles
DNA and Protein Adducts – blood/urine
NIH Genes, Environment and Health InitiativeExposure Biology Program
2009 20112010
Technology measuring DNA damage and Repair Capacity (MIT)
Multiplex, ultra-high sensitivity chip assays for proteins(Wadsworth)
ELISA microarray(PNNL)
Single Cell GenomicAnalysissystem(UC Berkeley)
Lab-on-Chip Biosensors for modified proteins(PNNL andUC Berkeley)
Biomarkers Gene expressionmarkers ofTSE (BU)
Urinary/blood markers for TSE (U Penn)
Biomarkers of response to EDCs (U Ala.)
Protein Adductomics(UC Berkeley)
Timeline for Biological Response Indicators Projects
NIH Genes, Environment and Health InitiativeExposure Biology Program
NIH Genes, Environment and Health InitiativeExposure Biology Program
Next Steps
• Continued Development
– Validation and Integration of Phase I tools
– Address ‘gaps’
• ‘Source’
• ‘Body Burden’
• Phenotypic Characterization
• Application
– Targeted GxE ‘Proof of Principle’ Studies
• Existing studies with environmental characterization
• Prospective studies in high priority, cross cutting diseases
New Directions in Understanding Susceptibility
Epigenetics
Epigenetics
GENOME DISEASEEPIGENOME
Epigenetic Changes Have Been Implicated in a Wide Variety of Human Diseases
Normal processesDevelopment
Cell differentiation Aging
External influencesEnvironmental exposures
Nutrition Chemical toxins
Metals Mediators of stress Drugs of abuse
Infection (including HIV)
Adverse health outcomesCancer
Cardiopulmonary diseaseAutoimmune disease
ObesityDiabetes
Neurodevelopmental disordersSchizophreniaAddictionDepression
NIEHS investments/priorities in epigenetic research
• Fetal Basis of Disease
• Environmental influences on epigenetic processes
– DNA methylation
– Histone modifications
– ncRNAs
• NIH Roadmap Epigenomics Program
• Trans-generational epigenetic inheritance
Increasing the Relevance and Translation of Exposure Science
Community Engagement
Benefits of Community Engagement
• Community input to help inform the science and/or refine the research focus of the project
• Participation of community members in the research process
• Increased trust between community and researchers
• More effective translation and dissemination of research findings
• Increased awareness of environmental hazards and community empowerment
Select NIEHS Environmental Public Health Partnerships • Partnerships between researchers and
community organizationResearch to Action
• Community-based participatory research CBPR
• Partnerships among communities, researchers and health care professionalsEnvironmental Justice
• Community Outreach and Education CoresEHS Core Centers
• Community Outreach and Translation Cores Superfund Research Program
• Community Outreach and Translation CoresChildren’s Environmental Health
• Community Outreach and Translation CoresBreast Cancer Centers
TIME
HUMAN HEALTH & DISEASE
Exposure Internal Dose
Early Biological
Effect
Altered Structure/ Function
Adverse EffectSources
Risk Paradigm
Environmental Health and Exposure Sciences: An Opportunity for Prevention and Improved
Public Health
Thank you!
