Environmental Health Sciences:

NIEHS and NTP

John Bucher, Ph.D., DABT
Associate Director
National Toxicology Program

National Institute of Environmental Health Sciences

National Institutes of Health U.S. Department of Health and Human Services

Outline and Take Home

NIEHS and NTP

What and why we study what we do
NIEHS strategic plan
Special susceptibilities
Genes and environment
Are we being served?
How to ensure quality?

Future of toxicology?
What we fund
National Institutes of Health
U.S. Department of Health and Human Services
National Institute of Environmental Health Sciences
One of the 27 Institutes and Centers of the National Institutes of Health
Located in Research Triangle Park, North Carolina

Wide variety of programs supporting our mission of environmental health:

Intramural laboratories Clinical research program
Extramural funding programs National Toxicology Program
Disease prevention Public health focus

National Institutes of Health

U.S. Department of Health and Human Services
US National Toxicology Program (NTP)
Interagency program
Established in 1978 US Department of Health
Headquartered at NIEHS and Human Services (DHHS)

Research on nominations
Thousands of agents evaluated in NIH CDC FDA
comprehensive toxicology studies
Results communicated through technical NIEHS NIOSH NCTR
reports, scientific publications, and the
web

Analysis activities
Report on Carcinogens https://ntp.niehs.nih.gov
Office of Health Assessment & Translation
NTP Interagency Center for the Evaluation
of Alternative Toxicological Methods
National Institutes of Health
U.S. Department of Health and Human Services
National Toxicology Program
Mission
Evaluate agents of public health concern
using tools of modern toxicology and
molecular biology

Goals
Coordinate toxicological testing within the
Department of Health and Human Services
Develop testing methods that reduce, refine,
or replace the use of animals
Develop data to strengthen scientific
knowledge about potentially hazardous
substances
Communicate findings to health, regulatory
and research agencies, scientific and
medical communities and the public National Institutes of Health
U.S. Department of Health and Human Services
NTP Studies

Chronic rodent cancer bioassays ~650

Genetic toxicity ~3000
Immunotoxicity ~150
Reproductive/developmental ~400
General and other toxicity ~900
High throughput screening ~8500

National Institutes of Health

U.S. Department of Health and Human Services
 HUMAN
HEALTH & DISEASE

TIME
National Institutes of Health
U.S. Department of Health and Human Services
ENVIRONMENT Includes:

Industrial chemicals Foods, nutrients, dietary

supplements
Agricultural chemicals
(pesticides) Prescription drugs

Physical agents Lifestyle choices and

(heat, non ionizing substance abuse
radiation)
Social and
By-products of combustion economic factors
and industrial processes
(dioxin, polyaromatic Microbiome
hydrocarbons)
National Institutes of Health
U.S. Department of Health and Human Services
NTP Research and Testing Program
Air/food/water contaminants
Combination AIDS therapeutics
Botanicals/dietary supplements
Endocrine disruptors
Flame retardants
Green chemicals
Mixtures toxicology
Mold
Nanoscale materials
Occupational exposures
Phototoxicology
Radiofrequency radiation
Risk assessment issues
National Institutes of Health
U.S. Department of Health and Human Services
Diseases with Known/Suspected Environmental
Component
Cancers

Birth defects (cleft palate, cardiac malformations)

Reproductive dysfunction (infertility,

endometriosis, testicular dysgenesis
syndrome)

Lung dysfunction (asthma, asbestosis)

COPD)

Neurodevelopmental disorders (autism, ADHD)

Neurodegenerative diseases (Parkinsons)

https://www.niehs.nih.gov/health/topics/index.cfm National Institutes of Health
U.S. Department of Health and Human Services
Environment and Cancer
Geographical distributions in rates and migration effects
Rapidly changing trends in prevalence not accounted for
by improved diagnostic procedures
Increased lung cancer in combustion byproduct-exposed
residents near smelters, incinerators, and power plants
Secondary cancers from anti-neoplastics (alkylating
agents)
Immunosuppressive agents as a class
International Agency for Research on Cancer (IARC)
and NTP Report on Carcinogens cancer listings
Human, experimental animal, and mechanistic data
integration
Stewart, Wild (2014) World Cancer Report, IARC, WHO

National Institutes of Health

U.S. Department of Health and Human Services
14th NTP Report on Carcinogens
Congressionally mandated list of agents, substances, mixtures, and
exposure circumstances known and reasonably anticipated to cause
cancer in humans

248 current listings

National Institutes of Health

U.S. Department of Health and Human Services
Research Challenges in Environmental Health

Investigating the timing of

exposure and windows of
susceptibility
Measuring individual
biological responses
and accounting for
genetic susceptibility
Tying mechanisms
such as altered gene
expression, epigenetic
modifications, to adverse
health outcomes
National Institutes of Health
U.S. Department of Health and Human Services
 National Institutes of Health
U.S. Department of Health and Human Services
Strategic Goal #1:
Identify and understand fundamental shared mechanisms or common biological
pathways (e.g., inflammation, epigenetic changes, oxidative stress, mutagenesis)
underlying a broad range of complex diseases, in order to enable the development
of broadly applicable prevention and intervention strategies.

Strategic Goal #2:

Understand individual susceptibility across the life span to chronic, complex
diseases resulting from environmental factors, in basic and population-based
studies, to facilitate prevention and decrease public health burden.

National Institutes of Health

U.S. Department of Health and Human Services
Strategic Goal #3:
Transform exposure science by enabling consideration of the totality of human
exposures and links to biological pathways and create a blueprint for incorporating
exposure science into human health studies.

Strategic Goal #4:

Understand how combined environmental exposures affect disease pathogenesis.

National Institutes of Health

U.S. Department of Health and Human Services
Strategic Goal #5:
Identify and respond to emerging environmental threats to human health on both a
local and global scale.

Strategic Goal #6:

Establish an environmental health disparities research agenda to understand the
disproportionate risks of disease and to define and support public health and
prevention solutions in affected populations.

National Institutes of Health

U.S. Department of Health and Human Services
Conceptual Shift for Environmental Health Science

OLD chemicals act by overwhelming

the body's defenses by brute force at
very high doses
NEW chemicals can act like
hormones and drugs to disrupt the
control of development and function at
very low doses to which the average
person is exposed
NEW susceptibility to environmentally
induced disease can vary widely, can
persist long after exposure, and
potentially across generations

National Institutes of Health

U.S. Department of Health and Human Services
 Windows of Susceptibility

Early Prenatal Mid-Late Prenatal Postnatal

Central nervous system (3 wks - 20 yrs)

Ear (4-20 wks)

Kidneys (4-40 wks)
Heart (3-8 wks)

Limbs
(4-8 wks)

Immune system (8-40 wks; competence & memory birth-10 yrs)

Skeleton (1-12 wks)

Lungs (3-40 wks; alveoli birth-10 yrs)

Reproductive system (7-40 wks; maturation in puberty)

Week 1-16 Week 17-40 Birth 25 years

National Institutes of Health
Source: Altshuler, K; Berg, M et al. Critical Periods in Development, OCHP Paper Series on Children's HealthU.S.
andDepartment of Health
the Environment, and Human
February Services
2003.
Developmental Origins of Disease:
Developmental exposures lead to disease throughout life

National Institutes of Health

U.S. Department of Health and Human Services
Low Dose

Our endocrine system: tiny amounts

of hormones with profound effects on
development and normal health
Chemical exposures, even at low doses,
can disrupt delicate endocrine system
and create a mechanism for disease
For some endocrine disruptors, biological changes can be
seen at low doses, but not at high doses
For example, low doses of bisphenol A can change brain
structure, function, and behavior in rats and mice exposed
during critical periods of development

National Institutes of Health

U.S. Department of Health and Human Services
NIEHS/NTP/FDA CLARITY Study

Consortium Linking Academic and Regulatory Insights on BPA

ToxicitY
Addresses controversy over safety of bisphenol A
A collaborative study combining a large multi-dose guideline/GLP
toxicology/cancer study through FDA lab with an academic
grants program
Includes dose levels ranging from those humans encounter to
those found toxic in traditional animal toxicology studies
12 grantees utilizing animals and tissues in their own laboratories
to understand the basis for the controversy and ultimately, the
adequacy of the traditional safety assessment paradigm
https://www.niehs.nih.gov/research/programs/endocrine/bpa_initiatives/index.cfm

National Institutes of Health

U.S. Department of Health and Human Services
The Diversity Outbred Mouse: Reality check

Diversity outbred male mice

Exposures: 0, 1, 10, 100 ppm benzene, 28 days, 6 hr/day by inhalation
600 mice total: 2 separate cohorts to assess reproducibility
Endpoints for hematotoxicity and genetic damage
% reticulocytes and micronucleated reticulocytes in bone marrow and blood

Variation in response was 9 fold greater than in isogenic

B6C3Fi hybrid mice
Calculated BMD was an ~ order of magnitude lower
Associated with variable expression of sulfotransferase
detoxification enzymes
Who are we protecting?
French et al. (2015) Environ Health Perspect; DOI:10.1289/ehp.1408202
National Institutes of Health
U.S. Department of Health and Human Services
Epigenetics: Heritable changes in gene expression
that occur without a change in DNA sequence

British Columbia Cancer Agency Branch http://www.roadmapepigenomics.org/

National Institutes of Health

U.S. Department of Health and Human Services
Epigenetic Changes Implicated in Human Diseases

Normal processes
Development
Cell differentiation Aging
Adverse health outcomes
Cancer
Cardiopulmonary disease
Autoimmune disease
Obesity
GENOME EPIGENOME DISEASE Diabetes
Neurodevelopmental disorders
Schizophrenia
Addiction
Depression
External influences
Environmental exposures
Nutrition
Chemical toxins
Metals
Mediators of stress
Drugs of abuse
Infection (including HIV)
National Institutes of Health
U.S. Department of Health and Human Services
Mouse Methylome Project
C57BL/6N female C3H/HeN male
Goal:
Develop tools for rapid screening of
segments of the B6C3F1 hybrid mouse
genome susceptible to epigenetic B6C3F1 male and female offspring
modifications

Outcome:
Identify differentially methylated regions C3H/HeN female C57BL/6N male

Determine inheritance (parent of origin)

Integration of methylation with gene
expression
C3B6F1 male and female offspring

National Institutes of Health

U.S. Department of Health and Human Services
The Microbiome: A new consideration
New genomic technologies have
enabled comprehensive
identification of the microbial
community inhabiting our bodies:
the microbiome
Studies reveal associations
between the composition of the
microbiome and health and disease
Commensal microbes have a role
in metabolism of environmental
toxicants
Environmental exposures to
chemicals, metals, antibiotics, etc.,
influence the composition of the
microbiome
https://commonfund.nih.gov/hmp National Institutes of Health
U.S. Department of Health and Human Services
The Exposome
Definition
An untargeted (hypothesis free)
assessment of the totality of
environmental exposures
How to measure
New tools are being developed to
monitor total exposures
Can use untargeted metabolomics
approach
Mixtures
Chemical
Non-chemical (infectious agents,
diet, pyscho-social)
Microbiome
An important contributor
National Institutes of Health
Rappaport and Smith (2010), Science, 330:460-461
U.S. Department of Health and Human Services
New Technologies for Exposure Science and the Exposome
https://www.niehs.nih.gov/about/events/pastmtg/2016/exposome-exposure/index.cfm

Psychosocial
Stress and
Addictive
Substances

Diet & Physical Activity

Biological
Response
Sensors for Indicators
Analysis of
Chemical
Exposures National Institutes of Health
U.S. Department of Health and Human Services
Citizen Science & Community-Engaged Research:
Looking ahead

Exposure Science Big Data

Dissemination & Economic Evaluation

Implementation Research National Institutes of Health
U.S. Department of Health and Human Services
Systematic Review: Evaluating environmental
health questions
Address the breadth of relevant data
Wide range of human study designs (e.g., clinical,
observational)
Animal studies
Mechanistic studies (in vitro and other relevant data)
Approach to reach hazard identification conclusions
Procedure to integrate evidence streams

Human studies Animal studies Mechanistic studies

National Institutes of Health
U.S. Department of Health and Human Services
Systematic Review

A scientific investigation addressing a specific question, using

explicit, pre-specified methods to identify, select, summarize, and
assess the findings of similar studies
Provides greater transparency in decision making
Used to:
Reach evidence-based conclusions
Clarify need for additional research

Existing methodologies primarily used

to assess healthcare interventions
e.g., Cochrane, AHRQ, GRADE

National Institutes of Health

U.S. Department of Health and Human Services
The Tox21 Community

National Institutes of Health

U.S. Department of Health and Human Services
 Purpose of Tox21: A new era in toxicology

Support the evolution of toxicology from a mostly observational science to a

predominantly predictive science focused upon mechanism-based, biological
observations using cultured cells, model tissues, and lower organisms.
National Institutes of Health
U.S. Department of Health and Human Services
Area of Emerging Emphasis for NTP and Toxicology

Develop new methods for efficient, thorough toxicological

assessments
Increase understanding of exposure-response relationships and
issues of dosimetry
Integrate results from new data rich
techniques (i.e. genomics, high throughput
screening) with traditional toxicology data
to provide public health context
Toxicity for the 21st Century or Tox21
MOU between NTP, EPA, FDA, and NCATS
High throughput, robotic testing of toxic compounds in cell and
molecular assays
Using knowledge of biological response to identify toxicity pathways
National Institutes of Health
U.S. Department of Health and Human Services
Tox21

Identify patterns of compound-

induced biological response in
order to:
Characterize toxicity/disease
pathways
Model low-dose extrapolation

Prioritize compounds for more

extensive toxicological evaluation
Develop predictive models for
biological response in humans
Current focus on nuclear receptors
and stress response pathways
National Institutes of Health
U.S. Department of Health and Human Services
pAC50 with Pearson Correlation >0.7 Connectivity
Network

National Institutes of Health

U.S. Department of Health and Human Services
17-Estradiol (Pearson >0.7) Nearest Neighbors

National Institutes of Health

U.S. Department of Health and Human Services
 ER Agonist
ER Antagonist

National Institutes of Health

U.S. Department of Health and Human Services
Benefits of Tox21

Information and informatics tools

from Tox21 will facilitate new
drug discovery and promote
translational research across
NIH by eliminating substances
with undesirable effects from
further development.
This federal multiagency
collaboration is realizing a new
vision for toxicological testing
and contributing to improving
public health.
https://ntp.niehs.nih.gov/results/tox21/index.html National Institutes of Health
U.S. Department of Health and Human Services
NIEHS Grants Program Announcement Topics: 2012-17
Autism spectrum disorders
Chronic fatigue syndrome
Chronic inflammation and age-related disorders
Health disparities
Modeling social behaviors
Transgenerational inheritance
Technologies for biomedical data management
Brain and nervous system disorders
Dietary supplements
Childrens chemical exposures
Oceans and human health
Climate change
https://www.niehs.nih.gov/funding/grants/announcements/announcements/pannouncements/index.cfm National Institutes of Health
U.S. Department of Health and Human Services
Thank you!
https://niehs.nih.gov

National Institutes of Health

U.S. Department of Health and Human Services