Nanoinformatics Challenges for Occupational Exposure Limits, Medical Surveillance, Exposure Registries, and Epidemiologic Research Paul A. Schulte, PhD Centers for Disease Control and Prevention National Institute for Occupational Safety and Health The findings and conclusions in this presentation have not been formally disseminated by the National Institute for Occupational Safety and Health and should not be construed to represent any agency determination or policy. December 8, 2011
Transcript
Nanoinformatics Challenges for Occupational Exposure Limits, Medical Surveillance, Exposure Registries, and
Epidemiologic Research
Paul A. Schulte, PhD
Centers for Disease Control and Prevention
National Institute for Occupational Safety and Health
The findings and conclusions in this presentation have not been formally disseminated by the National Institute for Occupational Safety and Health and should not be construed to represent any agency determination or policy.
December 8, 2011
Growth of Nanotechnology
Effective growth of nanotechnology
Depends on society’s perception of the safety of
nanomaterials to people and the environment
Will be delayed if perceptions of hazard and risk
are not addressed
Workers are the first in society
To have exposure to nanomaterials
Often at levels higher than consumers
Are likely to be the first people to show health
effects2
Hazard Exposure Risk Management
Toxicity data Exposure
data
•by job/task
•by sector
•by particle type
•by metrics
•by equipment
characteristics
Quantitative risk
assessments
Hazard
banding
Control
banding
Particle
characteristics
Qualitative risk
assessments
Specific
OELs*
Categorical
OELs*
Hazard
surveillance
data
Characteristics
of animal
models
Risk
communication
Control
guidance
Green chemistry
Safety
research data
•Explosivity
•Flammability
Job/exposure
matrices
Epidemiologic
research data
Medical
surveillance
guidance
Medical
surveillance
data
Exposure
registry data
Uncertainty
data
Control
research data
Compliance
research
information
Some Domains of Information Neededto Protect Nanomaterial Workers
*OEL (Occupational Exposure Limit) 3
Four Tools for Assessing and Protecting Nanomaterial Workers Health
Occupational Exposure Limits
Medical Surveillance
Epidemiologic Research
Exposure Registries
4
Definitions Specific to Nanomaterial Workers
Occupational exposure limits (OELs)
Concentration of a nanomaterial below which workers are likely
to have minimal risk
Medical surveillance
Individual or group monitoring for adverse health effects from
nanomaterials
Exposure registries
A system for collecting and maintaining a structured record,
comparable information on persons with known or suspected
occupational exposure to nanomaterials
Epidemiologic research
The study of groups of nanomaterial workers to determine
association between exposure to nanomaterials and adverse
health effects5
How can these tools help in nanomaterial worker protection?
Occupational Exposure Limits (OELs)
Medical Surveillance
Exposure Registries
Epidemiological Research
6
Major Components in the Protection of Nanomaterial Workers
7
Risk Characterization
Risk Management
Worker Protection
Hazard
Identification
Exposure
Assessment
8
Risk Characterization
Risk Management
Hazard
Identification
Exposure
Assessment
Worker Protection
9
Exposure Registries
Risk Characterization
Animal Studies
Human Studies
Worker Protection
Hazard
Identification
Exposure
Assessment
10
Risk Characterization
Animal Studies
Human
Studies
Worker Protection
Hazard
Identification
Exposure
Assessment
Risk Management
Medical Surveillance
OEL
Informatics Challenges
Sufficiency and structure of data and information bases
Linking diverse domains (developing the evidence base)
Developing decision-making tools and guidance based
on integrated information
Extent of dissemination of guidance
Information utilization, effectiveness, and impact
11
Informatic Aspects of Biomedical Functions
Biomedical Functions
Informatic
Functions
Occupational
Exposure Limits
(OELs)
Medical
Surveillance
Exposure
Registries
Epidemiological
Research
Search for
Information1 6 11 16
Establish
Evidence Basis2 7 12 17
Develop and
Issue Guidance3 8 13 18
Implement
Guidance4 9 14 19
Assess Impact 5 10 15 20
12
Example of Carbon
Nanotubes (CNT)
44 studies identified
Majority of studies
Rats and mice
Short-term exposure and
short-term follow-up
Different routes of
exposure
Occupational
Exposure Limits
(OELs)
Search for
Information1
Establish Evidence
Basis2
13
Establish Evidence Basis
17 (of 44) studies reported pulmonary fibrosis
29 reported pulmonary inflammation
2 reported neuroinflammation
14 reported granulomas
2 reported mesotheliomas
14
Extrapolate from animals
to workersOccupational
Exposure Limits
(OELs)
Develop and Issue
Guidance3
15
Develop KnowledgeQuantitative Risk Assessment (QRA) Methods to Develop
Recommended Exposure Limits for Carbon Nanotubes (CNT)
Assume equal risk at equivalent dose
Rodent
Determine tissue-specific dose
Calculate benchmark
dose*
Extrapolate
Working lifetime exposure
concentration
Equivalent tissue
dose
Estimate exposures leading to lung dose
Recommended
exposure limit
Technical feasibility of measurement and control
Adjust for species differences
(e.g. lung surface area)*Dose associated with specified level of risk.
Human
Experimental data of exposure andadverse effect
Measure or model
Dose-response modeling
16Based on Kuempel et al. [2006]
Extrapolate from animals
to workers
No chronic studies
> 10% risk of early stage
lung effects
Generalizability to all
types of CNT
Guidance on web
Recommended exposure
7 µg/m3
Occupational
Exposure Limits
(OELs)
Develop and Issue
Guidance3
17
Develop and Issue GuidanceAdequate Information
Available Toxicity & Physical-
Chemical Data
Suggestive
Comparative Potency
Reason by Analogy
Quantitative Risk Assessment
Adequate Minimal
Derive Health-Based
OEL
Hazard Banding
Structure-Activity
Relationship
[Adapted from Schulte et al. 2010 and Kuempel et al. 2011]
Adapted from Schulte et al. [2010] and Kuempel et al. [2011]
Benchmark Particles
Control Banding
23
Develop and Issue GuidanceSuggestive or Minimal
Information
Adjusting Current REL: In Concept
Where:
OELNP is the new occupational exposure limit for the nanoparticle and OELFP is the existing OEL for the fine particle.
SSANP and SSAFP are the specific surface areas (m2/g) of the nanoparticle and the fine particle material, respectively.
DFNP and DFFP are the respective deposition fractions of the nanoparticle or fine particle in the respiratory tract or region of the respiratory tract associated with the adverse response.
ActivNP/ActivFP is a measure of the surface reactivity (e.g., free radical activity) of the nanoparticle relative to the fine particles.
UF is a currently undefined factor that relates to the degree of certainty with regard to the health protectiveness of the existing OEL.
OELFP
(SSANP/SSAFP) x (DFNP/DFFP)(ActivNP/ActivFP) x (UF)OELNP =
Kuempel et al. [2007] 24
Health Hazard Bands
Based on the NIH/CDC Biosafety Level model
Developed by the pharmaceutical industry in
1980s
Increased potency of investigational new drugs
resulted in increased potential for adverse effects
from occupational exposure
Industry did not have experience establishing
very low OELs
Industry did not have analytical methods to
measure these low exposures
25
Health Hazard Bands (cont’d)
Assign chemicals into “categories” or “bands”
based on their inherent properties
Facilitates the implementation of “control bands”
Can this serve as a model for engineered
nanoparticles?
26
Exposure ManagementControl Banding—Concept
Low Dustiness Medium Dustiness High Dustiness
Hazard Group A
Small 1 1 1
Medium 1 1 2
Large 1 2 2
Hazard Group B
Small 1 1 1
Medium 1 2 2
Large 1 3 3
Hazard Group C
Small 1 1 2
Medium 2 3 3
Large 2 4 4
Hazard Group D
Small 2 2 3
Medium 3 4 4
Large 3 4 4
Hazard Group E
For all hazard group E substances, choose control approach 4
Parameters
Amount Used
Dustiness
Hazard Group (R-Phrase)
ilo.orgSource: T.J. Lentz, NIOSH
Control Approach
1. General Ventilation
2. Engineering Control
3. Containment
4. Specialist Advice
27
Physical Form
Task
DurationQuantity
milligrams
kilograms
15 minutes
8 hours
slurry/suspension highly disperseagglomerated
Factors Influencing Control Selection
Engineered Local
Exhaust Ventilation
Closed Systems
Occupational Health Hazardmild /
reversible
severe /
irreversible
28
Lack of certainty about
what health endpoint to
assess
Medical
Surveillance
Search for
Information6
Establish Evidence
Basis7
29
Challenge: Identify Tests For Medical Surveillance of Nanotechnology Workers
Target System Tests Endpoint Measured
Respiratory
Cardiovascular
Neurological
Other
30
Lack of certainty about
what health endpoint to
assess
Low positive predictive
value for some tests
Medical
Surveillance
Search for
Information6
Establish Evidence
Basis7
31
32
Lack of certainty about
what health endpoint to
assess
Low positive predictive
value for some tests
State of the art – limited
evidence (JOEM
Supplement Vol. 53, June
2011)
Medical
Surveillance
Search for
Information6
Establish Evidence
Basis7
33
34
Lack of comprehensive
exposure data
Lack of standardized
exposure measurement
approaches
Unresolved ethical, legal,
and social issues
Exposure
Registries
Search for
Information11
Establish Evidence
Basis12
Develop and Issue
Guidance13
35
Source: JOEM Vol 53, Number 6 Supplement, June 2011
36
The search for
information depends on
the existence of
information
Research needs to be
conducted and published
Conduct of research
depends on identifying
critical issues in studies
of nanomaterial workers
Epidemiological
Research
Search for
Information16
Establish Evidence
Basis17
Develop and Issue
Guidance18
37
Critical Issues
Heterogeneity of nanoparticles
Identification of study population
Temporal factors
Exposure characterization
Disease endpoints
Design and analysis
38
Fibrous
heterogeneous
Non-spherical
heterogeneous
Agglomerate fibrous
homogeneous
Agglomerate fibrous
heterogeneous
Spherical
homogeneous
Fibrous
homogeneous
Non-spherical
homogeneous
Agglomerate
homogeneous
Heterogeneous
concentric
Heterogeneous
distributed
Agglomerate
heterogeneous
Active particle
Multifunctional
particle
Source: Schulte, et al. [2009], adapted from Maynard
Diversity of Nanomaterials
39
Critical Issues
Heterogeneity of nanoparticles
Identification of study population
Temporal factors
Exposure characterization
Disease endpoints
Design and analysis
40
Transport
Commercial
Academic
Incorporation in Products
Maintenance of ProductsManipulation of ProductsApplication of Products - Medical Delivery
