Download Report

Presenting Uncertainty in the Context of
Toxicological, Biological Monitoring and
Exposure Information
William H. Farland, PhD, ATS
Presenting Risk Information and
Uncertainty
Concerns regarding how uncertainty and risks are
communicated and understood by the general public and
decision-makers
Recent approaches for improvements have been proposed
and utilized.
Examples:
Intergovernmental Panel on Climate Change (IPCC) adopted an
approach that provides the public with a likelihood scale that clearly
defines the probabilities associated with each outcome.
The Health and Environmental Sciences Institute (HESI) recently
published the results of a multi-sector Risk Assessment in the 21st
Century (RISK21) initiative which provides a highly visual
representation of estimates of risk with the goal of widening risk
communication efforts beyond technical experts
Presenting Risk Information and
Uncertainty
Health risk information is necessarily complex
and subject to interpretation.
Risk assessors continue to struggle with how to
best array and present data within IRIS and
similar data repositories.
Solutions should encompass approaches that
assist the risk assessor to demonstrate
inherent uncertainty in the data and the
derived risk values
Example of Risk Values
Comparison Table: Carbon
Tetrachloride
Example of Reference Dose
Comparison Table: Carbon Tetrachloride
Presenting Toxicological
Information Visually
Appropriately designed visual aids can improve comprehension of
risks associated with different medical treatments, screenings, and
lifestyles
Using IRIS as the example, we provide a working model of a
visualization approach for cancer/non-cancer risks to help put
relationships in context.
A series of figures that capture different types of information.
Allows for inclusion of exposure information, e.g. environmental
levels, intake levels, biomonitoring equivalents (BE’s), where
appropriate.
Gives risk managers and others the opportunity to put toxicity
values (reference doses or cancer probabilities) in the context of
exposure.
6
Presenting Toxicological
Information Visually
Intended for use by a risk assessor for
explanatory purposes
In describing relationships, it may appear that
each toxicity value is known with certainty
and represents a bright line between safe and
unsafe.
Although toxicity value point estimates are often
used in this manner, it is important to note
that the true definition, at least for an IRIS
value, recognizes that the value could be a
range that spans an order of magnitude of
uncertainty.
7
Oral Noncancer Basic Figure
The dose-response point that marks the
beginning of a low-dose extrapolation. This
point can be the lower bound estimate on
dose for an estimated incidence or a change
in response level from a dose-response model
(BMD), or a NOAEL or LOAEL for an observed
incidence, or change in level of response.
The shading in the figure
represents a decrease in the
value and the potential risk of
effects; higher value (darker
shade) to a lower value
(lighter shade).
Point of Departure
(POD)
Dose (mg/kg/day)
The range for the values are
not on scale but are allowing
the visualization of the
uncertainty between the POD
and the risk value.
Uncertainty
Factor (UF)
Uncertainty Factors can range from 0 to 3000
(maximum). The possible types of UFs are:
interspecies uncertainty (UFA); intraspecies
variability (UFH); subchronic to chronic
extrapolation (UFS); use of a LOAEL in absence
of a NOAEL (UFL); database incomplete (UFD)
Reference Value
An estimate of an exposure for a given duration to the
human population (including susceptible
subgroups that is likely to be without an appreciable
risk of adverse health effects over a lifetime. It is
derived from a BMDL, NOAEL, LOAEL or suitable point
of departure, with uncertainty/variability factors
applied to reflect limitations of the data used.
Durations include acute, short-term, subchronic, and
chronic and are defined individually in this glossary.
Carbon tetrachloride: Oral Noncancer
(USEPA)
Chosen PODs
• BMDL2x-ADJ = 3.9mg/kg-day
for elevated serum SDH
activity
• Based on subchronic oral
rat study
• Alternative PODs
4x10-3 RfD (EPA)
1000-fold UF
mg/kg-day
3.9 BMDL2x-ADJ (EPA)
Uncertainty Factor is based on
default 10-fold for intraspecies
differences (UFH), 10-fold for
interspecies extrapolation
(UFA), 3 for subchronic to
chronic extrapolation (UFS)
UF = 10x10x3x3 = 1000
RfD =
3.9 mg/kg-day (BMDL2x-ADJ)
1000 (UF)
RfD = 0.004 mg/kg-day
Alternative PODs
• NOAEL = 1 mg/kg-day (EPA)
• LOAEL = 10 mg/kg-day for
liver lesions (EPA)
Carbon tetrachloride: Oral Noncancer
(RIVM)
Alternative PODs
• LOAEL 10 mg/kg-day
for liver lesions
(RIVM)
1 NOAEL (RIVM)
4x10-3 TDI (RIVM)
250-fold UF
mg/kg-day
Chosen POD
• NOAEL = 1 mg/kg-day for
liver effects
• Based on a rat subchronic
oral study
• Alternative PODs
The basis for the uncertainty
factor was not provided.
RfD =
RfD =
1 mg/kg-day (NOAEL)
250(UF)
0.004 mg/kg-day
Carbon tetrachloride: Inhalation
mg/m
Noncancer
Comparison*
14.3
3
BMCL10(HEC) (EPA)
mg/m3
NOAECADJ (RIVM)
30-fold
UF
5.8 NOAELHEC (ATSDR)
100-fold UF
100-fold UF
6.4
0.19
cMRL (ATSDR)
0.1 RfC (EPA)
0.06
0.19
TCA (RIVM)
cMRL (ATSDR)
0.1
RfC (EPA)
0.06
TCA (RIVM)
*represents available alternative reference values
0.1 RfC (EPA)
0.0090
Background Range
(ATSDR)
0.0006
A BE is defined as
the concentration
or range of
concentrations in a
biological matrix
that is consistent
with a health-based
exposure guidance
value e.g RfD or
RSD
Equivalent
Concentration µg/L
mg/m3
Carbon Tetrachloride:
Comparison to Background and BE
0.19 BE
<LOD (0.005)
Background (NER)
Oral Carcinogenic Basic Figure
The shading in the figure
represents a decrease in the
value and the potential risk of
effects; higher value (darker
shade) to a lower value
(lighter shade).
Point of Departure
(POD)
Dose (mg/kg/day)
The range for the values are
not on scale but are allowing
the visualization of the
uncertainty between the POD
and the risk value.
The dose-response point that marks the beginning of
a low-dose extrapolation. This point can the lower
limit on Effective dose10 (LED10) which is the 95%
lower confidence limit of the dose of a chemical
needed to produce an adverse effect in 10 percent of
those exposed to the chemical, relative to control. It
can also be the Effective dose10 (ED10), which is the
dose corresponding to a 10% increase in an adverse
effect, relative to the control response.
An oral slope factor is an upper bound, approximating a
95% confidence limit, on the increased cancer risk from
a lifetime oral exposure to an agent. This estimate,
usually expressed in units of proportion (of a
population) affected per mg/kg-day, is generally
reserved for use in the low-dose region of the doseresponse relationship, that is, for exposure
corresponding to risks less than 1 in 100.
Risk Specific Dose
= Target Risk/CSF
Cancer Hazard
Classification
Cancer Classifications: There are five recommended US
EPA standard hazard descriptors: “Carcinogenic to
Humans,” “Likely to Be Carcinogenic to Humans,”
“Suggestive Evidence of Carcinogenic Potential,”
“Inadequate Information to Assess Carcinogenic
Potential,” and “Not Likely to Be Carcinogenic to
Humans.” Other Agencies such as IARC and RIVM use
other cancer classification descriptions.
Carbon tetrachloride:
Oral Cancer (USEPA)
mg/kg-day
Chosen POD
• LED10, lower 95% bound on exposure
at 10% extra risk: 1.54 mg/kg-day
• Alternative POD
1.54 (EPA)
1.4x10-4 (EPA)
Likely to be carcinogenic to
humans
• Risk Specific Dose (RSD): 1.4x 10-4
mg/kg-day
• Oral slope factor: 7x10-2 per mg/kgday
• Alternative Oral Slope Factor
• Target Organ: liver
• Species: Mouse (Nagano et al.,
2007b; JRBC, 1998)
• Extrapolation method: multistage
model, linear extrapolation from
LED10
• Classification: likely to be
carcinogenic to humans
• Other Agency Classifications
Alternative POD
• ED10, central estimate of
exposure at 10% extra risk:
2.27 mg/kg-day
RSD Calculation
• Divide 1E-5 (1 in 100,000
(E-5) risk level) by the
slope factor of 7E-2 per
(mg/kg)-day
Alternative Oral Slope Factor
• If ED10 was used the Oral
slope factor: 4x10-2 per mg/kgday
IARC Cancer classification:
2B (possible carcinogenic
to humans)
Summary
Visual display of key risk information:
Provides a general sense of the strength of the
available data and confidence in the overall
assessment;
Reminds us of the uncertainty in the values displayed;
Provides for useful comparisons with other derived
values and exposure levels; and
Provides an educational tool for presenting this
information to non-risk assessors.
“All models (of communication) are wrong (for some
audiences), but some are useful!”
(With apologies to George Box)
Co-Authors
Nancy Beck, American Chemistry
Council
Judy Lakind, LaKind Associates
Patricia Nance, Toxicology Excellence
for Risk Assessment (TERA)
Ted Simon, Ted Simon, LLC