Risk Characterization

Risk Characterization: Pulling It All
Together to Describe Public Health Risks

Juleen Lam, PhD, MHS, MS
California State University, East Bay
Component
Four: Risk
Characterization
2
Introduction
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Risk Characterization: What Is It?—1
► Policy tool
► Answers the right questions to inform decision-making
4
Risk Characterization: What Is It?—2
► Risk characterization brings together the assessments and characterizations of hazard,

dose response, and exposure to make risk estimates for the exposure scenarios of interest
► Outlined in Problem Formulation
5
Ex-CDC Director
Julie
Gerberding
Image source: public domain. Retrieved on January 17, 2020, from

https://commons.wikimedia.org/w/index.php?curid=178342 6
Risk Characterization?
► Health officials have warned for years that a virulent avian flu could kill millions
of people
► After Hurricane Katrina, US politicians have been expressing alarm
► President Bush said an avian flu pandemic could be “a catastrophe” so serious that troops
might be needed to cordon off whole sections of the United States (2005)
7
The Challenge of Risk Assessment
► Characterization of risks that is:

► Scientifically sound
► Useful to decision makers
► Understandable and credible to the public
8
Risk Characterization
► Integrate and summarize the hazard identification, dose-response assessment, and

exposure assessment
► Develop public health risk estimates
► Develop a framework to define the significance of the risk
► Present assumptions, uncertainties, and scientific judgments
9
Tools in Risk Characterization—1
► NOAEL—no observed
adverse effect level
► LOAEL—lowest observed
10
► NOAEL—no observed
► RfD—reference dose
► RfC—reference
concentration
11
► NOAEL—no observed ► TLV—threshold limit

adverse effect level values
► RfC—reference
concentration
12

► LOAEL—lowest observed ► MOE—margin of

adverse effect level exposure
► RfC—reference
concentration
13


► RfD—reference dose ► Q1*—slope factor
► RfC—reference ► Unit risk

concentration
14
► NOAEL—no observed ► TLV—threshold limit ► BMD—benchmark dose



concentration
15

► ID50—infectious dose 50

concentration
16

adverse effect level exposure ► LD50—lethal dose 50

concentration
17

adverse effect level exposure ► LD50—lethal dose 50
► RfD—reference dose ► Q1*—slope factor ► Qualitative estimates

concentration
18
Qualitative Risk Characterization
► Sometimes, you are not able to quantify risk but can qualitatively express the risk
characterization
► Bird flu
► E. coli 0157:H7
19
Estimated Total 0157 illnesses
Median 95% confidence interval
from all sources
Magnitude of
Total number of cases 75,000 50,000–120,000
the E. coli
Severe cases 7,500 5,800–11,000
0157:H7 Hospitalized 1,600 1,200–2,400
Problem HUS/TTP 380 280–590
Death 50 25–90
Prop. identified illnesses due to G. Beef ~Pert (16%, 18%, 40%)
Total from G. Beef Median 95% confidence interval
Total number of cases 16,000 9,500–29,000
Severe cases 1,600 1,100–2,800
Hospitalized 350 230–600
HUS/TTP 80 50–150
Death 10 5–20
20
E. coli ID50?
► Infective dose
► Unknown, but from a
compilation of outbreak data,
including the organism’s ability
to be passed person-to-person
in daycare settings and nursing
homes, the dose could be as
few as 10 organisms, which is
similar to that of Shigella spp
(FDA/CFSAN)
21
Section B
Measures of Risk Characterization:
Examples of Tools for Public
Health Decision-Making: Part 1
Conventional Rating Scheme for Lethal Doses in Humans
Probable lethal oral dose for humans

Toxicity rating Dose (mg/kg b.w.) For average adult
Practically nontoxic More than 15,000 More than 1 quart
Slightly toxic 5,000–15,000 1 pint to 1 quart
Moderately toxic 500–5,000 1 ounce to 1 pint
Very toxic 50-500 1 teaspoon to 1 ounce
Extremely toxic 5-50 7 drops to 1 teaspoon
Super toxic Less than 5 Less than 7 drops
2
Chlorine Gas Release Using the TLV
 Time-weighted average (TLV-TWA): 0.5

ppm—carcinogenicity designation A4
 Short-term exposure limit (TLV-STEL): 1

ppm—carcinogenicity designation A4
 TLV basis—critical effect(s): irritation
 Carcinogenicity designation A4 (not

classifiable as a human carcinogen):
inadequate data on which to classify
the substance as a human and/or
animal carcinogen
3
Reference Dose (Acceptable Daily Intake)
 Widely used to set limits on exposure for food and other media
 Traditionally 1/100 of rodent NOAEL

 Safety factor of 10 for relative sensitivities of humans and rodents (interspecies
variation)
 Safety factor of 10 for variation in sensitivities among humans (intraspecies
variation)
 Additional safety factors (e.g., 10 for children)
 Not a “safe” level
4
Reference Dose (RfD)
 NOAEL = no observed adverse effect level
 UF = uncertainty (safety) factors
 BMDL = lower limit of the benchmark dose
5
Measures of Risk Characterization:
Examples of Tools for Public Health
Decision-Making: Part 2
Using Reference ► Mercury RfD is 0.0001 mg/kg b.w./day
Dose (RfD) to
► Allowable intake for 70-kg adult
Calculate a
► 0.0001 × 70 = 0.007 mg/day
Level for
Mercury in ► For 10-kg child
Drinking Water ► 0.0001 × 10 = 0.001 mg/day
2
Using RfD to ► Adult “safe” concentration
Calculate a
0.007 mg/day
Level for 2 liters/day
= 0.0035 mg/liter
Mercury in
Drinking Water ► Child “safe” concentration
0.001 mg/day
= 0.001 mg/liter
1 liter/day
3
Cancer Potency Factor (CPF)
► Estimate of the upper limit of the “potency” of a carcinogen
► Carcinogenic potency is the slope of the linear dose-response model
► The steeper the slope, the more dangerous the substance
► Units are “upper limit of lifetime risk per 1 mg/kg b.w./day”
𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅 = 𝐶𝐶𝐶𝐶𝐶𝐶 � 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑
4
Calculation of a
Slope Factor
(q1)
5
For Quantitative Risk Assessment
► Risk = LADD × q*
► Risk = probability of an individual developing cancer
► LADD = lifetime average daily dose (mg/kg/day)
► q* = slope factor [(mg/kg/day)-1]
6
Using Cancer ► EPA chloroform potency factor =
Potency Factors ► 0.006 in units of lifetime risk
► Per 1 mg/kg b.w./day
to Calculate
Cancer Risk—1
7
Using Cancer ► Concentration in water = 50 ppb = 0.050 mg/liter
Potency Factors ► Two liters/day = 0.1 mg consumed
► Average body weight = 70 kg
to Calculate 0.1 mg/day
► Average daily dose =
Cancer Risk—2 70 kg b.w.
► Dose = 0.0014 mg/kg b.w./day
8
Using Cancer ► Risk = CPF x dose
Potency Factors
► (0.006 risk per mg/kg b.w./day) x (0.0014 mg/kg b.w./day) =
to Calculate 0.000008
Cancer Risk—3
9
Using Cancer ► Eight of every 1,000,000 consuming dose for a full lifetime will
Potency Factors develop cancer
to Calculate
Cancer Risk—4
10
Margin of BMDL
MOE =
Exposure ED
► NOAEL = no observed adverse effect level (chronic or acute;

depends on the situation)
► ED = exposure dose
► BMDL = lower limit of benchmark dose
► Larger is better—more protective
► If MOE > 100, then regulatory action may not be necessary for
children? Maybe 1,000!
11
The Hazard Index (HI)
Exposure
HI =
RfD
12
Dose-Response
Assessment:
Two-Step
Approach
13
Critique of BMDL Approach to RfD
► Uses too many uncertainty factors:

► BMDL calculated off of 95% confidence interval
► Divide by uncertainty factors
14
Section D
Application of Risk Characterization Tools:
Case Examples
Margin of Exposure (MOE)
n Examines the difference between the …

u Actual human exposure (ED)
and
u Benchmark dose (BMDL)
%&'(
n MOE =
)'
2
TABLE 8-3 Population Margins of Exposure (MOE)a for Selected BMDLs and Exposure Estimates (ppm of Hg in
maternal hair or estimated equivalent to maternal hair)
MOE
Estimated MeHg Exposure in Selected Populations
New Jersey Pregnant EPA Region V Population c U.S. Women of Childbearing
Women b Age d
Study Selected BMDL Mean 95th Mean (0.29) 95th Mean (0.36) 95th
(value, ppm) (0.53) Percentile Percentile (1) Percentile
(2.0) (2.4)
New Zealand Most sensitive (4) 7.5 2.0 13.8 4 11.1 1.7
Faroe Islands Most sensitive (10) 18.9 5.0 34.5 10 27.8 4.2
Faroe Islands Most-sensitive- 22.6 6.0 41.4 12 33.3 5.0
reliable, cord-blood
derived (12)
Seychelles Islands Median (22) 41.5 11 77.3 22 61.1 9.2
New Zealand, Faroe Lower 5% (7) 13.2 3.5 24.1 7 19.4 2.9
Islands and Seychelles
Islands
(Integrative analysis)
Iraq (11)e 20.8 5.5 37.9 11 30.6 4.6
a
MOE, BMDL/exposure estimate.
b
Data from Stern et al. (2000).
cData from Pellizzari et al. (1999).
d
Data from Smith et al. (1997).
e
Current RfD basis.
Abbreviations: BMDL, lower 95% confidence limit on the benchmark dose; RfD, reference dose.
Source: National Research Council. (2000). Toxicological Effects of Methylmercury. Washington, DC: The National Academies Press. 3
MOE
Women b Age d
(2.0) (2.4)
derived (12)
Islands
Iraq (11)e 20.8 5.5 37.9 11 30.6 4.6
a
b
d
e
Current RfD basis.
MOE
Women b Age d
(2.0) (2.4)
derived (12)
Islands
Iraq (11)e 20.8 5.5 37.9 11 30.6 4.6
a
b
d
e
Current RfD basis.
MOE
Women b Age d
(2.0) (2.4)
derived (12)
Islands
Iraq (11)e 20.8 5.5 37.9 11 30.6 4.6
a
b
d
e
Current RfD basis.
MOE
Women b Age d
(2.0) (2.4)
derived (12)
Islands
Iraq (11)e 20.8 5.5 37.9 11 30.6 4.6
a
b
d
e
Current RfD basis.
Blood Mercury
Levels
8
Vermillion
Boulevard and
Prentiss Avenue,
New Orleans
9
Sample Type,
Location, and
Date
Source: U.S. Environmental Protection Agency. 10

A Selected Result and Other Information
n DDT in sediment
u 0.026 mg/kg
n Child soil ingestion

u Default (65th percentile) = 200 mg/day
u High-end (>90th percentile) = 1,000 mg/day
n RfD = 0.0005 mg/kg b.w./day
11
Child’s Daily Exposure
Exposure Using
Concentration Ingestion Units Conversion Default Ingestion
0.026 𝑚𝑔 200 𝑚𝑔 1 𝑘𝑔
∗ ∗ 6
𝑘𝑔 𝑑𝑎𝑦 10 𝑚𝑔
= 5.2 𝑥 10−7 𝑚𝑔/𝑘𝑔 𝐵𝑊/𝑑𝑎𝑦
10 𝑘𝑔 𝐵𝑊
Exposure Using
Concentration Ingestion Units Conversion High-End Ingestion
12
Child’s Margin of Exposure
n Margin of exposure = RfD/ED

u DDT RfD = 0.0005 mg/kg b.w./day
n MOE (default) = 0.0005/5.2 x 10–7 = 962
n MOE (high-end) = 0.0005/2.6 x 10–6 = 192
13
Margin of Exposure (MOE)
*+,)( ./ %&'(
n Margin of exposure =
)'
0
n The combined MOET =
(0/&+)3 ) 5 (0/&+)6 ) 5 ... 5 (0/&+)8 )
14
The Hazard Index (HI)
𝐸𝑥𝑝𝑜𝑠𝑢𝑟𝑒D 𝐸𝑥𝑝𝑜𝑠𝑢𝑟𝑒I 𝐸𝑥𝑝𝑜𝑠𝑢𝑟𝑒J

𝐻𝐼; = + +
𝑅𝑓𝐷D 𝑅𝑓𝐷I 𝑅𝑓𝐷J
15
Section E
Descriptive Risk Characterization to Inform the Policy

Process
 Summary of Risk
- The risk characterization should contain a discussion and
interpretation of the numerical estimates that affords the risk
manager some insight into the degree to which the quantitative
estimates are likely to reflect the true magnitude of human risk
2
 The values supported by a risk characterization throughout the

process are as follows:
- Transparency in the environmental decision making
- Clarity in communication
- Consistency in core assumptions and science policies from case
to case
- Reasonableness
3
Content of Risk Characterization Summary
 Primary conclusions about hazard, dose response, and exposure,

including equally plausible alternatives
 Nature of the key supporting information and analytic methods
 Risk estimates and their attendant uncertainties, including key uses
of default assumptions when data are missing or uncertain
 Statement of the extent of extrapolation of risk estimates from
observed data to exposure levels of interest (i.e. margin of
exposure) and its implications for certainty or uncertainty in
qualifying risk
4
Content of Risk Characterization Summary
 Significant strengths and limitations of the data and analyses,

including any major peer reviewers’ issues
 Appropriate comparison with similar risk analyses or common risks
with which people may be familiar
 Comparison with assessment of the same problem by another
organization
5
 Risk characterization is a synthesis and summary of information

about a potentially hazardous situation that addresses the needs
and interests of decision makers and of interested and affected
parties
 Risk characterization is a prelude to decision making and depends
on an iterative analytic-deliberative process
6
Criteria for an Effective Analytic-Deliberative Process
 Getting the science right

 Getting the right science
 Getting the right participation
 Getting the participation right
 Developing an accurate, balanced, and informative synthesis
7
Understanding Risk: Seven Principles
1. A decision-driven activity
- Risk characterization should be a decision-driven activity
directed toward informing choices and solving problems
8
2. A broad understanding
- Coping with a risk situation requires a broad understanding of
the relevant losses, harms, or consequences to the interested
and affected parties
9
3. An analytic-deliberative process
- Risk characterization is the outcome of an analytic-deliberative
process
- Analysis uses rigorous, replicable methods, evaluated under the
agreed protocol of expert community
- Deliberation is important at each step of the process that
informs decisions (i.e., which harms to analyze and how to
describe uncertainties and disagreements)
10
4. Problem formulation
- The analytic-deliberative process leading to a risk
characterization should include early and explicit attention to
problem formulation
- Representation of the spectrum of interested and affected
parties at this early state is imperative
11
5. The analytic-deliberative process should be mutual and recursive

- Analysis and deliberation are complementary and must be
integrated throughout the process leading to risk
characterization: deliberation frames analysis, analysis informs
deliberation, and the process benefits from feedback between
the two
12
6. Diagnosis of the decision situation

- Risk characterization should begin with developing a provisional
diagnosis of the decision situation so that the
analytic/deliberative process leading to the characterization
will match the needs of the decision, particularly in terms of
level and intensity of the effort and representation of parties
13
7. Organizational capability
- Organization responsible for making risk decisions should build
organizational capability to conform to the principles of sound
risk characterization
14
It Is Hard Work!
15

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Risk Characterization: Pulling It All

Together to Describe Public Health Risks

► Answers the right questions to inform decision-making

► Risk characterization brings together the assessments and characterizations of hazard,

Image source: public domain. Retrieved on January 17, 2020, from

► Characterization of risks that is:

► Integrate and summarize the hazard identification, dose-response assessment, and

► Develop public health risk estimates

► Develop a framework to define the significance of the risk

► Present assumptions, uncertainties, and scientific judgments

► NOAEL—no observed ► TLV—threshold limit

► NOAEL—no observed ► TLV—threshold limit

► LOAEL—lowest observed ► MOE—margin of

► NOAEL—no observed ► TLV—threshold limit

► LOAEL—lowest observed ► MOE—margin of

► RfD—reference dose ► Q1*—slope factor

► RfC—reference ► Unit risk

► NOAEL—no observed ► TLV—threshold limit ► BMD—benchmark dose

► LOAEL—lowest observed ► MOE—margin of

► RfD—reference dose ► Q1*—slope factor

► RfC—reference ► Unit risk

► NOAEL—no observed ► TLV—threshold limit ► BMD—benchmark dose

► RfD—reference dose ► Q1*—slope factor

► RfC—reference ► Unit risk

► NOAEL—no observed ► TLV—threshold limit ► BMD—benchmark dose

► RfD—reference dose ► Q1*—slope factor

► RfC—reference ► Unit risk

► NOAEL—no observed ► TLV—threshold limit ► BMD—benchmark dose

► RfD—reference dose ► Q1*—slope factor ► Qualitative estimates

► RfC—reference ► Unit risk

Probable lethal oral dose for humans

 Time-weighted average (TLV-TWA): 0.5

 Short-term exposure limit (TLV-STEL): 1

 TLV basis—critical effect(s): irritation

 Carcinogenicity designation A4 (not

 Traditionally 1/100 of rodent NOAEL

 Additional safety factors (e.g., 10 for children)

 Not a “safe” level

 NOAEL = no observed adverse effect level

 UF = uncertainty (safety) factors

 BMDL = lower limit of the benchmark dose

► Estimate of the upper limit of the “potency” of a carcinogen

► Carcinogenic potency is the slope of the linear dose-response model

► The steeper the slope, the more dangerous the substance

► Units are “upper limit of lifetime risk per 1 mg/kg b.w./day”

𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅 = 𝐶𝐶𝐶𝐶𝐶𝐶 � 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑

► Risk = probability of an individual developing cancer

► LADD = lifetime average daily dose (mg/kg/day)

► q* = slope factor [(mg/kg/day)-1]

► NOAEL = no observed adverse effect level (chronic or acute;

► BMDL = lower limit of benchmark dose

► Larger is better—more protective

► Uses too many uncertainty factors:

n Examines the difference between the …

Source: U.S. Environmental Protection Agency. 10

n Child soil ingestion

n RfD = 0.0005 mg/kg b.w./day

n Margin of exposure = RfD/ED

n MOE (default) = 0.0005/5.2 x 10–7 = 962

n MOE (high-end) = 0.0005/2.6 x 10–6 = 192

𝐸𝑥𝑝𝑜𝑠𝑢𝑟𝑒D 𝐸𝑥𝑝𝑜𝑠𝑢𝑟𝑒I 𝐸𝑥𝑝𝑜𝑠𝑢𝑟𝑒J

Descriptive Risk Characterization to Inform the Policy

 The values supported by a risk characterization throughout the