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Risk Assessment and Management
Jonathan M. Links, PhDJohns Hopkins University
Section A
Overview
4
Objectives of Risk Analysis
Balance risks and benefitsSet target levels of riskSet priorities for program activitiesEstimate residual risks and extent of risk reduction after stepsare taken to reduce risk
5
What Is Risk?
The potential for realization of unwanted, negative consequences of an eventThe probability of an adverse outcomeThe downside of a gamble (the total gamble must be considered)Safe means “without risk”There is usually no such thing as zero risk
6
Risk Analysis Activities: Risk Assessment
Risk assessment− The systematic characterization of potential adverse
health effects resulting from human exposure to hazardous agents
7
Risk Analysis Activities: Risk Management
Risk management− The process of weighing policy alternatives and selecting
the most appropriate regulatory action based on the results of risk assessment and social, economic, and political concerns
8
Risk Analysis Activities: Risk Communication
Risk communication− The process of making risk assessment and risk
management information comprehensible to lawyers, politicians, judges, business and labor, environmentalists, and community groups (public)
9
Four Steps of Risk Assessment
Hazardidentification
Dose-responseassessment
Exposureassessment
Riskcharacterization
Riskcommunication
Riskmanagement
10
Risk Assessment Process
Human exposure evaluation data
Dose-response evaluation data
Hazard identification data
Risk characterization
Level of potential risk to humans
11
1. Hazard Identification
? ?Agent Effect
Example: Does a chemical of concern cause an adverse effect?
12
1. Hazard Identification
Agent LD50 (mg/kg)
Sucrose 30,000
Ethanol 10,000
Aspirin 1,000
Phenobarbital 150
Caffeine 192
DDT 113
Strychnine 16
Sodium cyanide 6
Nicotine 1
Tetrodotoxin 0.1
Dioxin 0.001
Botulism toxin 0.00001
13
1. Hazard Identification
Review and analyze toxicity data− What is the LD50 for various agents?
Weigh the evidence that an agent causes various toxic effects− Description of the specific form of toxicity (neurotoxicity,
carcinogenicity, etc.)Evaluate whether toxic effects in one setting will occur in other settings− Quantification of the concentrations at which they are
present in the environment
14
Sources of Toxicity Data
Human studies− Case reports− Cluster analyses− Epidemiologic studies
Animal studies− Specialized tox. studies− Generalized tox. studies
In vitro studies
15
Range of Observed Human Studies
Case reports− Clinicians observations− Surveillance systems− Clusters
Descriptive studies− Vital statistics− Cancer registry data
16
Range of Observed Human Studies
Analytic studies− Cohort studies− Case-control studies
17
Why Animal Studies?
Good correlation with human disease− Human carcinogens cause cancer in animals
Acute toxic doses are similar in humans and a variety of animalsAnatomical, physiological, and biochemical patterns are similar among mammalsAccepted by the scientific community
18
Design Issues for Animal Testing
Route of administrationTest speciesControlsNumber of test subjectsDose selectionDuration of studyObservations to be made
19
National Toxicology Program (NTP) Testing Guidelines
NTP guidelines for carcinogenicity testing− Two species of animal
Rats (Fisher 344)Mice (B6C3F1)
− Number and gender of animals per group50 males50 females2%+ incidence (one cancer in group of 50)
− Doses (one group per dose)Maximum tolerated dose (MTD)One-half MTDOne-fourth MTD0 (vehicle controls)
20
NTP Guidelines for Carcinogenicity Testing
Regimen for dosing− Begin at 6 weeks and end at 24 months of age
Endpoints− 38 histopathologic samples/animal examined
21
Potential Endpoints
RespiratoryBlood and lymphLiverKidneyNervous systemSkinReproductive toxicityTeratogenicity
22
Criteria for Causality
Temporality− Exposure precedes effect
Biological plausibilityConsistencyDose-responseStrength of associationSpecificity
Section B
Dose-Response Assessment
24
2. Dose-Response Assessment
? ?Dose Response
How is the identified adverse effect influenced by the level of exposure or dose?
25
Dose-Response Curve
26
Dose-Response Relationship: Carcinogen
27
Dose-Response Relationship: Non-Carcinogen
Dose (mg/kg/day)Source: Adapted from Cockersham, L. G. and Shane, B. S.
28
Uncertainty Factors
LOAEL = Lowest observable adverse effects level; the lowest dose tested that produced an effectNOAEL = No observable adverse effects level; the highest dose tested that did not produce an effect
(Toxicity Study)LOAEL or NOAELUncertainty Factor
= “Safe Level”
29
Uncertainty (Safety) Factors
Uncertainty (safety) factors for risk assessment of non-cancer effects− 10 for human variability− 10 for extrapolation from animals to humans− 10 for use of less than chronic data− 10 for using LOAEL instead of NOAEL
30
Hazard ID and Dose-Response Assumptions, Defaults
Major EPA assumptions and defaults for hazard identification and dose-response data− Select human data over animal data− Use animal data when human data is inadequate− Select most sensitive animal species/strain− Apply standard uncertainty factors to scale between
species− Apply linearized multistage model for low-dose
extrapolation
31
Linear Extrapolation in Quantitative Risk Assessment
Illustration by JHSPH CTLT
32
3. Exposure Assessment
? ?Agent People
What exposures are experienced or anticipated under different conditions?
33
Human Exposure Evaluation
Where is the agent found?What are the routes of exposure?How many people are exposed?Who is exposed?What is the intensity, frequency, and duration of exposure?
34
Exposure Assessment
Characterization of the exposure settingIdentification of the exposure pathwayQuantification of exposure
Exposure = intensity x frequency x duration
Exposure = how much x how often x how long
35
Hierarchy of Exposure Data or Surrogates
Types of DataApprox. toActual Exp.
1. Quantitative personal dosimetermeasurements
Best
2. Quantitative ambient measurements invicinity of residence or activity
3. Quantitative surrogates of exposure—e.g., estimates of drinking water or foodconsumption
4. Residence or employment in proximity ofsource of exposure
5. Residence or employment in general geo-graphic area (e.g., county) of site or sourceof exposure
Poorest
36
4. Risk Characterization
What is the estimated likelihood of the adverse effect occurring in a given population?
Hazardidentification
Exposureassessment
Dose-response
Riskcharacterization
37
4. Risk Characterization
Integrate and summarize the hazard identification, exposure assessment, and dose-response assessmentDevelop public health risk estimatesDevelop a framework to define the significance of the riskPresent assumptions, uncertainties, and scientific judgements
38
Risk Assessment As “Science”
Imprecise, as it lacks full scientific evidence to support many of the conceptsMany assumptions are made, since complete data are often not availableMany models are based on hypothetical mechanism, which may or may not be scientifically validated
39
Risk Assessment As “Science”
Great deal of uncertainty is inherent in the exerciseDue to uncertainty and the desire to protect human populations, risk assessments are generally conservative and overestimate risk
40
Risk Assessment Uncertainties
Hazard identification– Use of animal data– Negative epidemiologic
studies
Human exposure evaluation
– Modeling vs. ambient– Monitoring vs. biological
monitoring– Inappropriate exposure
paradigm
Dose-response evaluation
– Extrapolation from high tolow dose
– Extrapolation from animalsto humans
– Misclassification of response
Risk characterization – Qualitative or quantitative
41
Ranges of Some Estimated Carcinogenic Risks
Range of estimates of human carcinogenic risk of selected chemicals
Agent Low estimate High estimate High/low
Saccharin .001/106 5,200/106 5.2 x 106
Vinyl chloride 1/108 107/108 107
Trichloroethylene 1/106 7 x 104/106 7 x 104
Section C
Legal Aspects of Risk
43
Legal Aspects of Risk
“De minimis” concept (de minimis non curat lex—the law does not concern itself with trifles)− In some cases, the computed risk is so small that it does
not justify regulation− Designed to protect down to a level of one in a million
Essentially zero, virtually a “safe dose”
44
Legal Aspects of Risk
Risk assessment− To determine what level of an agent will produce an
effect in one individual out of one million exposed individuals
45
One in a Million Risks
Risks estimated to increase chance of death in any year by 0.000001 (one in a million)
Activity Type of Risk
Smoking 1.4 cigarettes Cancer, heart disease
Spending 1 hour in a coal mine Black lung disease
Living 2 days in New York City Air pollution
Traveling 300 miles by car Accident
Traveling 10 miles by bicycle Accident
One chest X-ray Cancer (radiation)
Eating 1 tbsp. of peanut butter Cancer (aflatoxin)
Drinking 30 12-oz. cans of soda Cancer (saccharine)
Living 20 years within 20 miles of a nuclear power plant
Cancer (radiation)
Source: Data from Wilson, R. (1979). Technol Rev, 81, 41–46.
46
Risk Communication
Risk communication is an interactive process of exchange of information and opinion among individuals, groups and institutions. It involves multiple messages about the nature of risk and other messages, not strictly about risk, that express concerns, opinions, or reactions to risk messages or to legal and institutional arrangements for risk management.
Source: NRC. (1989). Risk Communication.
47
The Receding Zero
It is commonly believed that any amount of unwanted chemicals in our air, food, or water is harmful; that is not soThe mere presence of a chemical is insufficient to warrant alarmPeople are naturally distressed when they hear that trichloroethylene is in their drinking water—water believed to be pure
48
The Receding Zero
The fact is that the very definition of purity has been turned upside down by our ever-increasing ability to measure smaller and smaller amounts of substancesAs that ability has increased, we have come to realize that “purity” is elusive, permanently limited by the intensity of our analytic method
49
Minimum Detectable Level
Minimum amount or concentration of an agent in a sample that can be reliably detectedDepends on the sensitivity of the assay procedureShould be matched to the specific problems− Analytic sensitivity as rigorous as necessary, not as
rigorous as possible
50
Grasping Common Analytic Sensitivities
Unit1 part per million
(ppm)1 part per billion
(ppb)1 part per trillion
(ppt)
Length 1 inch/16 miles 1 inch/16,000 miles1 inch/16,000,000 miles (a 6-inch leap on a journey to the sun)
Time 1 minute/2 years 1 second/32 years 1 second/320 centuries
Money 1 cent/$10,000 1 cent/$10,000,000 1 cent/$10,000,000,000
Weight1 oz salt/32 tons of potato chips
1 pinch of salt/10 tons of potato chips
1 pinch of salt/10,000 tons of potato chips
Volume1 drop vermouth/80 fifths of gin
1 drop vermouth/500 barrels of gin
1 drop vermouth/25,000 hogsheads of gin
Area 1 sq. ft./23 acres 1 sq. ft./36 sq. miles 1 sq. inch/250 sq. miles
Quality1 bad apple/2,000 barrels
1 bad apple/2,000,000 barrels
1 bad apple/2,000,000,000 barrels
51
Dimensions of Underlying Risk PerceptionsHIGHER PERCEIVED RISK
LOW
ER P
ERC
EIVE
D R
ISK H
IGH
ER PERCEIVED
RISKDimensions of underlying risk perceptions and the characterization of the dimension
LOWER PERCEIVED RISKSource: DeVries, J.
52
The Key Is to Balance Perception with Actual Risk
53
Ways to Identify Intervention Strategies and Prioritize
“Risk-based” approach− Define an acceptable level of risk and do whatever it takes
to reduce risk to that level
54
Ways to Identify Intervention Strategies and Prioritize
“Risk-informed” approach− Define an acceptable level of risk and see whether or not
risk can be reduced to that level given economic, political, and social considerations (if so, great; if not, redefine the acceptable level of risk)
55
“Risk-Based” Approach
1. Define an acceptable level of risk2. Refer back to the quantitative risk assessment to determine
what exposure or dose confers that level of risk3. Identify intervention strategies to achieve limit of exposure
or dose to that required, and calculate the costs of each option
4. Pick the intervention that costs the least
56
“Risk-Informed” Approach
1. Do steps 1–3 on the previous slide2. Determine if all the options are at odds with economic,
political, and social considerations− If not, pick that option which is most consistent with
economic, political, and social considerations− If so, re-evaluate the acceptable level of risk, and repeat
the process
57
How Much Is a Saved Life Worth?
Safety regulations are rarely free of costIf seat belts cost, say $50 per car, and equipping a million cars with seat belts will save 1,000 lives, the regulators must be assuming that lives are worth at least $50,000 a piece
Source: (January 29, 1995). The New York Times.
58
How Much Is a Saved Life Worth?
Taking this line of thinking to its logical conclusion (with themajor regulations taken into consideration)—a saved life is worth about $3 million to $5 million
Source: (January 29, 1995). The New York Times.
59
Cost per Life Saved
Activity/process Dollar amount
Child restraints in cars 1.3 million
Dual master brake cylinders 7.8 million
Asbestos banned in brake linings 230,000
Asbestos banned in automatic transmissions 1.2 billion
Radiation safety standards for X-ray equipment
400,000
Radiation standards for uranium mine tailings 190 million
Source: (January 29, 1995). The New York Times.
60
Key Points
Risk analysis consists of risk assessment, risk management, and risk communicationIt provides a systematic approach to the understanding and reduction of risk, but must consider both “objective” and “subjective” factors, many of which are hard to quantitate
61
Key Points
The four main risk assessment activities are:1. Hazard identification2. Dose-response assessment3. Exposure assessment4. Risk characterizationRisk analysis provides the underpinning for the problem-solving paradigm