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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