Risk Assessment -1Quantitative Microbial Risk Assessment

ENVR 890-2

Mark D. Sobsey

Spring, 2009

WHO Health-Risk Based Framework: Application to WHS

These principles apply to all types of WSH activities

WHO Health-Risk Based Framework: Application to WHS

• A risk-based framework

• Source-to-consumer management approach to protection from exposure to environmental agents

• Establishes health based-targets for control (specific microbes and chemicals)

• Sets acceptable level of risk appropriate to setting and population

• Helps establish and carry out Management Plans (Safety Plans) to achieve control

• Includes independent surveillance

• Is an integrated, proactive approach

• Consistent across, compatible with and applicable to all WSH measures

Approaches to Risk Estimation• Direct Approach: Epidemiological Analysis

– Ex. Intervention trial (RCT) or Prospective Cohort Study– Has been used to assess risk from drinking water, recreational

water and reclaimed water exposures– Problems with sensitivity (sample size issue)– Trials can are expensive (esp. in developed countries)

• Indirect approach: Mathematical models– Modeling system: ex.: Risk Assessment– Must account for properties of infectious disease processes– Pathogen specific models– Uncertainty and variability may make interpretation difficult

• Combined Epidemiological/Quantitative Microbial Risk Assessment– Dynamic modeling of disease risks in exposed populations

under defined environmental conditions – uses analytical tools and data from both epidemiology and

QMRA

Risk Assessment ParadigmsNational Academy of Sciences Paradigm

Hazard Identification and Problem Formulation are synonymous

“Analysis” corresponds to “Exposure Assessment” and “Health Effects Assessment”

Risk Characterization is the main outputI

Informs risk management, decision-making and policy; iterative & dynamic process

US EPA Integrated Risk Assessment Process

Kinds of Environmental Risk AssessmentsHuman health risk assessment• characterize potential adverse health effects of human exposures to

environmental hazards. – quantitative or qualitative in nature. – Key elements: planning and scoping, identify acute hazards,

evaluate health effects, assess exposures & characterize risks.Ecological risk assessment• Evaluate the likelihood that adverse ecological effects may occur or

are occurring as a result of exposure to one or more stressors. – Systematically evaluate and organize data, information,

assumptions, and uncertainties in order to help understand and predict the relationships between stressors and ecological effects in a way that is useful for environmental decision making.

– Key elements: planning and scoping, problem formulation, evaluating toxicity/health effects, assess exposures and characterize risks.

Important Differences Between Microbial & Chemical Risks: the Chemical

• Unique and specific structures that define (predict) activities

• Many molecules may be neded for an effect; gradation of effects

• Do not multiply/reproduce

• No secondary spread

• Accumulation and compartmentalization

• Metabolism and chemical reactivity

• Detoxification

• Threshold (no adverse effect level)

• Cumulative effects

• Magnitude of exposure influences magnitude of adverse effects and their appearance/manifestation

• Distinctive health effects based on chemical reactions with specific molecules, tissues and organs; Structure-Activity Relationships (SAR)

Important Differences Between Microbial & Chemical Risks: The Microbial

• A single microbe (one unit) is infectious and can cause dramatic effects; magnitude of effects not always related to exposure level

• Microbes multiply in a host (increases adverse effects)

– Can spread to different compartments (organs & tissues) in host

• Microbes multiply in environmental media (some microbes)

• Microbes are capable of secondary spread

– Can first infect a host from an environmental route of exposure (water, food, etc.)

– Can then spread to other hosts by person-to-person transmission

• Some microbes cause a wide range (spectrum) of adverse effects

• Microbes can change: mutate, evolve, adapt, change gene expression, etc.

Quantitative Microbial Risk Assessment

Definition:Applications of the principles of risk assessment

to the estimation of the consequences from anticipated or actual exposure to infectious microorganisms

Rationale for its emphasis:Most of the disease burden associated with lack

of access to or deficiencies in water, sanitation and hygiene is from infectious agents (microbes)

Exposure, Level of Protection and Microbial Risk: The Relationship

Risk

Exposure Level of Protection (e.g., technologic control)

= Confidence Region or Interval

Adapted from: National Academy of Sciences - National Research Council framework by US EPA and the International Life Sciences Institute (ILSI)

Quantitative Risk Assessment for Agents from Environmental Sources: a Conceptual

Framework

Risk Communication

Risk Management and Communication

RISK ASSESSMENT FOR ENVIRONMENTALLY TRANSMITTED PATHOGENS: ILSI/EPA PARADIGM

PROBLEM FORMULATION: HAZARD IDENTIFICATION

CHARACTERIZATIONOF EXPOSURE EFFECTS

CHARACTERIZATION OF HUMAN HEALTH EFFECTS

RISK CHARACTERIZATION

ILSI/EPA Risk Assessment Framework and Steps: Analysis Phase

QRA for Agents from Environmental Sources: Steps in the Conceptual Framework

Conducting Hazard Identification for Microbes

• Identify microbe(s) that is (are) the causative agent(s) of disease

• Develop/identify diagnostic tools to:

– identify symptoms; symptom complex

– identify infection

– isolate causative microbe in host specimens

– identify causative microbe in host specimens

• Understand the disease process from exposure to infection, illness (pathophysiology) and death

• Identify transmission routes

• Identify transmission scenarios

Conducting Hazard Identification for Microbes

• Assess virulence factors and other properties of the microbe responsible for disease, including its life cycle/natural history

• Identify and apply diagnostic tools to determine incidence and prevalence in populations and investigate disease outbreaks

• Develop models (usually animals) to study disease process and approaches to treatment

• Evaluate role of immunity in overcoming/preventing infection and disease and possible vaccine development

• Study the epidemiology of the microbe associated with exposure scenarios

QRA for Agents from Environmental Sources: Steps in the Conceptual Framework

Purpose: determine the quantity or dose

Dose = number, quantity or amount of microorganisms corresponding to a single exposure (e.g., by ingestion)

Exposure Assessment

•Average or typical dose

–A measure of central tendency (mean or median)

•Distribution of doses

–microbe quantity varies in time and space

–described as a probability or frequency distribution

–a probability density function

CHARACTERIZATION OF EXPOSURE - ELEMENTS INCLUDED IN PATHOGEN CHARACTERIZATION:

OCCURRENCE

• Temporal distribution, duration and frequency

• Concentration in food or environmental media

• Spatial distribution

– clumping, aggregation, association with particles, clustering

• Niche

– ecology and non-human reservoirs: Where are they in the environment and what other host harbors them?

– potential to multiply/survive in specific media

CHARACTERIZATION OF EXPOSURE - ELEMENTS INCLUDED IN PATHOGEN CHARACTERIZATION:

OCCURRENCE

• Survival, persistence, and amplification

• Seasonality

• Meteorological and climatic events

• Presence of control or treatment processes

– reliability and variability of processes

• Indicators/surrogates for indirect evaluation

– predictive of pathogen

ELEMENTS CONSIDERED IN PATHOGEN CHARACTERIZATION

• Virulence and pathogenicity of the microorganism

• Pathologic characteristics and diseases caused

• Survival and multiplication of the microorganism

• Resistance to control or treatment processes

• Host specificity

• Infection mechanism and route; portal of entry

• Potential for secondary spread

• Taxonomy and strain variation

• Ecology and natural history

KEY: Multiple sources and high endemicity (continued presence) in humans, animals and environment

• High concentrations released into or present in environmental media (water, food, air, etc.)

• High carriage rate in human and animal hosts

• Asymptomatic carriage in non-human hosts

• Ability to proliferate in water and other media

• Ability to adapt to and persist in different media or hosts

• Seasonality and climatic effects

• Natural and anthropogenic sources

Pathogen Characteristics or Properties Favoring Environmental Transmission

Microbe Levels in Environmental Media Vary Over Time Occurrence of Giardia Cysts in a Water: Cumulative Frequency

Distribution

Pathogen Characteristics or Properties Favoring Environmental Transmission

• Ability to persist or proliferate in environment

• Ability to survive or penetrate treatment processes

• Stable environmental forms

– spores, cysts, oocysts, stable outer viral layer (protein coat), bacterial capsule (outer polysaccharide layer), etc.

• Resistance to biodegradation, heat, cold (freezing), drying, dessication, UV light, ionizing radiation, pH extremes, etc.

• Resists proteases, amylases, lipases and nucleases

– Possesses DNA repair mechanisms and other injury repair processes

• Colonization, biofilm formation, resting stages, protective stages, parasitism

– Spatial distribution

– Aggregation, particle association, intercellular accumulation, etc.

Virulence properties: structures or chemical constituents that contribute to pathophysiology

• Outer cell membrane of Gram negative bacteria: an endotoxin (fever producer)

• Exotoxins: release toxic chemicals• Pili: for attachment and effacement to cells and tissues• Invasins: to facilitate cell invasion• Effacement factors• Spores

• highly resistant to physical and chemical agents• very persistent in the environment

• plasmids, lysogenic bacteriophages, etc.

Virulence Properties of Pathogenic Bacteria Favoring Environmental Transmission

Genetic properties favoring survival and pathogenicity

•Double-stranded DNA or RNA

•DNA repair

•Ability for genetic exchange, mutation and selection

–recombination

–plasmid exchange, transposition, conjugation, etc.

–point mutation

–reassortment

–gene expression control

•Virulence properties: expression, acquisition, exchange

•Antibiotic resistance

Pathogen Characteristics or Properties Favoring Environmental Transmission

Role Emergence and Selection of New Microbial Strains on Exposure Risks

• Antigenic changes in microbes can create changes that overcome immunity, increasing risks of re-infection or illness

– Antigenically different strains of microbes appear in hosts or are created in the environment; are selected for over time and space

– Constant selection of new strains by antigenic shift and drift

– Genetic recombination, reassortment , bacterial conjugation, bacteriophage infection or bacteria and point mutations

• Antigenic Shift in viruses:

– Major change in virus genetic composition by gene substitution or replacement (e.g., reassortment); Influena A viruses (e.g., H?N?)

Role Emergence and Selection of New Microbial Strains on Exposure Risks

• Antigenic Drift:

– Minor changes in genetic composition, often by mutation involving specific codons in existing genes (point mutations)

– A single point mutation can greatly alter microbial virulence

• Microbial mimicking of host antigens; e.g. malaria

– Antigens expressed by pathogen resemble host antigens; they can change

Other Pathogen Characteristics or Properties Favoring Environmental

Transmission

• Ability to Cause Infection and Illness– Low infectious dose

– High probability of infection and illness from exposure to one or a few microbes

• Infects by multiple routes– Ingestion: gastrointestinal (GI)

– Inhalation: respiratory

– Cutaneous: skin

– Eye

– Other routes

CHARACTERIZATION OF EXPOSURE:ELEMENTS CONSIDERED IN EXPOSURE

ANALYSIS• Identification of water, food or other media/vehicles of exposure

• Units of exposure (e.g number of cells)

• Routes of exposure and transmission potential

• Size of exposed population

• Demographics of exposed population

• Spatial and temporal nature of exposure

(single or multiple; intervals)

• Behavior of exposed population

• Treatment (e.g. of water), processing (e.g., of foods), and recontamination

QRA for Agents from Environmental Sources: Steps in the Conceptual Framework

Outcomes of Infection Process to be Quantified

Hospitalization

Infection Asymptomatic Infection

Mortality

Disease

Advanced Illness, Chronic Infections and Sequelae

Acute Symptomatic Illness: Severity and Debilitation

Exposure

Sensitive Populations

CHARACTERIZATION OF HUMAN HEALTH EFFECTS:ELEMENTS OF HOST CHARACTERIZATION

• Age

• Immune status

• Concurrent illness or infirmity

• Genetic background or status

• Pregnancy

• Nutritional status

• Demographics of the exposed population (density, movement or migration, etc.)

• Social and behavioral traits and conditions

CHARACTERIZATION OF HUMAN HEALTH EFFECTS:ELEMENTS OF HOST CHARACTERIZATION

• Infectivity

• Illness

• Duration of illness

• Severity of illness

• Morbidity, mortality, sequelae of illness

• Extent or amount of secondary spread

– Initial host from an environmental exposure spreads infection and illness to others

• Quality of life

• Chronicity or recurrence

Characteristics or Properties of Pathogens -Interactions with

Hosts • Disease characteristics and spectrum

– Signs, symptoms, pathophysiology

• Persistence in hosts:

– Chronicity

– Persistence

– Recrudescence

– Sequelae and other post-infection health effects

– cancer, heart disease, arthritis, neurological effects

– Yes, some microbes can cause these conditions!

• Secondary spread

Elements That May be Included in Dose-Response Analysis

• Statistical model(s) to analyze or quantify dose-response relationships

– probability of infection/illness as a function of microbe dose

• Human dose-response data

• Animal dose-response data

• Utilization of outbreak or intervention data

• Route of exposure or administration

Elements That May be Included in Dose-Response Analysis

• Source and preparation of exposure material or inoculum

• Organism type and strain

– including virulence factors or other measures of pathogenicity

• Characteristics of the exposed population

– age, immune status, etc.

• Duration and multiplicity of exposure

Dose-Response Data and Probability of Infection for Human Rotavirus

Dose # Dosed # Infected 90,000 3 3 9,000 7 5 900 8 7 90 7 6 9 7 1

0.9 7 0 0.09 5 0

Dose-Response Models and Extrapolation to Low Dose

Range• Most dose-response data for microbes are

for:– high doses of the microbes

– few hosts

• Practicalities and cost limits

• Dosing hundreds or thousands of volunteers is not possible

• But, many people become ill during epidemics– if we can be there, we can study them as “natural”

experiments

Dose-Response Models and Extrapolation to Low Dose

Range• Real world exposures to microbes from water,

food and air are often much lower microbial doses than used in human volunteer studies

• It becomes necessary to extrapolate the dose-response relationship of human volunteer studies– Extrapolation to the low dose range

– This is the range where there are no experimental data points having discrete values above zero from the low exposure doses

• a best-fit modelling approach is employed

Models Typically Applied in Microbial Dose-Response Analyses

Exponential model

Pinfection = 1 - e-rx

•r = probability of infection

•x = mean concentration/dose

•Assumes

– organisms are distributed randomly (Poisson)

– approaches a linear model at low doses

Models Typically Applied in Microbial Dose-Response Analyses

• Exponential (linear) model; two populations:

– one-hit kinetics, but

– two classes of human susceptibility to microbe

– or perhaps two form of microbes with different infectivity or illness risks

• Beta-Poisson: a distributed threshold model

– assumes Poisson distribution of microbes and a Beta-distributed probability of infection

– r is not a constant but a probability distribution (Beta-distribution)

– two variables in the model

Probabilities of Exposure and Infection

• Pexp (j Dose) = Probability of having j pathogenic microbes in an ingested dose

• Pinf (j Inf) = Conditional probability of infection from j pathogens ingested

Probability of Exposure

Exponential Dose-Response Model

Beta-Poisson Dose-Response Model

Rotavirus Dose-Response Relationships:Experimental Data, Exponential Model

and Beta-Poisson Model

Daily and Annual Risks of Various Outcomes from Exposure to Water Containing

Rotaviruses4 Rotaviruses per 1000 Liters

Human Infectivity of Norwalk Virus

• Infectious at low dose; about as infectious as rotavirus• Dispersed virus more infectious than aggregated virus• Aggregated NV in susceptible subjects, (ID50) = 1,015 genome copies

– About 2.6 (aggregated) particles. • For completely disaggregated viruses ID50 = 18 viruses

Teunis, PFM CL. Moe, PLiu, SE. Miller, L Lindesmith, RS. Baric, J Le Pendu, and RL. Calderon (2008) Norwalk Virus: How Infectious is It? J. Med. Virol. 80:1468–1476.

Comparing Risks of Disease Agents

• Comparing chemical to microbial risks as well as among agents of each type

• Effects vary widely in severity, mortality rates and time scale of exposure

• Need to protect both quality and quantity of life

• WSH policy needs to be linked to overall public health policy

• Decision making process needs to take social and economic factors into account

Desirable attributes of an integrated measure of risk

• Address probability, nature and magnitude of adverse health consequences

• Incorporate age and health status of those affected

• Disability Adjusted Life Year (DALY) has become the metric used by WHO and others as the common risk measure for microbial and chemical agents