Microbial Risk Assessment -1

Download Report

Transcript Microbial Risk Assessment -1

Risk Assessment -1
Quantitative 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 Paradigms
National Academy of Sciences Paradigm
US EPA Integrated Risk Assessment Process
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
Kinds of Environmental Risk Assessments
Human 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
= Confidence Region or Interval
Risk 
Exposure 
 Level of Protection (e.g., technologic control)
Quantitative Risk Assessment for Agents from
Environmental Sources: a Conceptual Framework
Risk Communication
Adapted from: National Academy of Sciences - National Research Council framework by US EPA and the International
Life Sciences Institute (ILSI)
RISK ASSESSMENT FOR ENVIRONMENTALLY
TRANSMITTED PATHOGENS: ILSI/EPA PARADIGM
PROBLEM FORMULATION: HAZARD IDENTIFICATION
CHARACTERIZATION
OF EXPOSURE EFFECTS
CHARACTERIZATION OF
HUMAN HEALTH EFFECTS
RISK CHARACTERIZATION
Risk Management and Communication
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
Exposure Assessment
Purpose: determine the quantity or dose
Dose = number, quantity or amount of
microorganisms corresponding to a single
exposure (e.g., by ingestion)
• 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
Pathogen Characteristics or Properties
Favoring Environmental Transmission
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
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 of Pathogenic Bacteria Favoring
Environmental Transmission
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.
Pathogen Characteristics or Properties
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
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
Exposure
Advanced
Illness,
Chronic
Infections
and
Sequelae
Infection
Disease
Asymptomatic
Infection
Acute Symptomatic Illness:
Severity and Debilitation
Sensitive Populations
Mortality
Hospitalization
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 DoseResponse Analysis
• Statistical model(s) to analyze or quantify doseresponse 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 DoseResponse 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 doseresponse 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 Betadistributed probability of infection
– r is not a constant but a probability distribution (Betadistribution)
– 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 Rotaviruses
4 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