Transcript Chapter 1

Chapter Two
Risk Concepts
Risk and Risk Assessment
Risk: the probability that a substance or situation will
produce harm under specific conditions. Risk is a
combination of two factors: the probability that an
adverse event will occur and the consequences of the
adverse event. - The Presidential/Congressional
Commission on Risk Assessment & Risk
Management, Vol. 1, 1997.
Risk assessment is a systematic, analytical method used
to determine the probability of adverse effects. A
common application is to evaluate human health and
ecological impacts of chemical releases to the
environment.
Risk Examples
• What is the probability that certain types of
cancer will develop in people exposed to
benzene from gasoline?
• What is the likelihood that workers exposed to
lead will develop nervous system disorder?
• Risk is normally formulated as the probability
for an individual to suffer an adverse effect
from an event.
Safety Assessment vs. Environmental
Risk Assessment
• From engineering perspective, it may be useful to think of risk
as safety issues extrapolated from the present to the long term.
That is, safety may be thought of as the likelihood of
immediate adverse consequences, and environmental risk as
the likelihood of long-term adverse consequences.
• One important distinction between the environmental risk and
conventional safety issues is that while the consequences of
chemical accidents are readily linked to their causes, chronic
exposures from chemicals often are not.
• Any risk assessment should be carefully and fully documented,
including specific references for data used and calculations
used to reach a conclusion. This is due to the “volatility” of
input data.
Risk Assessment: Introductory
Concepts
Risk = F(exposure x hazard)
Chapters 5,6
Chapters 2,5
Steps in risk assessment
»
»
»
»
Hazard assessment
Exposure assessment
Dose/response relationships
Risk characterization
Hazard
Hazard is the potential for a substance or situation to
cause harm or create adverse impacts on person or the
environment.
The magnitude of the hazard reflects the potential
adverse consequences, including mortality, shortened
life-span, impairment of bodily function, sensitization
to chemicals in the environment, or diminished ability
to reproduce.
For chemicals the term hazard is typically associated
with the toxic properties of a chemical specific to the
types of exposure.
Exposure
Exposure denotes the magnitude and the length
of time the organism is in contact with an
environmental contaminant, including
chemical, radiation, or biological contaminants.
In this course, the exposure term will be for
human exposure (ingestion, inhalation and
dermal).
Hazard Assessment
A chemical exposure hazard assessment answers
the questions: What are the adverse health
effects of a chemical? Under what conditions?
The most common effects, or endpoints, studied
are various kinds of cancers, but other types
of adverse health effects such as endocrine
disruption or reproductive toxicity are also
currently being studied.
Cancer
Cancer can be caused by two different types of
chemical substances – genotoxic carcinogens
and nongenotoxic carcinogens.
Genotoxic chemicals are believed to have no
threshold amount below which they will NOT
cause cancer.
Nongenotoxic carcinogens are believed to have a
safe threshold quantity.
Hazard Assessment for Cancer
US EPA guidelines:
1.
2.
3.
4.
5.
6.
Group A: Carcinogenic to humans (20 chemical);
Group B1: Probably carcinogenic to humans based on
limited human data;
Group B2: Probably carcinogenic to humans based on
sufficient animal data, inadequate human evidence;
Group C: Possibly carcinogenic to humans;
Group D: Not classified for human carcinogenicity;
Group E: Evidence for non-carcinogenicity for humans.
Cancer Slope Factor (Example)
A study of the potential of acrylonitrile to produce brain
tumors in Fischer 344 rats was conducted by
administering the carcinogen in drinking water for 24
months. The results of the study for female rats are
tabulated below:
excess deaths  m  dose rate (mg/kg-day)
 (excess risk)
0.3802
m

 0.0234
 (dose, mg/kg-day) 16.27
Hazard Assessment for Non-Cancer
Endpoints
• Adverse effects other than cancer and gene mutations
are generally assumed to have a dose or exposure
threshold.
• The 1st step to evaluate potential risk for non-cancer
effects requires identification of a critical effect for
which the magnitude of the response can be assessed.
• The Reference Dose (RfD) or Reference
Concentration (RfC) approach is used to evaluate
such chronic effects.
Reference Dose (RfD) and Reference
Concentration (RfC)
The RfD is defined as “an estimate of a daily
exposure to the human population that is likely
to be without appreciable risk of deleterious
effects during a lifetime” (US EPA, 2000). It is
expressed as mg pollutant/kg body weight/day.
The RfC is expressed in mg per cubic meter.
Either one of them can be interpreted as the
baseline “safe” dose or concentration to which
a real exposure may be compared.
Deriving RfD and RfC
The basic approach involves
1. determining a “no-observed-adverse-effect
level (NOAEL)” or “lowest-observedadverse-effect level (LOAEL)” from an
appropriate animal study or human
epidemiologic study, and
2. applying various uncertainty and modifying
factors to arrive at RfD and RfC.
Uncertainty Factors
An RfD based on NOAEL from long-term animal study might
incorporate (1) a factor of 10 to account for the uncertainty in
extrapolating from the test species to humans, (2) a factor of
10 to account for the variation in sensitivity within the human
population, and (3) a factor of 10 to extrapolate from subchronic test exposures to potentially chronic human exposures.
An RfD based on LOAEL typically contains an additional factor
of 10 to account for the extrapolation from LOAEL to NOAEL.
Another modifying factor is sometimes applied to account for
uncertainties in data quality.
The combination of these uncertainty factors can result in highly
conservative interpretations.
RfD Formula
Example
In a 3-month subchronic study in mice, the NOAEL for
tris (1,3-dichloro-2-propyl) phosphate was 15.3
mg/kg body weight/day; the LOAEL was 62 mg/kg
body weight/day at which dose abnormal liver effects
were noted.
Based on NOAEL
RfD 
Based on LOAEL
NOAEL
15.3

 0.015mg/kg-day
FA FH FS 10 10 10
LOAEL
62.0
RfD 

 0.0062mg/kg-day
FA FH FL FS 10 10 10 10
Hazard Assessment
Indicators of chemical toxicology
Carcinogenic effects - Slope Factor (SF), Weight of Evidence (WOE) classification
Noncarcinogenic effects - No Observable Adverse Effects Level (NOAEL),
Reference Dose (RfD), Reference Concentration (RfC), Permissible Exposure
Limit (PEL), Threshold Limit Value (TLV)
Sources of Data for Health Effects
1. The Material Safety Data Sheet - MSDS
2. NIOSH Pocket Guide to Chemical Hazards (www.cdc.gov/niosh.npg/gpdstart.html)
3. Integrated Risk Information System (IRIS) (http://www.epa.gov/ngispgm3/iris/index.html)
4. National Library of Medicine (ToxNet) (http://sis.nlm.nih.gov/sis1)
5. Casarett and Doull’s “Toxicology, the Basic Science of Poisons”, Macmillan
6. Patty’s Industrial Hygiene and Toxicology, John Wiley & Sons
Structure Activity Relationships
(SAR)
The US EPA often use SARs when estimating
hazard and other elements of risk.
SARs estimate hazards by drawing analogies
with chemically similar substances (a
structural analog) whose hazard has already
been studied.
Structural activity is defined as the relationship
between the structural property of a molecule
and its biological activity (health effects).
Dose Response Curve
How large a dose causes what kind of effect?
Effective Dose
(reversible)
Toxic Dose
(irreversible)
Lethal Dose
Crowl and Louvar, Chemical Process Safety: Fundamentals with Applications, Prentice Hall, 1990
Dose-Response
• This analysis enables risk assessors to estimate a “safe”
dose.
• For a given chemical, there is a separate curve for each
adverse effect.
• The outcome of the overall dose-response effort helps
tell the assessor what the toxicological endpoint of
concern is.
• The dose-response study also provides the NOAEL.
• For cancer, dose-response analysis is appropriate for
Group A and B substances. Fewer than 10% of the
80000 or so chemicals in commerce currently have
dose-response curves.
Concerns of Dose-Response Analysis
1. Different species may have different responses.
2. Very high doses, to the point of acute poisoning of
the test animal, are sometimes necessary to generate
a statistically significant effect.
3. Since it may take a long time for cancers to be
detected in laboratory animals, some otherwise
well-designed experiments may have been too brief.
4. The route of exposure can also affect the outcomes
of an analysis.
Exposure Assessment
• The amount of a substance that comes into
contact with the external boundaries of a
person is called exposure.
• The quantity that crosses the external boundary
is defined as dose and the amount absorbed is
the internal dose.
• The ratio of the internal dose to exposure is
called bioavailability of the substance.
Exposure Routes
Exposure Routes
• Most dermal exposures result from hand contact and
may occur while performing common worker
activities such as sampling, drumming, filter
changing, and maintenance. (Bioavailability: 5%)
• Inhalation exposure may be in the form of vapors,
aerosols, or solid particulates. Exposure to vapor
may occur due to vapors generated during activities
such as drumming and sampling, or from fugitive
emissions from small process leaks (Close to 100%
bioavailability).
• Ingestion and percutaneous exposure (injection
through the skin) are not usually of interest.
Exposure Assessment
1. The preferred approach is to use personal
monitoring data for the chemical of interest
at the site.
2. Monitoring data for the chemical at sites with
similar operations.
3. Data for a surrogate chemical.
4. Mass balance model
5. Biomarker
Exposure Assessment (Ch 6)
• Occupational Exposure- exposure to people in the workplace
• Community Exposure- exposure outside the workplace
Different modeling approaches and assumptions
Exposure Assessment Methodology - Community Exposure
1. Identify all waste stream components and concentrations
2. Estimate release rates to the air, water, and soil
3. Choose proper exposure pathways (through environment) and routes (into
humans)
4. Determine exposure concentrations at the point of exposure to humans
using measurements or an environmental fate and transport model
Exposure Assessment
Exposure Routes
1. Inhalation
2. Ingestion
3. Dermal (skin)
Multiple pathways
are possible
Exposure assessment - H2S release
example
Atmospheric
dispersion
Model, Ca
x = 300 m
H=0m
 H2 
Ca 
exp 2 
 y zv x
 2 z 
Q
Q = 0.025 kg/s H2S
Rural release, daytime neutral atmosphere, x<500m, vx=4 m/s
Ca 
0.025 kg / s
 7.17  10 6 kg / m 3  1.71 mg / m 3
1.78
 (.01082 (300 m) (4 m / s))
Rural release, nighttime stable atmosphere, x<500m , vx=2.5 m/s
Ca 
yz = 0.01082 x1.78
yz = 0.0049 x1.66
0.025 kg / s
 5.02  105 kg / m3  50.2 mg / m3
1.66
 (.0049 (300 m) (2.5 m / s))
Risk Characterization of Cancer
Risk is defined as the probability of developing
cancer (in excess of the background cancer
level) from a particular chemical is a subpopulation is exposed to that chemical over a
lifetime.
Risk  f  Hazard, Exposure
Risk Characterization of NonCancer Endpoint
Hazard Quotient 
(estimated chronic dose) or (estimated exposure level)
1
RfD
Module 1: Risk Characterization
Carcinogenic
Risk Example
(inhalation route)
(Ca  CR  EF  ED)

Risk i = 
 SF
(BW  AT)

i
Result: # excess cancers per 106
cases in the population;
10-4 to 10-6 acceptable
Exposure Dose
(mg/kg/d)
Dose - Response Relationship,
Slope Factor (mg/kg/d)-1
Exposure Factors
CR = contact rate (m3 air breathed / day)
EF = exposure frequency (days / yr)
ED = exposure duration (yr)
BW = body weight (kg)
AT = averaging time (days) - 25,550 days for carcinogenic risk