Human
Health
Risk
Assessment
Overview
Michael
S.
Metzger
Michael
S.
Metzger
U.
S.
EPA
U.
S.
EPA
Office
of
Pesticide
Programs
Office
of
Pesticide
Programs
(
703)
305
(
703)
305­
5883
5883
Metzger.
michael@
epa.
gov
Metzger.
michael@
epa.
gov
April
4,
2006
April
4,
2006
2
Risk
Assessment
Paradigm
Risk
Assessment
Paradigm
Hazard
Identification
Dose
Response
Assessment
Exposure
Assessment
Risk
Characterization
*
From
the
National
Research
Council's
Risk
Assessment
in
the
Federal
Government:
Managing
the
Process,
1983.
3
Hazard
Assessment:
Hazard
vs.
Risk
Hazard
Assessment:
Hazard
vs.
Risk

Risk
=
f
(
hazard,
exposure)


Hazard
=
Toxicity
4
Standard
Guideline
Toxicity
Study
Requirements
Standard
Guideline
Toxicity
Study
Requirements
 
Acute
toxicity
battery
 
Subchronic
oral
toxicity
in
rats
 
Subchronic
dermal
toxicity
in
rats
and
rabbits
 
Subchronic
inhalation
toxicity
in
rats
 
Developmental
toxicity
in
rats
and
rabbits
 
2­
Generation
reproduction
in
rats
 
Chronic
/
carcinogenicity
in
rats,
dogs,
and
mice
 
Acute
(
ACN)
and
subchronic
(
SCN)
neurotoxicity
in
rats
 
Delayed
neurotoxicity
in
hens
 
Mutagenicity
testing
battery
(
in
vitro)

 
Developmental
neurotoxicity
(
DNT)
in
rats
 
Dermal
absorption
 
Rat
metabolism
5
Hazard
Characterization
Hazard
Characterization

Important
toxicological
effects
including
developmental
/

fetal,
reproductive,
endocrine,
carcinogenic,
and
others

Any
critical
exposure
periods
and
routes

Metabolism
and
potential
for
bioaccumulation

Quality
of
the
data
and
uncertainties

Toxicity
data
available
for
related
chemicals

Pertinence
of
the
observed
toxicity
to
humans

Availability
of
related
epidemiological
data

Toxic
mode
of
action
information
6
Dose
Dose­
response
Assessment
and
Endpoint
response
Assessment
and
Endpoint
Selection:
Definitions
Selection:
Definitions

Point
of
Departure
(
POD):
Any
dose
level
used
to
quantify
risk
(
generic)


Endpoint:
Toxic
Effect
upon
which
the
risk
assessment
is
based

Lowest
Observed
Adverse
Effect
Level
(
LOAEL):

Lowest
dose
from
a
study
at
which
adverse
toxic
effects
were
observed

No
Observed
Adverse
Effect
Level
(
NOAEL):
The
dose
below
the
LOAEL
at
which
no
adverse
toxic
effects
are
observed
7
Benchmark
Dose
(
BMD)
Approach
Benchmark
Dose
(
BMD)
Approach
BMD:
The
dose
associated
with
a
specified
measure
or
change
of
a
biological
effect,
generally
in
the
range
of
1%
to
10%.

BMDL:
A
lower
one­
sided
confidence
limit
on
the
BMD.

 
Uses
all
data
points
from
one
or
more
toxicity
studies
to
statistically
derive
a
dose­
response
curve
 
Improved
estimate
of
the
dose­
response
relative
to
using
NOAELs/
LOAELs
­
POD
less
dependent
on
dose
spacing
 
Used
for
some
single
chemical,
and
all
cumulative
risk
assessments
8
Dose
Dose­
response
Assessment
and
Endpoint
Selection
response
Assessment
and
Endpoint
Selection
Endpoints
selected
for
risk
assessment
must
be
the
most
sensitive
endpoint
for
each
population,

and
relevant
to
humans.


Most
sensitive
(
protective)
 
Most
protective
POD
(
e.
g.
lowest
NOAEL,
highest
q*)


Relevant
 
Toxicity
seen
in
animal
studies
could
also
occur
in
humans
9

3
Major
routes:
oral,
dermal,
inhalation

Toxic
effects
seen
and
severity
of
toxic
effects
can
vary
by
route

Of
particular
concern
for
portal
of
entry
effects

Must
assure
that
route
of
dosing
in
animal
study
matches
human
exposure
route
 
or
characterize
any
mismatch
Dose
Dose­
response
Assessment
and
Endpoint
Selection:

response
Assessment
and
Endpoint
Selection:

Route
Route
10
Dose
Dose­
response
Assessment
and
Endpoint
Selection:

response
Assessment
and
Endpoint
Selection:

Duration
Duration
Chemical­
specific
Cancer
6
months
­
lifetime
Chronic
1­
6
months
Intermediate­
term
(
IT)
1­
30
days
Short­
term
(
ST)
1­
day
Acute
Duration
of
Continuous
Exposure
Scenario
11
Uncertainty
and
Safety
Factors
Uncertainty
and
Safety
Factors
°
"
One
of
several,
generally
10­
fold
factors,
used
in
operationally
deriving
the
RfD
and
RfC
from
experimental
data"
(
http://
www.
epa.
gov/
iris/
gloss8.
htm)

°
Intraspecies
 
variability
among
humans
°
Interspecies
 
extrapolating
animal
data
to
humans
°
Extrapolating
from
less­
than­
lifetime
to
lifetime
exposures
°
LOAEL
to
NOAEL
°
Incomplete
data
base
°
FQPA
12
Expressing
Risks
Expressing
Risks
%
Reference
Dose
(%
RfD):

RfD
=
NOAEL
UFs
(
all
except
FQPA
SF)

%
RfD
=
Exposure
x
100
RfD
Margin
of
Exposure
(
MOE)

MOE
=
NOAEL
Exposure
13
Expressing
Risks
Expressing
Risks
%
PAD
=
Exposure
x
100
PAD
%
Population
Adjusted
Dose
(%
PAD):

PAD
=
NOAEL
UFs
(
all
including
FQPA
SF)
14
Aggregate
Risk
Assessment
Aggregate
Risk
Assessment
Aggregate
risk
includes
combined
exposure
from:


Food

Drinking
water

Other
non­
occupational
exposures
(
e.
g.

residential,
playing
golf)

Aggregate
assessments
done
for
all
durations
of
exposure
Oral,
dermal
and
inhalation
routes
aggregated
if
common
toxic
effects
are
expected
from
the
different
routes
15
Cumulative
Risk
Assessment
Cumulative
Risk
Assessment
Total
risk
aggregated
for:


all
potential
exposure
scenarios

all
routes
of
exposure

across
chemicals
which
have
a
common
mechanism
endpoint
Chemical
A
­

Chemical
B
­

Chemical
C
­
Food,
drinking
water,

residential
exp
Food,
drinking
water,

residential
exp
Food,
drinking
water,

residential
exp
Cumulative
Risk
}
16
Cumulative
Risk
Assessment
Cumulative
Risk
Assessment

Uses
the
BMD
approach

Utilizes
Relative
Potency
Factors
(
RPFs;
index
chemical
=
1)
which
correct
exposure
estimates
for
comparison
to
a
common
POD

POD
for
index
chemical
which
has
highest
quality
toxicity
data
base
among
chemicals
in
Common
Mechanism
Group
(
CMG)


http://
www.
epa.
gov/
oppfead1/
trac/
science/#
common
17
Questions
