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Robert G. Sussman, Ph.D.

, DABT
Managing Principal, Eastern Operations
SafeBridge Consultants, Inc.
Mountain View, CA New York, NY Liverpool , UK
Paracelsus (1493 1541)
All substances are poisons; there is none without a
poison. The right dose differentiates a poison from
a remedy.
This is the foundation for setting an
Occupational Exposure Limit (OEL)
Acceptable airborne concentration for worker
exposure; similar to OSHA PEL or ACGIH TLV
Some sub-population of workers, due to individual
susceptibility, may be adversely affected at
concentrations at or below the OEL
OEL is sometimes developed to protect even sensitive
subgroups, e.g., women of child bearing age, asthmatics
Developed when a drug reaches significant
manufacturing amounts or critical FDA stage
Simultaneous development of sensitive analytical
method required for industrial hygiene monitoring
Time Weighted Average (TWA 8 hr)
The concentration for an 8-hour workday, 40-hour work
week, to which nearly all workers maybe repeatedly
exposed, day after day, without adverse effect.
Short Term Exposure Limit (STEL)
The concentration to which workers can be exposed for a
short period of time without suffering irritation,
irreversible tissue damage, or significant narcosis.
Used when allowable excursions above an 8 hour TWA may
produce an effect
Useful for fast acting drugs - set limit close to effect level
Government agencies
OSHA PELs
German MAKs
NIOSH RELs
EPA NCELS
Consensus groups
ACGIH TLVs
AIHA WEELs
Company-specific chemicals Novel compounds
No PELs, TLVs, WEELs, RELs, MAKs, etc.
Requirements under European regulations to set OELs
TSCA Section 8, New Chemical Use
Responsibility of employer to provide a safe workplace
Protect other company assets
Dont trust the existing limit
Pharmaceuticals have not usually had OELs developed
by OSHA or ACGIH
Collect data
Evaluate human and animal studies
Identify critical endpoint(s)
Most sensitive adverse effect relevant to
humans
For pharmaceuticals, often related to
pharmacological action of drug
Select risk assessment methodology
Nomenclature
Physicochemical properties
Animal data
Human use and experience
Rationale
Key studies considered
Selection of critical endpoint(s)
Selection of safety factors (optional)
Discussion of uncertainties
Other considerations
Physicochemical properties
Toxicological properties
Animal data
Human use and experience
Toxicokinetics / pharmacokinetics
Controlled studies
Experimental tests with humans
Epidemiological studies of worker populations
Clinical trials of therapeutic agents
Case Reports
Accidental or intentional poisonings
Medicinal interactions
Workplace or anecdotal reports
Absorption
Distribution
Metabolism
Elimination
Identifying the key study & critical endpoint
Preference for human data
Chronic studies by the most relevant route
Most sensitive animal species and organ system
target
NOAEL vs LOAEL
Data quality
%

R
e
s
p
o
n
s
e
Dose
UF
OEL
NOEL NOAEL LOAEL FEL
Slight decrease
in body weight
Fat in liver cells
(critical effect)
Convulsions
Enzyme
changes
Analogy
Correlation
Low dose extrapolation for carcinogens
Margin of safety/uncertainty factor
Incomplete data set for chemical of interest
OEL set based on data for homologous chemical
qualitative structure activity relationship
OEL
a
= OEL
b
Assumes similar toxicity for compounds in a
structural series ... not always a valid assumption
Useful for commodity chemicals
Steroid X is structurally similar to steroid Y
(they differ by one OH group)
Steroid Y has an OEL and an extensive data set
No information available on steroid X
OEL
steroid X
= OEL
steroid Y
In pharmaceutical industry, would probably use
banding
CH
CH
3 3
-
-
CH
CH
2 2
-
-
CH
CH
2 2
-
-
CH
CH
3 3
CH
CH
3 3
-
-
CH
CH
2 2
-
-
CH
CH
2 2
-
-
CH
CH
2 2
-
-
CH
CH
3 3
CH
CH
3 3
-
-
CH
CH
2 2
-
-
CH
CH
2 2
-
-
CH
CH
2 2
-
-
CH
CH
2 2
-
-
CH
CH
3 3
Butane
Butane
Pentane
Pentane
Hexane
Hexane
TLV (ppm)
TLV (ppm)
600
600
50
50
800
800
CH
3
OH


Benzene Toluene Phenol
0.5 ppm 20 ppm (NIC) 5 ppm
TLV
Similar to analogy
Compares specific quantifiable property related
by potency
OEL
b
= (PC
b
/PC
a
) x OEL
a
PC is a physicochemical or pharmacological property
PC must be established as a valid predictor of the
biological effect upon which the OEL is based
OEL for propionic acid based on irritation
Irritation potential = f(acidity) = f(pK
a
)
Bromopropionic acid = 70x more acidic than
propionic acid
OEL
bromopropionic
acid = TLV
propionic
acid / 70
Synthetic analogues of endogenous products
Synthetic hormone C toxicity unknown
Known to be 5 times as potent as endogenous
hormone D extensive data set with OEL
OEL
D
(40 g/m
3
) is based on pharmacological effect
OEL
C
= (PC
c
/PC
d
) x OEL
D
OEL
C
= 1/5 x 40 g/m
3
= 8 g/m
3
Derive an acceptable human exposure level by applying
Derive an acceptable human exposure level by applying
safety/uncertainty factors to the no
safety/uncertainty factors to the no
-
-
observed
observed
-
-
adverse
adverse
-
-
effect level (NOAEL)
effect level (NOAEL)
u u
Identify the critical endpoint
Identify the critical endpoint
u u
Define the no
Define the no
-
-
effect level
effect level
u u
Consider sources of uncertainty
Consider sources of uncertainty
u u
Calculate an occupational exposure limit for
Calculate an occupational exposure limit for
inhalation in the workplace
inhalation in the workplace
where:
NOEL = No Observed Effect Level
TD = Therapeutic dose
BW = Body Weight
UF
1,2,3
= Uncertainty Factors
= Adjustment for pharmacokinetics
V= Volume breathed in an 8-hour day (10 m
3
)
NOEL x BW
NOEL x BW
UF
UF
1,2,3 1,2,3
x
x

x V
x V
TD
TD
UF
UF
1,2,3 1,2,3
x
x

x V
x V
OEL =
OEL =
or
or

"NOT SAFE"
region of
adverse
effects
"SAFE
region of
no effects
Fog of
uncertainty
INCREASING DOSE
OEL
Above OEL
Human-to-human variability in response
Animal-to-human extrapolation
LOAEL to NOAEL extrapolation
Study duration
Severity
Exposure route
u Default = 10
u Renwick, 1993
u Data-derived adjustment factors
u May use 3-10 based on supportable scientific
judgment
Healthy
Population
N
u
m
b
e
r

o
f

I
n
d
i
v
i
d
u
a
l
s
PK Parameter
50% 95%
Sensitive
Subpopulation
Healthy
Population
N
u
m
b
e
r

o
f

I
n
d
i
v
i
d
u
a
l
s
PK Parameter
50%
95%
Allometric Scaling
Uses surface area of the animal to scale
equivalent doses
Surface area is related to relative metabolism of
the species better than body weight
Factors used for various species are as follows:
Monkey = 2
Rat = 6
Mouse = 12
Default (10)
Comparison of data from Physicians Desk Reference
Maximum Therapeutic Dose
Minimum Therapeutic Dose
Severity of effect (3 to 10)
Use Benchmark Dose mathematic low dose
extrapolation model
3
Time (days) Time (days)
A
m
o
u
n
t

i
n

B
o
d
y
A
m
o
u
n
t

i
n

B
o
d
y
(
m
g
)
(
m
g
)
1.5 1.5
1.0 1.0
0.5 0.5
0 0
From Sargent & Kirk (1988) From Sargent & Kirk (1988)
Linearized multistage (LMS) model
Mathematical curve-fitting of data points
Essentially linear dose-response at low doses
Extrapolate using straight line to origin - assumes no
threshold
Specify acceptable cancer rate
Use ratio of response to a risk level you feel is acceptable (1
in a million; 1 in 1000)
Determine dose corresponding to that cancer rate
(RSD risk specific dose)
Antihistamine
Rare allergic reactions in the class
Induces drowsiness
Equivocal in NTP cancer bioassay
Minimum therapeutic dose (LOAEL) = 30 mg
Plasma elimination half-life = 3.0 hours
TD = 30 mg
UF
1
= 3
UF
2
= 10
= 1
V = 10 m
3
OEL =
OEL =
OEL =
OEL =
OEL =
OEL =
0.1 mg/m
0.1 mg/m
3 3
(8
(8
-
-
hr TWA)
hr TWA)
TD
TD
UF
UF
1,2,3 1,2,3
x
x

x V
x V
30 mg
30 mg
30 x 1 x 10 m
30 x 1 x 10 m
3 3
Data gaps / Uncertainties / Limitations
animal-to-human extrapolation
human-to-human variability in response
no human data by inhalation route
inadequate number of normal humans tested
inadequate testing in the opposite sex
need for exposure control before sufficient data available
artificial precision due to significant figures
Other considerations
Skin notation
Sensitizer notation
robert.sussman@safebridge.com
212-727-0717 x2