Route-to-route

extrapolation of VOCs
Components of this package
Guidance document (2006)

White paper

Spreadsheet for simple r-to-r extrapolation
Purpose
The purpose of this guidance document and the white paper
is to provide a consistent approach in risk extrapolation of
chemicals through different routes of exposure.


What is R-to-R extrapolation?
Route-to-route extrapolation techniques are used to quantify the
chemical concentration to produce similar magnitude of the effect
through different routes of exposure
Exposure
route 1
Exposure
route 3
Exposure
route 2
Similar Internal dose Similar magnitude of effect
R-to-r R-to-r
Exposure
Concentration
Absorbed Dose
Tissue Dose of
Toxic Moiety
Toxic Moiety-
-Target Interaction
Perturbation
Cellular
Changes
Adverse Effects
Exposure to Effects
Limited and extensive data base
Internal dosimetry
Conc.
mg*L
-1
Time (Hr)
Blood concentration profiles of a hypothetical chemical following oral, inhalation and
dermal exposure
oral
inhalation
dermal
Route-to-route extrapolation a quantitative
toxicity data base
Route-to-route extrapolation quantifies the toxicological equivalent
dose of a chemical through different routes of exposure.


This requires quantitative chemical specific data base - e.g. ADME
data.


Route-to-route extrapolation is generally carried out at
concentrations equivalent to the LOAEL or NOAEL doses.



Why should we do R-to-R
extrapolation?
In the absence of chemical specific dose-response information
through any route of exposure and if there is a need to assess the
toxicity through this route of exposure, r-to-r extrapolation becomes
necessary.

To reduce the uncertainties by using advanced r-to-r extrapolation.

Potentially be used as a tool for mechanistic understanding.


Methods of R-to-R extrapolation and
the order of preference
Internal dosimetry (critical organ - e.g. blood, CNS), which
can also include the metabolites
Absorbed dose
Administered dose
Application of TK data for route-to- route
extrapolation
Extrapolation using TK data and PBTK model data rich situation
Extrapolation using route/chemical specific absorption data
Extrapolation using basic physiological data
Dose calculations
Exposed Dose
Dose
inhaled
= Cair x Qp
BW

NOAEL
inhalation
= NOAEL
oral
x Body weight / Qp


Absorbed Dose
Dose
inhaled
(mg/kg/d) = Cair x Qp x t x Fi
BW

NOAEL
inhalation
= NOAELoral x BW x Fo
Qp x F
i
Fi = fraction inhaled
Fo = fraction absorbed orally
Qp = Alveolar ventilation rate
Equations for converting the dose from one route of
exposure to another on the basis of the fraction absorbed

Dermal
To
Oral

Inh.
Dermal

NOAELdermal*Fd
Fo

NOAELdermal*BW*Fd
Qp*t*Fi
F Oral
r
o
m


NOAELoral*Fo
Fd


NOAELoral*BW*Fo
Qp*t*Fi
Inh.
NOAELinh* Qp*t*Fi
BW*Fd
NOAELinh* Qp*t*Fi
BW*Fo

The decision tree showing the level of
sophistication in carrying out r-to-r
extrapolation.
Use default extrapolation factors based on
administered dose
Is a valid BBDR model available for the routes and
species of interest?
Are route-specific TK data or models available?
Route-to-route extrapolation not recommended
Toxicity -based assessment
Internal dose based assessment
Is the POD based on a systemic toxic effect?
Is the fraction absorbed by both routes known for the
chemical of concern or a closely related chemical?
Absorbed dose-based assessment
YES
NO, DNK
YES
NO
YES
NO
YES
NO
Availability of chemical specific data
Physicochemical and Biochemical Parameters used in PBTK Modeling of
Toluene (Haddad et al., 2001)-

Human Parameters Values

Blood: air 15.6

Fat: air 1021

SPT: air 27.7

RPT: air 83.6

Liver: air 83.6

Vmax (mg/h/kg) 3.44

Km (mg/L) 0.13

Internal Dose (inhalation)
|
.
|

\
|
+
+
=
b
p
c
v c inh p
a
P
Q
Q
C Q C Q
C
ss
Ca = Arterial blood concentration
Qp = Alveolar ventilation rate
C
inh
= Concentration in inhaled air,
Cv = Concentration in mixed venous blood,
Pb = Blood:air partition coefficient, and
Qc = Cardiac output
PBTK Model schematic
(Mumtaz et al., 2011)
Internal Dosimetry
Ca = Arterial blood concentration
QLC = the ratio between blood flow rate to the liver and the
rate of cardiac output
C
i
= Concentration in inhaled air
P
b
= Blood:air partition coefficient
E = Metabolic extraction ratio
( ) E QLC
P
C
Ca
b
i
ss
*
1
+
|
.
|

\
|
=
Effect of Metabolic Clearance
0 , = E when
b
i
P
C
Cass
1
1+
=
1 , = E when
b i ss P C Ca * =
Factors affecting r-to-r extrapolation
on top of chemical specific info.
Chemical Mixture
Interference due to metabolism and elimination


Alveolar ventilation rate
Increased respiration

Limitations of R-to-R extrapolation
Lack of toxicokinetic data especially for metals (eg. Nickel oral
absorption factor)

Lack of mechanistic understanding for chemical toxicity, especially
through different routes of exposure

Lack of data to validate route to route extrapolation

Limited to chemicals that exhibits systemic toxicity
When do we require r-to-r extrapolation
Site specific human health risk assessment.


Development of media-specific chemical standards


Providing toxicological opinion
HHRA
Human-health-risk-assessment (HHRA): Risk quantification
during HHRA requires both chemical specific exposure data and
chemical specific toxicological benchmark dose (e.g. RfD).

SSRA are usually carried out considering all the possible media of
exposure.

However, the benchmark dose may not be available for all the
routes of exposure for many chemicals.

Hence, a route-to-route extrapolation should be carried out during
the process of risk assessment. HHRA can range from EA,
Brownfields, CBRA, GLC.
Media specific chemical standards
When setting media specific standards, toxicological
information may predominantly be available with any
one specific route of exposure (e.g. benzene
inhalation route). In such cases, route-to-route
extrapolation becomes a mandate to extrapolate
toxicological information from one route of exposure to
the other.
Others
When expressing a toxicological opinion in a briefing
note or as an expert witness or in a emergency
situation, if detailed toxicological dose response
information is not available for a particular route of
exposure for a chemical, route-to-route extrapolation is
essential.

What did we get from here?
A decision tree

A table of conversion factors

Explained in,

A guidance document

A white paper

A spreadsheet to carryout quantitative r-to-r extrapolation

Additional reading

Chiu W.A., White P. (2006): Steady-state solutions to PBPK models
and their applications to risk assessment I: Route-to-route
extrapolation of volatile chemicals. Risk Analysis. 26(3): 769-780.

Falk-Filipsson A., Hanberg A., Victorin K., Warholm M., Wallen M.
(2007): Assessment factors applications in health risk assessment
of chemicals. Environ. Res. 104(1): 108-127.

Chiu W.A., Barton H.A., DeWoskin R.S., Schlosser P., Thompson
C.M., Sonawane B., Lipscomb J.C., Krishnan K. (2007): Evaluation
of physiologically based pharmacokinetic models for use in risk
assessment. J. Appl. Toxicol. 27(3): 218-237.

Lu Y., Rieth S., Lohitnavy M., Dennison J., El-Masri H., Barton
H.A., Bruckner J., Yang R.R. (2008): Application of PBPK
modeling in support of the derivation of toxicity reference values
for 1,1,1-trichloroethane. Regul. Toxicol. Pharmacol. 50(2): 249-
260.

Borghoff S.J., Parkinson H., Leavens T.L. (2010): Physiologically
based pharmacokinetic rat model for methyl tertiary-butyl ether;
comparison of selected dose metrics following various MTBE
exposure scenarios used for toxicity and carcinogenicity
evaluation. Toxicol. 275(1-3): 79-91.

Mielke H., Abraham K., Gotz M., Vieth B., Lampen A., Luch A.,
Gundert-Remy U. (2011): Physiologically based toxicokinetic
modeling as a tool to assess target organ toxicity in route-to-route
extrapolation the case of coumarin. Toxicol. Lett. 202(2): 100-
110.