Transcript SOT

Update on Formaldehyde Case Study:
Adaptation of the Biologically Based Dose Response
Model for Formaldehyde Carcinogenicity to Consider
Endogenous Formaldehyde
Harvey Clewell
The Hamner Institutes for Health Sciences
Research Triangle Park, NC
The Hamner Institutes for Health Sciences | SOT Meeting March 9, 2011
NAS Report on the EPA Risk Assessment for Formaldehyde
The Hamner Institutes for Health Sciences | SOT Meeting March 9, 2011
Yes, formaldehyde caused tumors in the rat nose
60
50
Monticello et al., 1991
40
30
20
10
0
0
0.7
2
6
Exposure Concentration (ppm)
The Hamner Institutes for Health Sciences | SOT Meeting March 9, 2011
10
15
Tumor Response (%)
Kerns et al., 1983
But formaldehyde is an endogenous
metabolite present in all cells
production
H
H
CH2O
OH
OH
[GSH]
H
H
air
spaces
SG
OH
CH2(OH)2 is formed in cells by metabolism of
amino acids and during one carbon pool
metabolism.
CH2(OH)2 complexes with glutathione to form
hydroxymethylglutathione (Kdiss~ 1.0 mM).
Total tissue FA in the nasal mucosa in rats, in
the absence of any inhalation exposure, was
0.42 + 0.09 umoles/g (i.e., 12,600 ppb)
cell
The Hamner Institutes for Health Sciences | SOT Meeting March 9, 2011
0.35
8.0
0.30
7.0
Formaldehyde is an
Endogenous Compound
0.25
6.0
5.0
0.20
4.0
0.15
3.0
0.10
CH2O (mM)
Used
with
formaldehyde in the nose
to infer tissue levels of
FAcetal - conventional
approach to evaluate
kinetics of tracer and of
total concentration
14CHO
14C-DPX-data
bound (nmol/mg DNA)
Andersen et al. 2010
2.0
14C-DPX
0.05
1.0
0.00
0.0
0.0
5.0
10.0
15.0
Inhaled FA Concentration (PPM)
Lu et al (2010) have group have measured
exogenous and endogenous adducts
Even in an unexposed nose
there are significant levels of
endogenous formaldehyde and
of formaldehyde-DNA adducts.
The Hamner Institutes for Health Sciences | SOT Meeting March 9, 2011
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Goal: adapt BBDR model to describe
endogenous formaldehyde
K0 (production rate)
Airborne
CH2O
k21
Inhalation
rate
first-order metabolism,
exhalation, diffusion, etc.
kadj
CH2(OH)2
k23
cross-linking
f (FAcetal)
k32
[GSH]
FDH
GSCH2OH
Vmax, Km
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formic acid &
GSH
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Risk Assessment for Formaldehyde
Using BBDR Model
Inhaled ppm
CFD modeling
Tissue flux
DPX data
Tissue dose
Cell proliferation
Mutagenicity
Cancer model
Time-to-tumor data (rat)
Tumor response
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Simulations of tumor response in rats
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CFD Modeling for Cross-Species Dosimetry
Calibration of flux-DPX relationship
F344 Rat
Rhesus Monkey
Human
8
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Calibration against human lung cancer data
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Final risk assessment model: 95% upper
confidence limit on mutagenicity
95% UCL on KMU
DPX dose-response for Rhesus monkey
3
DPX (pmol/mm)
10
10
-1
-2
DPX
Vmax: 91.02. pmol/mm3/min
Km: 6.69 pmol/mm3
kf: 1.0878 1/min
10
10
-3
Tissue thickness
ALWS: 0.5401 mm
MT: 0.3120 mm
NP: 0.2719 mm
-4
1
2
3
4
5
6
7
PPM
5.5000E-04
5.0000E-04
4.5000E-04
4.0000E-04
3.5000E-04
Cell division
3.0000E-04
2.5000E-04
2.0000E-04
0
1
2
3
10
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Case Study on Formaldehyde
Goals
• Add description of endogenous formaldehyde to BBDR
model and recalibrate against original data as well as new
data from Swenberg
• Evaluate alternative assumptions/approaches to
characterize range of plausible risk estimates
• Evaluate the compatibility of low-dose linear risk estimates
with endogenous tissue concentrations
• Evaluate impact of data and model uncertainties on the
estimation of human risk
The Hamner Institutes for Health Sciences | SOT Meeting March 9, 2011