The Hamner Institutes for Health Sciences | SOT Meeting March 9, 2011

Update on Formaldehyde Case Study:

Adaptation of the Biologically Based Dose Response Model for Formaldehyde Carcinogenicity to Consider

Endogenous Formaldehyde

Harvey ClewellThe 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

0

10

20

30

40

50

60

Tu

mo

r Resp

on

se (%)

0 0.7 2 6 10 15

Exposure Concentration (ppm)

Kerns et al., 1983

Monticello et al., 1991

The Hamner Institutes for Health Sciences | SOT Meeting March 9, 2011

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)

But formaldehyde is an endogenous metabolite present in all cells

production

[GSH]

H

OHHOH

H

SGHOH

cellair

spaces

CH2O

The Hamner Institutes for Health Sciences | SOT Meeting March 9, 2011 5

Andersen et al. 2010

Used 14C-DPX-data with formaldehyde in the nose to infer tissue levels of FAcetal - conventional approach to evaluate kinetics of tracer and of total concentration

14C-DPX

Lu et al (2010) have group have measured exogenous and endogenous adducts

Formaldehyde is an Endogenous Compound

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 6

Airborne CH2O

K0 (production rate)

formic acid &GSH

cross-linking f (FAcetal)

first-order metabolism,exhalation, diffusion, etc.

k23 k32

Vmax, Km

FDH

k21

[GSH]

CH2(OH)2

GSCH2OH

kadj

Inhalation rate

Goal: adapt BBDR model to describe endogenous formaldehyde

The Hamner Institutes for Health Sciences | SOT Meeting March 9, 2011

Cell proliferation

Mutagenicity Cancer model

Tumor response

Inhaled ppm

Tissue dose

Tissue flux

Risk Assessment for FormaldehydeUsing BBDR Model

CFD modeling

DPX data

Time-to-tumor data (rat)

The Hamner Institutes for Health Sciences | SOT Meeting March 9, 2011

8

Simulations of tumor response in rats

The Hamner Institutes for Health Sciences | SOT Meeting March 9, 2011 9

9

CFD Modeling for Cross-Species Dosimetry

F344 Rat

Rhesus Monkey

Human

Calibration of flux-DPX relationship

The Hamner Institutes for Health Sciences | SOT Meeting March 9, 2011

10

Calibration against human lung cancer data

The Hamner Institutes for Health Sciences | SOT Meeting March 9, 2011

11

Final risk assessment model: 95% upper confidence limit on mutagenicity

2.0000E-04

2.5000E-04

3.0000E-04

3.5000E-04

4.0000E-04

4.5000E-04

5.0000E-04

5.5000E-04

0 1 2 3 4 5 6 7

1 2 3 4 5 6 710

-4

10-3

10-2

10-1

PPM

DP

X (p

mol

/mm

3 )

DPX dose-response for Rhesus monkey

Vmax: 91.02. pmol/mm3/min

Km: 6.69 pmol/mm3 kf: 1.0878 1/min Tissue thickness ALWS: 0.5401 mm MT: 0.3120 mm NP: 0.2719 mm

95% UCL on KMU

DPX

Cell division

The Hamner Institutes for Health Sciences | SOT Meeting March 9, 2011

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