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 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 Tumor Response (%) Exposure Concentration (ppm) Kerns et al., 1983 Monticello et al., 1991

The Hamner Institutes for Health Sciences | SOT Meeting March 9, 2011 CH 2 (OH) 2 is formed in cells by metabolism of amino acids and during one carbon pool metabolism. CH 2 (OH) 2 complexes with glutathione to form hydroxymethylglutathione (K diss ~ 1.0 mM). Total tissue FA in the nasal mucosa in rats, in the absence of any inhalation exposure, was umoles/g (i.e., 12,600 ppb) But formaldehyde is an endogenous metabolite present in all cells production [GSH] cell air spaces CH 2 O

The Hamner Institutes for Health Sciences | SOT Meeting March 9, Andersen et al 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 14 C-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, Airborne CH 2 O K 0 (production rate) formic acid & GSH cross-linking f (FAcetal) first-order metabolism, exhalation, diffusion, etc. k 23 k 32 Vmax, K m FDH k 21 [GSH] CH 2 (OH) 2 GSCH 2 OH k adj 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 Formaldehyde Using BBDR Model CFD modeling DPX data Time-to-tumor data (rat)

The Hamner Institutes for Health Sciences | SOT Meeting March 9, Simulations of tumor response in rats

The Hamner Institutes for Health Sciences | SOT Meeting March 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, Calibration against human lung cancer data

The Hamner Institutes for Health Sciences | SOT Meeting March 9, Final risk assessment model: 95% upper confidence limit on mutagenicity 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