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Harvey Clewell The Hamner Institutes for Health Sciences Research Triangle Park, NC

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.

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Harvey Clewell The Hamner Institutes for Health Sciences Research Triangle Park, NC

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  1. 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

  2. NAS Report on the EPA Risk Assessment for Formaldehyde

  3. Yes, formaldehyde caused tumors in the rat nose 60 Kerns et al., 1983 50 Monticello et al., 1991 40 30 Tumor Response (%) 20 10 0 0 0.7 2 6 10 15 Exposure Concentration (ppm)

  4. But formaldehyde is an endogenous metabolite present in all cells • 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) production CH2O [GSH] air spaces cell

  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 Formaldehyde is an Endogenous Compound 14C-DPX 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.

  6. Goal: adapt BBDR model to describe endogenous formaldehyde K0 (production rate) k21 first-order metabolism, exhalation, diffusion, etc. Inhalation rate Airborne CH2O kadj cross-linking f (FAcetal) CH2(OH)2 k23 k32 [GSH] FDH formic acid & GSH GSCH2OH Vmax, Km

  7. Tissue flux Cell proliferation Tissue dose Cancer model Mutagenicity Tumor response Risk Assessment for FormaldehydeUsing BBDR Model Inhaled ppm CFD modeling DPX data Time-to-tumor data (rat)

  8. Simulations of tumor response in rats

  9. CFD Modeling for Cross-Species Dosimetry Calibration of flux-DPX relationship F344 Rat Rhesus Monkey Human

  10. Calibration against human lung cancer data

  11. Final risk assessment model: 95% upper confidence limit on mutagenicity 95% UCL on KMU DPX Cell division

  12. 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

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