• Can formaldehyde-related effects alter its toxicokinetics?

• Are formaldehyde-induced cross-links useful biomarkers of exposure?

• Can inhaled formaldehyde have systemic genotoxic effects?

• Are useful computational pharmacokinetic models for formaldehyde inhalation available?

• Has a mode of action for formaldehyde carcinogenesis been identified?

• What is the status of BBDR models for formaldehyde?

• Should the BBDR models available for formaldehyde be used in EPA’s quantitative assessment?

Some of those questions could be answered by weighing the evidence from research studies considered in the draft IRIS assessment; others could not be answered by the committee with high confidence.

Overall, the committee found that the chapters describing the toxicokinetics, modes of action, and various models are well organized and that the draft IRIS assessment accurately reflects the current understanding of the toxicokinetics of inhaled formaldehyde and provides a thorough review of the metabolism, cytotoxicity, and genotoxicity of formaldehyde. The literature review in the draft IRIS assessment appears to be up to date and to include all major and recent studies published as of the release date.

The committee notes that EPA satisfactorily describes the current understanding of endogenous formaldehyde. It is well established that formaldehyde is produced endogenously by enzymatic and nonenzymatic pathways or as a detoxification product of xenobiotics during cellular metabolism (ATSDR 1999). There is also broad agreement that formaldehyde originating from metabolic or dietary sources is normally present at low concentrations in all tissues, cells, and bodily fluids. The concentration of endogenous formaldehyde in the blood of rats, monkeys, and humans is about 0.1 mM (Heck et al. 1985; Casanova et al. 1988). Background concentrations in the liver and nasal mucosa of the rat are 2-4 times those in the blood (Heck et al. 1982). Endogenous tissue formaldehyde concentrations are similar to concentrations (about 0.05 mM) that induce genotoxicity and cytolethality in vitro (Heck and Casanova 2004).

Heck et al. (1985) did not observe an increase in blood formaldehyde concentrations in rats and humans after exposure to inhaled formaldehyde at 14.4 ppm (2 hr) or 1.9 ppm (40 min), respectively. Subchronic studies conducted in rhesus monkeys have also shown that blood formaldehyde concentration was not measurably altered by exposure to airborne formaldehyde at 6 ppm for 6 hr/day 5 days/week for 4 weeks (Casanova-Schmitz et al. 1984).