Meeting report: summary of IARC Monographs on formaldehyde, 2-butoxyethanol, and 1-tert-butoxy-2-propanol

Environmental Health Perspectives, Sept, 2005 by Vincent James Cogliano, Yann Grosse, Robert A. Baan, Kurt Straif, Marie Beatrice Secretan, Fatiha El Ghissassi

The toxicokinetics of inhaled formaldehyde have been well studied (Agency for Toxic Substances and Disease Registry 1999). More than 90% of inhaled formaldehyde is absorbed in the upper respiratory tract (Heck et al. 1985). Absorbed formaldehyde can be oxidized to formate and carbon dioxide or can be incorporated into biologic macromolecules. Formaldehyde has a half-life of about 1 min in rat plasma (Rietbrock 1965). Inhalation exposure has not been found to alter the endogenous concentration of formaldehyde in the blood of rats, monkeys, or humans (Casanova et al. 1988; Heck et al. 1983, 1985). Oral exposure to [sup.14]C-formaldehyde resulted in some excretion in urine and feces within 12 hr (Galli et al. 1983). Dermal application of [sup.14]C-formaldehyde resulted in some urinary excretion in rats and monkeys (Jeffcoat et al. 1983).

Evidence shows that formaldehyde is genotoxic in multiple in vitro models and in exposed humans and laboratory animals. Human studies reported increased DNA-protein crosslinks in workers exposed to formaldehyde (Shaham et al. 1996, 2003), and this is consistent with studies in laboratory rats and monkeys. Cellular proliferation increases considerably at concentrations > 6 ppm and amplifies the genotoxic effects of formaldehyde. The working group concluded, "The current data indicate that both genotoxicity and cytotoxicity play important roles in the carcinogenesis of formaldehyde in nasal tissues." On the other hand, with respect to the potential for formaldehyde to induce leukemia, the working group was not aware of any good rodent models for acute myeloid leukemia in humans. Several possible mechanisms were considered, such as clastogenic damage to circulating stem cells. There is a single study reporting cytogenetic abnormalities in the bone marrow of rats inhaling formaldehyde (Kitaeva et al. 1990). The working group concluded, "Based on the data available at this time, it was not possible to identify, a mechanism for the induction of myeloid leukaemia in humans." This is an area needing more research.

The working group concluded that formaldehyde is carcinogenic to humans (group 1), based on sufficient evidence in humans and sufficient evidence in experimental animals. Based on the information now available, this classification is higher than those of previous IARC evaluations (IARC 1982, 1987, 1995).

2-Butoxyethanol. 2-Butoxyethanol was tested for carcinogenicity by inhalation exposure in male and female mice and rats [National Toxicology Program (NTP) 2000]. Clear increases in tumor incidence were observed only in mice. In male mice exposed to 2-butoxyethanol, there was a dose-related increase in the incidence of hemangiosarcomas of the liver. In female mice, there was a dose-related increase in the incidences of combined forestomach squamous-cell papillomas and carcinomas (mainly papillomas). In female rats, there was a positive trend in the occurrence of benign or malignant pheochromocytomas (mainly benign) of the adrenal medulla, but this equivocal result could not be attributed with confidence to exposure to 2-butoxyethanol. No increases were observed in male rats. The epidemiologic data were inadequate for this compound.

Regarding mechanisms of carcinogenesis, the working group considered that hemolysis and associated oxidative stress in the liver have been proposed to be linked to the induction of mouse liver neoplasia. They also considered that, in view of lower sensitivity to hemolysis of human erythrocytes and higher human liver concentrations of the antioxidant vitamin E, the induction of liver tumors in humans would be improbable through this pathway, but it was noted that other potential mechanisms have not been investigated. The working group observed that the mouse forestomach tumors are associated with high local exposure to 2-butoxyethanol and high local concentrations of the toxic metabolite 2-butoxyacetic acid.