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 working group concluded that 2-butoxyethanol is not classifiable as to its carcinogenicity to humans (group 3), with limited evidence in experimental animals and inadequate evidence in humans.

1-tert-Butoxy-2-propanol. 1-tert-Butoxy-2-propanol was tested for carcinogenicity by inhalation exposure in male and female mice and rats (Doi et al. 2004; NTP 2003). In a single study in both male and female mice, a dose-related increase in the combined incidence of liver tumors (hepatocellular adenomas and carcinomas), including hepatoblastomas, was observed. When hepatocellular carcinomas and hepatoblastomas were combined, there was a significant trend for the increase in malignant tumors in females. In male rats, there were marginal, nonsignificant increases in the incidences of renal tubule adenomas (with one carcinoma at the highest dose) and hepatocellular adenomas, but these findings were considered to be equivocal. In female rats, there were no dose-related increases in tumor incidence. No epidemiologic data were available for this compound.

With regard to mechanisms of carcinogenesis, the working group found the available data inadequate to elucidate a potential mechanism for the mouse liver tumors. They found the renal effects largely consistent with the [[alpha].sub.2u]-globulin-associated nephropathy that occurs in male rats, but concluded that the available evidence satisfies only some, but not all, of the IARC criteria for the mechanism associated with accumulation of [[alpha].sub.2u]-globulin. Regarding the potential for genotoxic effects, the working group was not able to draw any meaningful conclusion in view of the scarcity of the data available.

The working group concluded that 1-tert-butoxy-2-propanol is not classifiable as to its carcinogenicity to humans (group 3), with limited evidence in experimental animals and inadequate evidence in humans.

Discussion

A theme common to these three evaluations is the consideration of mechanistic information to develop and evaluate hypotheses about the sequence of steps leading to the induction of tumors in experimental animals. The hypothesized mechanisms described in these evaluations provide an interesting set of cases that range from a vast literature on respiratory-tract tumors in rats induced by inhalation of formaldehyde to some more tentative hypotheses about the various tumors observed in animals after exposure to glycol ethers. Both types of mechanistic data sets were of use in the evaluation process.

The evaluation of formaldehyde as carcinogenic to humans shows the importance of mechanistic information in the classification of carcinogens. For the nasopharyngeal tumors, the working group discussed the convergence of the epidemiologic, experimental, and mechanistic evidence. If the evidence in humans had been less than sufficient, the strong mechanistic evidence in exposed humans and sufficient evidence in experimental animals might still have led to classification as group 1. The extensive mechanistic data for formaldehyde-induced respiratory cancer provide strong support for the empirical observation of nasopharyngeal cancer in humans, although computer models that predict an anterior-to-posterior gradient of formaldehyde deposition in the upper respiratory tract would predict that formaldehyde would cause cancer in the nose as well as the nasopharynx in humans.