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

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.

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.