Formaldehyde, 2-Butoxyethanol and 1-tert-Butoxy-2-propanol (Vol. 88, 2-9 June 2004)
Twenty-six scientists from
ten countries met
in June 2004 to assess the carcinogenic hazard to humans of
two glycol ethers: 2-butoxyethanol and 1-tert-butoxy-2-propanol.
Several IARC Monographs evaluations of formaldehyde had been undertaken previously, the most recent ones in 1987 (Supplement 7) and 1995 (Volume 62). The re-evaluation of formaldehyde was given high priority by the 2003 IARC Monographs Advisory Group.
Formaldehyde is produced worldwide on a large scale. It is widely used in the production of resins that bind wood products, pulp and paper; in glasswool and rockwool insulation; in plastics and coatings, textile finishing, chemical manufacture; and as a disinfectant and preservative (formalin). Common sources of exposure include vehicle emissions, particle board and similar building materials, carpets, paints and varnishes, foods and cooking, tobacco smoke, and the use of formaldehyde as a disinfectant. Levels in outdoor air are generally low but higher levels can be found in some homes.Occupational exposure to formaldehyde occurs in a wide variety of occupations and industries: for example, it is estimated that more than one million workers are exposed to some degree across the European Union. Short-term exposures to high levels have been reported for embalmers, pathologists and paper workers. Lower levels have usually been encountered during the manufacture of man-made vitreous fibres, abrasives and rubber and in formaldehyde production industries. A very wide range of exposure levels has been observed in the production of resins and plastic products. The development of resins that release less formaldehyde and improved ventilation has resulted in decreased exposure levels in many industrial settings in recent decades.
Nasopharyngeal cancer mortality was statistically significantly increased in a cohort study of United States (US) industrial workers exposed to formaldehyde, and in two other US and Danish cohort studies. Five of seven case-control studies also found elevated risk for formaldehyde exposure. The Working Group considered it was “improbable that all of the positive findings…could be explained by bias or by unrecognised confounding effects” and concluded that there is sufficient evidence in humans that formaldehyde causes nasopharyngeal cancer. Leukaemia mortality, primarily myeloid-type, was increased in six of seven cohorts of embalmers, funeral-parlour workers, pathologists, and anatomists. These findings had previously been discounted because an increased incidence of leukaemia had not been seen in industrial workers. Recent updates, however, report a greater incidence of leukaemia in two cohorts of US industrial workers and US garment workers, but not in a third cohort of United Kingdom chemical workers. The Working Group concluded that there is “strong but not sufficient evidence for a causal association between leukaemia and occupational exposure to formaldehyde”. Several case-control studies have associated exposure to formaldehyde with sinonasal adenocarcinoma and squamous-cell carcinoma. However, no excess of sinonasal cancer was reported in the updated cohort studies. The Working Group concluded that there is limited evidence in humans that formaldehyde causes sinonasal cancer.
In rats, several inhalation studies have shown that formaldehyde induces squamous-cell carcinoma of the nasal cavity. Four drinking-water studies gave mixed results. Formaldehyde also shows cocarcinogenic effects when inhaled, ingested, or applied to the skin of rodents.
Formaldehyde is genotoxic in in-vitro models, animals and humans. Increased numbers of DNA–protein crosslinks have been found in peripheral blood lymphocytes of exposed workers, in the upper respiratory tract of monkeys, and in the rat nasal mucosa. Cell proliferation increases substantially at formaldehyde concentrations higher than six parts per million in rats, amplifying the genotoxic effects. The Working Group concluded that, “both genotoxicity and cytotoxicity have important roles in the carcinogenesis of formaldehyde in nasal tissues”. By contrast, the Working Group could not identify a mechanism for leukaemia induction, and this tempered their interpretation of the epidemiological evidence.
Overall, the Working Group concluded that formaldehyde is carcinogenic to humans (Group 1), on the basis of sufficient evidence in humans and sufficient evidence in experimental animals—a higher classification than previous IARC evaluations.
The evaluations of 2-butoxyethanol and other glycol ethers like 1-tert-butoxy-2-propanol were given high priority by the 2003 IARC Monographs Advisory Group.
2-butoxyethanol is widely
used as a solvent in
paints and paint thinners, glass and surface cleaners, personal-care
and as a chemical intermediate. An inhalation study
in male and female rats and mice found increased
incidence of liver
haemangiosarcoma in male mice, of forestomach squamous-cell papilloma
carcinoma in female mice, and equivocal results in female rats. A link
haemolysis and mouse liver neoplasia has been proposed, but the Working
noted that other potential mechanisms have not been investigated.
increasingly as a solvent in coatings, glass and surface cleaners,
adhesives, and nailpolish lacquers. An inhalation study in male and female rats and mice found
increased incidence of liver tumours,
including hepatoblastoma, in male and female mice and equivocal results
rats. There was a discussion about whether to regard hepatoblastoma as
tumour or a variant of hepatocellular carcinoma.
The Working Group
2-butoxyethanol and 1-tert-butoxy-2-propanol are not
to their carcinogenicity to humans (Group 3) on the basis of limited
evidence in experimental animals and inadequate evidence in