Formaldehyde,
2-Butoxyethanol and 1-tert-Butoxy-2-propanol
Twenty-six scientists from
ten countries met
in June 2004 to assess the carcinogenic hazard to humans of
formaldehyde and
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
products,
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
and
carcinoma in female mice, and equivocal results in female rats. A link
between
haemolysis and mouse liver neoplasia has been proposed, but the Working
Group
noted that other potential mechanisms have not been investigated.
1-tert-butoxy-2-propanol
is used
increasingly as a solvent in coatings, glass and surface cleaners,
inks,
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
in male
rats. There was a discussion about whether to regard hepatoblastoma as
a rare
tumour or a variant of hepatocellular carcinoma.
The Working Group
concluded that
2-butoxyethanol and 1-tert-butoxy-2-propanol are not
classifiable as
to their carcinogenicity to humans (Group 3) on the basis of limited
evidence in experimental animals and inadequate evidence in
humans.