Formaldehyde Inhalation studies

Formaldehyde is classified as a probable human carcinogen by the International Agency for Research on Cancer (lARC) and as a suspected human carcinogen by the American Conference of Governmental Industrial Hygienists (ACGIH). This is based on limited human evidence and on sufficient evidence in experimental animals (136). Lifetime inhalation studies with rodents have shown nasal cancer at formaldehyde concentrations that overwhelmed cellular defense mechanisms, ie, 6 to 15 ppm. No nasal cancer was seen at 2 ppm or lower levels (137). 

A number of 3-day inhalation studies (Feron et al. 1995a, Cassee et al. 1996, 1998) were carried out in male rats with formaldehyde, acetaldehyde, and acrolein and mixtures of two or three of these toxicants (Table 10.10). They aU produce the same type of adverse effect (nasal cytotoxicity) but with different target sites (different regions of the nasal mucosa). The nasal changes seen after... 

Coon RA, Jones RA, Jenkins LJ Jr, et al Animal inhalation studies on ammonia, ethylene glycol, formaldehyde, dimethylamine, and ethanol. Toxicol Appl Pharmacol 16 646-655, 1970... 

There is evidence of possible carcinogenicity of formaldehyde from two inhalation studies on rats and mice (SEDA-10, 423) (SEDA-11, 477) (SEDA-12, 571) (13). 

Formaldehyde vapors used in controlled-exposure inhalation studies can be generated by heating commercial formalin, aqueous solutions containing 30-50% formaldehyde by weight plus methanol or other substances to inhibit intrinsic polymerization, or by heating solid paraformaldehyde, a formaldehyde polymer. Unless noted otherwise, inhalation studies used in the preparation of this profile provided clear evidence that formaldehyde was the only added gas in the experimental atmosphere. 

No histological evidence for formaldehyde effects on cardiovascular tissues was found in intermediate-duration inhalation studies, using a 6 hour/day, 5 day/week exposure protocol, with mice exposed to up to 40 ppm for 13 weeks (Maronpot et al. 1986), Rhesus monkeys exposed to 6 ppm for 6 weeks (Monticello et al. 1989), rats exposed to up to 20 ppm for 13 weeks (Woutersen et al. 1987), or rats exposed to up to 10 ppm for 13 or 52 weeks (Appelman et al. 1988). Similarly, no evidence for... 

No evidence Ifom histological examinations or blood chemistry monitoring for formaldehyde-induced kidney effects has been found in intermediate-duration inhalation studies with rats. Rhesus monkeys, or mice (Appelman et al. 1988 Maronpot et al. 1986 Monticello et al. 1989 Woutersen et al. 1987), or in chronic inhalation studies with rats and mice (Kamata et al. 1997 Kems et al. 1983b). Appelman et al. (1988) noted that rats exposed to 10 ppm, 6 hours/day, 5 days/week for 52 weeks had "frequent oliguria Kems et al. (1983b) also measured urinalytic variables in rats and mice exposed to up to 14.3 ppm by a similar protocol for 24 months, but did not report a similar finding. 

Studies of animals exposed for life to formaldehyde in air or drinking water also show that formaldehyde primarily damages tissue at portals-of-entry (i.e., the upper respiratory tract and the gastrointestinal tract) evidence for toxic effects at distant sites is less consistent. Replicated inhalation studies have shown that formaldehyde induced malignant nasal tumors in rats at high exposure concentrations (10-15 ppm) that also induced nasal epithelial necrosis and cellular proliferation, but not at lower concentrations (0.3-2 ppm) that did not markedly damage nasal epithelial tissue (Albert et al. 1982 ... 

Intermediate-duration inhalation studies with several species of animals clearly identify the upper respiratory tract as the critical target tissue for airborne formaldehyde and suggest that degenerative changes to the upper respiratory tract epithelium may not occur with exposure to concentrations 1 ppm. Formaldehyde-induced epithelial damage in the upper respiratory tract similar to that observed in the Cynomolgus monkeys has been observed in Rhesus monkeys exposed to 6 ppm for 6 hours/day,... 

The deposition of gases and particles In the nasopharyngeal region of the respiratory tract Is likely to be of Industrial Importance, since the work place Is often contaminated with relatively large particles likely to be deposited In the nasopharynx and not In the lung. Recently. Inhalation studies of formaldehyde spurred comparative studies of the... 

The formation of other gaseous compounds (e.g., formaldehyde, acrolein, aromatic aldehydes) in the motor and their concentration in air has not been discussed, even after demonstration of the mutagenic activity of the gas phase of engine exhaust. Also, the biological activity of gaseous products is seldom studied (except in inhalation studies where results are not yet known) and the interpretation of such data differs among the reporting authors. 

For dimercaptomethane (No. 1661), the NOEL of 15 mg/kg bw per day for one hydrolysis product, formaldehyde, from a 2-year study in rats (Til et al., 1989) and the NOEL of 6.5 mg/kg bw per day for the other hydrolysis product, hydrogen sulfide, from a 90-day inhalation study in rats (Chemical Industry Institute of Technology, 1983) provide adequate margins of safety (75 million and >32 million, respectively) in relation to currently estimated levels of intake of this substance from use as a flavouring agent. 

Ocular Effects. A case-control study of office workers was conducted by Baj et al. (1994) to evaluate the risks of chronic exposures to inhaled formaldehyde, phenol and isomers of organic chlorohydrocarbons from Ksylamit which is a widely used liquid wood preservative reported to consist of a mixture of chlorinated benzenes, pentachlorophenol, alpha-chloronaphthalene, chloroparafifin, and kerosene . Twenty-two workers (18 women and 4 men) exposed for at least 6 months were the cases, and 29 non-exposed, non-smoking volunteers matched for age, sex, and place of residence were the controls. The authors indicate that all of the exposed workers developed chronic complaints, among them burning eyes, but that no remarkable increase in morbidity was found during the 6 months of exposure to Ksylamit , nor during the 3-year follow-up study (details of which were not provided). The authors attribute these symptoms to the irritant effect of the inhaled Ksylamit probably (based on the references provided) due to the formaldehyde vapor they assert emanates from the woodpreserving liquid. 

Formaldehyde has been shown to be carcinogenic in two strains of rats, resulting in squamous cell cancers of the nasal cavity after repeated inhalation of about 14 ppm. In one study, 51 of 117 male and 42 of 115 female Fischer 344 rats developed this tumor, but no nasal tumors were seen at 0 or 2 ppm. No other neoplasm was increased significantly. In a similar study of mice, this nasal tumor occurred in two male mice at 14.3 ppm. None of the excesses was statistically significant except for the high-exposure rats. °... 

DNA-protein cross-links caused by formaldehyde, a metabolite from the GST pathway, have been demonstrated in mice but not hamsters exposed to dichloromethane (Casanova et al., 1992). Similarly, in-vitro studies have not demonstrated DNA-protein cross-links in rat, hamster or human hepatocytes exposed to concentrations of dichloromethane of up to 5 mM. This is equivalent to the time-weighted average concentration predicted to occur in mouse liver during a 6-h inhalation exposure to a dichloromethane concentration of > 10 000 ppm [34 700 mg/m ] (Casanova et al., 1997). 

Karns, W. D. "Long-Tern Inhalation Toxicity and Carcinogenicity Studies of formaldehyde in Rats and Mice." The Third Chemical Industry Institute of Toxicology Conference on Toxicology, Raleigh, NC, 1980. 

Rodent and human studies have shown that MTBE is rapidly absorbed following inhalation exposure. In addition, rodent studies have shown rapid distribution of MTBE after oral and intraperitoneal exposure. Dermal absorption occurs more slowly. Evidence supports metabolic transformation of MTBE by P450 enzymes to the parent alcohol, t-butyl alcohol (TBA), and formaldehyde in rodents and humans. Further oxidative metabolism of TBA seems to be slow, and glucuronidation is a major competing pathway. Formaldehyde metabolism to formate is very rapid. The toxicokinetic parameters of MTBE and TBA depend on the dose and route of administration although they appear to be linear following inhalation exposures up to 50 ppm. 

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