Evaluation of the toxicity of indomethacin in a 4-week study, by oral route, in the marmoset (Callithrix jacchus)

Formaldehyde (FA) has been commercially produced since the early 1900s. Its widespread use in a variety of applications is known to result in appreciable exposure of workers and of a section of the general population. Formaldehyde is a normal metabolite in mammalian systems. It occurs in air as a product of the natural photooxidation of automobile exhaust, combustion processes, incinerators; formaldehyde has been found in municipal and industrial effluents and is present in food either naturally (fruits and vegetables, in the order of parts per million), or as a result of its use as a food additive. The use of FA and its derivative, hexamethylenetetramine (HMT), which gradually decomposes to FA under acidic conditions as antimicrobial agents in food, raises questions about their potential chronic oral toxicity. Furthermore, since FA is a very reactive compound and reacts with different macromolecules such as proteins and nucleic acids, the safety evaluation of FA as a cheese additive must take into account the toxicity of the reaction products between FA and milk components. Biochemical aspects, acute and short-term toxicity studies including mutagenicity, multigeneration, and reproduction studies, long-term carcinogenicity studies after oral administration of FA and HMT are reviewed in this paper. The results of these studies indicate that repeated oral exposure of a relatively large amount of FA that could overwhelm the normal metabolic capacity of animals to convert FA into formiate, CO2, and water produces histopathological gastric changes. This paper correlates the hazard caused by the exposure to low levels of FA, as far as its carcinogenic potential by oral route is concerned per se or regarding its use as a food additive. Based on the evidence that FA is formed naturally in food and is a normal mammalian metabolite and that a threshold for carcinogenicity exists both after exposure by inhalation and oral administration, it may be deduced that FA is not carcinogenic at low levels of exposure.