Accidental formaldehyde intake or its mal use as a food additive for preservative purposes may lead to deleterious effects on almost all body systems.
After daily oral administration of 80 mg/kg formaldehyde for 4 weeks, many histological gastric changes were observed. These results are in agreement with those obtained by previous researchers . In contrast, others  did not observe any adverse effect in the stomach of dogs and rats after oral administration of formaldehyde at doses up to 150 mg/kg body weight/day in drinking water for a period of 13 weeks. This discrepancy can be explained by the differences in the strains of animals used .
The present study revealed that there was highly significant increase in the thickness of the lining epithelium of the fore-stomach and glandular-stomach associated with hyperplasia. The scanned luminal surface of the fore-stomach revealed numerous keratin scale. These findings are in agreement with those of previous studies [1,22] in which the effects were attributed to the irritating, corrosive, and toxic effects of formalin.
This study showed inflammatory cellular infiltration and dilated blood vessels in the mucosa of the fore-stomach and the glandular-stomach as well as multiple erosions and edematous spaces in the glandular-stomach. Necrotic debris was detected by a scanning electron microscope. Similar results were found by some investigators  in their study on gastric mucosa. All of the previous pathological observations indicate the occurrence of gastritis as reported by various authors [24,25]. Other investigators  reported that formaldehyde ingestion induces corrosive damage and hemorrhage of the gastrointestinal tract, which depends on the duration of contact. Furthermore, the local gastrointestinal effects, including ulcers and perforation, can be attributed to the necrotic effects of formaldehyde on the mucus membrane . Moreover, some researchers  found that, in a case study of attempted suicide, ingestion of formalin causes disorders in the oral cavity and the gastrointestinal tract. The stomach shows the most severe damage in such cases because contact of formalin with the gastric mucosa is longer than in the other parts of the gastrointestinal tract. Gastric ulcers and mild hemorrhage are frequently seen. They added that ingestion of formalin could lead to peritonitis without perforation because of gastric wall inflammation. The cicatricle stricture of the stomach tends to be a major problem in the late phase of formalin ingestion.
Bacteria over the surface epithelium of the glandular-stomach were observed by scanning electron microscope in the experimental group of this study. Some investigators  reported that the upper gut and stomach are usually sterile. These data may suggest the occurrence of bacterial translocation and passage of viable bacteria from the gastrointestinal tract to normally sterile tissues, inducing inflammatory reaction in all the examined light microscopic sections. This may be due to decreased gastric acidity, leading to invasion by microbes. This phenomenon of bacterial translocation is associated with septic morbidity as it leads to deterioration or breakdown of gut barrier function [27,28].
Regional loss of papillation of the fore-stomach surface epithelium was observed in this study. Also, loss of gastric pits associated with distorted normal architecture of the glandular-stomach could be observed. In addition, highly significant decrease in alcian blue PAS reaction of the mucus neck cells was detected compared with the control. Some authors  explained that the reduction of the secretion may be due to atrophic changes. Similarly another authors  reported the presence of atrophic gastritis in their study.
The present study revealed cytoplasmic vacuolation of gastric gland cells accompanied by hyperplasia of the gastric epithelial cells. Previous studies  mentioned that these degenerative and proliferative gastric changes are most probably related to the cytotoxic properties of formaldehyde. Other studies  reported regenerative activity in the glandular stomach and increase in the number of mucus cells in deep gastric pits of the fundic mucosa of rat provided 5% formalin in their drinking water. Other researchers  reported that the highest tumor response should be expected at sites with the highest cell proliferation activity.
Some glandular-stomach sections in the present study showed gastric changes in the form of glandular cystic dilatation. Glandular cystic dilatation was observed after gastric operation by previous researchers . They attributed this result to an inflammatory cause and reactive hyperplastic change of the gastric glands that is probably not a preneoplastic state. Other authors  reported that repeated oral intake of large amounts of formaldehyde could disrupt the normal metabolic capacity of animals to convert formaldehyde into forminate, carbon dioxide, and water, producing histopathological gastric changes. Various authors  have reported that epithelial metaplasia may become dysplastic and constitutes a background for the development of carcinoma. Other authors  concluded that formaldehyde, administered with drinking water, was shown to be carcinogenic on the basis of an increased incidence of total malignant tumors and oncological lesions varying in site and histotype. These tumors included malignant mammary tumors, oncological lesions of the stomach and intestine, testicular interstitial cell adenomas, and hemolymphoreticular neoplasias. Furthermore, other investigators  have reported that rodents and nonhuman primates show dose-related cytotoxic-proliferative and metaplastic lesions, which indicates that formaldehyde might be carcinogenic for exposed humans. However, there was insufficient evidence on the carcinogenic potential of formaldehyde for humans as the data available through epidemiological studies were limited due to lack of consistency, dose– response pattern, and inadequate estimation of exposure. Moreover, the same authors reported that at irritating and cytotoxic concentrations, inflammatory and regenerative processes, which were also observed in the present study, become the dominant risk factors by promoting formaldehyde-induced genotoxic events and malignant cell transformations.
As regards the Feulgen reaction for DNA used in this study, there was a significant decrease in the reaction in the experimental group. This indicates a decrease in the DNA content of the gastric cell nuclei. This result is in disagreement with the results of a previous study , which showed no evidence of carcinogenicity of formaldehyde even after 2 years of oral administration. However this result is in accordance with that of another study , in which nuclear changes in the stomach, duodenum, ileum, and colon were found and the strongest genotoxic effect was observed in the stomach. These data suggested that formaldehyde not only causes nuclear damage at the site of application but also at distant sites. Some authors  reported a significant decrease in the nuclear DNA content of the testis and prostate. Other authors  assumed that a threshold for carcinogenicity exists after exposure by inhalation and oral administration. The rates of gastric tumor incidences in male rat administered 1500 mg/l were 4% in the original study  and increased to 14% in the re-evaluation study . The carcinogenicity of formaldehyde may result from its ability to induce DNA–protein cross-links . Some researchers  suggested that formaldehyde is genotoxic as a result of its ability to arrest DNA replication. They added that, although DNA–protein cross?links could be removed and DNA could be repaired, failure to remove the blockage before cell division or incomplete repair could cause cell death or a mutation.
On the basis of the previous data, this study concluded that oral formaldehyde intake has deleterious effects on albino rat stomach in the form of irritating and regenerative effects as well as DNA damage that may be precancerous.
Therefore, it is recommended to prohibit the mal use of formaldehyde as a food additive, and appropriate control measures or alternative additives should be used.
There is no conflict of interest to declare.
Pandey CK, Agarwal A, Baronia A, Singh N. Toxicity of ingested formalin and its management. Hum Exp Toxicol. 2000;19:360–366
Soffritti M, Belpoggi F, Lambertin L, Lauriola M, Padovani M, Maltoni C. Results of long-term experimental studies on the carcinogenicity of formaldehyde and acetaldehyde in rats. Ann N Y Acad Sci. 2002;982:87–105
Schulte HA, Bernauer U, Madle S, Mielke H, Herbst U, Richter Reichhelm HB, et al.
Assessment of the carcinogenicity of formaldehyde. Bundesinstitut für Risikobewertung. Report No.: CAS No. 50-00-0. 2006; P. 7 - 113.
Lian CB, Ngeow WE. The adverse effect of formalin: a warning against mishandling. Ann Dent. 2000;7:56–58
Quievryn G, Zhitkovich A. Loss of DNA-protein crosslinks from formaldehyde-exposed cells occurs through spontaneous hydrolysis and an active repair process linked to proteosome function. Carcinogenesis. 2000;21:1573–1580
Krasner SW, McGuire MJ, Jacangelo JG, Patania NL, Reagan KM, Marco AE. Occurrence of disinfection by-products in US drinking water. J Am Water Works Assoc. 1989;81:41–53
Tomkins BA, McMahon JM, Caldwell WM, Wilson DL. Liquid chromatographic determination of total formaldehyde in drinking water. J Assoc Off Anal Chem. 1989;72:835–839
Glaze WH, Koga M, Cancilla D. Ozonation byproducts. 2. Improvement of an aqueous-phase derivatization method for the detection of formaldehyde and other carbonyl compounds formed by the ozonation of drinking water. Environ Sci Technol. 1989;23:838–847
Becher G, Ovrum NM, Christman RF. Novel chlorination by-products of aquatic humic substances Sci Total Environ. 1992;117–118:509–520
Restani P, Galli CL. Oral toxicity of formaldehyde and its derivatives. Crit Rev Toxicol. 1991;21:315–328
Vargova M, Wagnerova J, Liskova A, Jakubovsky J, Gajdova M, Stolcova E, et al. Subacute immunotoxicity study of formaldehyde in male rats. Drug Chem Toxicol. 1993;16:255–275
Drury RA, Wallington EA Carleton's histological techniques. 19805th ed London Oxford University Press P. 41-50, 140-163 & 248-249.
Bancroft JD, Gamble M Theory and practice of histological techniques. 20025th ed London; New York Churchill Livingstone P. 53-121, 173 & 217.
Hayat MA Fixation for electron microscopy. 1981 New York Academic Press:206–261 Inc; P.
Bozzola JJ, Russell LD Electron microscopy: Principles and techniques for biologists. 19992nd ed Boston Jones and Bartlett Publishers:48–202
Kaczmarek E, Górna A, Majewski P. Techniques of image analysis for quantitative immunohistochemistry Rocz Akad Med Bialymst. 2004;49(Suppl. 1):155–158
Dawson B, Trapp RG Basic and clinical biostatistics. 20013rd ed New York Lange Medical Books-McGraw Hill:161–218
Khan A, Hussain SM, Khan MZ. Effects of formalin feeding or administering into the crops of white leghorn cockerels on hematological and biochemical parameters. Poult Sci. 2006;85:1513–1519
Babar AM, Khan MZ, Ahmad S, Khan A, Bachaya HA, Anwar MI. Toxico-pathological effects of formalin (37% formaldehyde) feeding in broiler chicks. Pak Vet J. 2001;21:13–16
Til HP, Woutersen RA, Feron VJ, Clary JJ. Evaluation of the oral toxicity of acetaldehyde and formaldehyde in a 4-week drinking-water study in rats. Food Chem Toxicol. 1988;26:447–452
Johannsen FR, Levinskas GJ, Tegeris AS. Effects of formaldehyde in the rat and dog following oral exposure. Toxicol Lett. 1986;30:1–6
Tobe M, Naito K, Kurokawa Y. Chronic toxicity study on formaldehyde administered orally to rats. Toxicol. 1989;56:79–86
Til HP, Woutersen RA, Feron VJ, Hollanders VH, Falke HE, Clary JJ. Two-year drinking-water study of formaldehyde in rats. Food Chem Toxicol. 1989;27:77–87
Cawson RA, McCarcken AW, Marcus PBCawson RA, McCarcken AW, Marcus PB. Diseases of the gastrointestinal tract Pathological mechanisms and human disease. 1982 St Louis The C.V. Mosby Co.:335 In: , editors. p.
Kumar V, Abbas AK Robbins pathologic basis of disease. 19996th ed Saunders, Philadelphia; London; Tokyo W.B.:789–790 chapter (18);
Yanagawa Y, Kaneko N, Hatanaka K, Sakamoto T, Okada Y, Yoshimitu SI. A case of attempted suicide from the ingestion of formalin. Clin Toxicol. 2007;45:72–76
MacFie J. Current status of bacterial translocation as a cause of surgical sepsis. Br Med Bull. 2004;71:1–11
Deitch EA. Bacterial translocation or lymphatic drainage of toxic products from the gut: What is important in human beings? Surgery. 2002;131:241–244
Takahashi M, Hasegawa R, Furukawa F, Toyoda K, Sato H, Hayashi Y. Effects of ethanol, potassium metabisulfite, formaldehyde, and hydrogen peroxide on gastric carcinogenesis in rats after initiation with N-methyl-N’-nitro-N-nitrosoguanidine. Jpn J Cancer Res. 1986;77:118–124
Niv Y, Turani H. Cystic changes in gastric glands after gastric surgery and in the intact stomach. J Clin Gastroenterol. 1991;13:465–469
Migliore L, Ventura L, Barale R, Loprieno N, Castellino S, Pulci R. Micronuclei and nuclear anomalies induced in the gastro-intestinal epithelium of rats treated with formaldehyde. Mutagenesis. 1989;4:327–334
Majumder PK, Kumar VL. Inhibitory effects of formaldehyde on the reproductive system of male rats. Indian J Physiol Pharmacol. 1995;39:80–82
Soffritti M, Maltoni C, Maffei F, Biagi R. Formaldehyde: an experimental multipotential carcinogen. Toxicol Ind Health. 1989;5:699–730
Fennell TR. Development of methods for measuring biological markers of formaldehyde exposure. Res Rep Health Eff Inst 1994:1–20; discussion 21-26.
Heck H, Casanova M. Pharmacodynamics of formaldehyde: Applications of a model for the arrest of DNA replication by DNA-protein cross-links. Toxicol Appl Pharmacol. 1999;160:86–100