Exploring the properties of formocresol in dentistry—a comprehensive review

4.1.1 Composition

Chemically, the Buckley’s formocresol is composed of 31% water base, 15% glycerin to prevent formaldehyde from polymerizing to para formaldehyde, 19% formaldehyde as an alkylating agent, and 35% tricresol as a protein-coagulating phenolic substance [12]. Although studies have indicated that many dentists continue to use formocresol at full dosage, it has been advised that it be administered either in a 1:5 or 1:25 dilution [12, 13, 14]. It is understood that it is due to non-availability of dilution solution and that recommendations have been made to the manufacturer to develop 1:5 dilution of formocresol replacing the full strength formulation and that which is as effective as full strength medicament [2].

4.1.2 Mode of action

The emission of formaldehyde vapors, which act as a germicidal agent and reversibly inhibit many enzymes involved in the inflammatory process, is thought to be the mode of action of formocresol [12]. The pulp tissue is fixed as a result, and further enzymatic decay is prevented [15]. It was initially employed to render all non-viable tissues within the root canal inert. Recently, techniques have been developed to preserve the integrity of radicular pulp while just fixing the superficial layers of pulp [7]. Cresol is very lipophilic and has been shown to completely destroy cellular integrity, which presumably would allow the formaldehyde component of formocresol for deeper tissue fixation [16].

4.1.3 Clinical procedure

Using sterile cotton pellets, the pulp chamber is dried, and then the cotton pellets are moistened with formocresol. The surplus formocresol is then blotted over sterile gauze before being applied to the pulp stumps. After removing the cotton pellets and drying the pulp chamber, zinc oxide-eugenol is applied over the pulp stumps. The procedure is finished by cementing the stainless-steel crowns. The aforementioned method was initially done in 5 visits and the recommended application time was 5 minutes [2, 7]. Recent research, however, suggest that contact for few seconds may be sufficient and may even be preferable to the previous method [12]. Since 1960, it has been done as a single visit technique due to economic and behavior management factors [6].

4.2.1 Systemic effects

Recent assessments have revealed that modern dentists still employ formocresol despite the widespread systemic dissemination of formaldehyde during formocresol pulpotomy [8]. High dosages of intravenously injected formocresol can cause a systemic toxic response that is defined by changes in blood and urine enzymes as well as histological evidence of kidney, liver, heart, and lung damage [8]. The distribution of radioactively labeled formaldehyde in the viscera, urine, bone, dentine, and periodontal ligament was shown in a study by Ranly DM (1985) on formocresol pulpotomy in a single molar in rats [17]. After receiving thorough dental care with at least one pulpotomy, 30 children were examined by gas chromatography and mass spectrometry in another study by Kahl J et al. [18] (2008). It was discovered that neither formaldehyde nor cresol were present in the blood samples. Instead, their research showed that after the placement of formocresol pellets, benzyl alcohol could be found in traces in their blood samples. Since these compounds are neither carcinogenic nor mutagenic, it is believed that their presence is insignificant. The half-life of formocresol, on the other hand, is well known to be 1–2 minutes, and studies have shown that formaldehyde is rapidly converted into formic acid and carbon dioxide after its application. As a result, it is assumed that formocresol exposure is within the allowed exposure limits [7]. Also the studies where more number of formocresol pulpotomies were done on a small animal like dog represents a considerably higher exposure to systemic formocresol than would occur when performing one or two pulpotomies on a child [8].

4.2.2 Mutagenicity and carcinogenicity

Due to the presence of formaldehyde, the International Agency for Research on Cancer has categorized formocresol as a potential carcinogen [19]. Additionally, mutagenic and genotoxic effects of cresol on mammalian cells are now established [13, 20]. We are often exposed to formaldehyde due to the type of food we eat and the environment we live in, which can harm specific body organs and systems [21]. It has been discovered that the degree of such damage is directly proportional to the formaldehyde dose. For instance, formaldehyde has been reported to impact the eyes, neurological system, and upper respiratory system at levels as low as 0.05 parts per million (ppm), while higher dosages of about 5 ppm can harm the lower respiratory tract and, at doses of 20 ppm and above, can cause death [21]. The World Health Organization has determined that the daily average intake of formaldehyde is 7.8 mg, ranging from 1.5 to 14 mg [16]. An adult consumes 10.55 mg of formaldehyde daily, assuming a contribution of 9.4 mg from food, 1 mg from inhalation, and 0.15 mg from water [16]. If formocresol is diluted 1:5 and applied to a no. 4 cotton pellet that has been squeezed dry, the estimated formaldehyde dose related to one pulpotomy treatment is 0.02 to 0.10 mg [16].

Numerous genetic abnormalities have been linked to formaldehyde exposure in cells, including chromosomal abnormalities, development of micronuclei and sister chromatid exchanges (SCEs), and deletions that result in the production of DNA-protein cross-links (DPX) [22, 23, 24, 25]. Formation of DPX has been demonstrated in a study by Heck DA et al. [22] (1990) in the upper respiratory tract when rats were exposed to higher doses of formaldehyde. According to a study by Lu Z-S et al. [26] (2003) on human buccal mucosal cells, exposure to greater amounts of gaseous formaldehyde increases the risk of cancer development because it causes DNA breaks and the production of DPX. However, a research by Quievryn and Zhitkovitch (2000) revealed that DPX are either spontaneously hydrolyzed or the chromosomal damage is reversed by proteolytic destruction within a few hours of their production [27]. In a research by Zarzar PA et al. [28] (2003) on 20 children using Buckley’s formula, no chromatid gaps, breaks, or chromosomal abnormalities were noted. They stated that although chromosomal abnormalities were discovered in 1 child (5%) there was no proof that this was specifically caused by either formocresol or other factors that could have caused such a finding [28]. In vitro research by Ribeiro and Scolastici (2005) [29] using the single cell gel (comet) assay revealed possible genetic damage caused by formocresol in mammalian cells, and research by Kreiger and Garry (1983) [30] found that no mutations in cultured human lymphocytes were found below a formaldehyde threshold of 5 mg/L in the culture medium. In contrast, genotoxic events have been shown by Hagiwara M et al. [31] (2006) and Nishimura H et al. [32] (2008) when the dosage of formocresol was much lower than the normal dose used in pulpotomy.

The aforementioned findings have led various researchers to recommend that formocresol no longer be used in dental procedures. Research showing that formaldehyde does not have mutagenic or carcinogenic effects at low exposure levels, on the other hand, has been used by some to promote the use of formocresol [14]. There is no strong scientific evidence against it, therefore clinicians may continue to use it cautiously.

4.2.3 Allergic and immunogenic effects

There are conflicting studies on the allergenicity of formocresol. Studies have shown that after formocresol pulpotomy in dogs, formaldehyde-specific antibodies are formed [33]. A review on immunology of pulpal-periapical infections by Morse DR (1977) indicated that the endodontics “flare-ups” such as pain, swelling and bone resorption following the use of formocresol occur as consequence of immunological reaction [34]. Formocresol may act as a hapten, which binds to host proteins and stimulates an immunological response [34]. According to case reports by Cambruzzi and Greenfield (1983) [35] and Kopczyk RA et al. [36] (1986), formocresol caused necrosis of the crestal bone and the surrounding soft tissue, as well as a significant loss of the alveolar bone that served as support.

Female patients are more immunologically reactive to formaldehyde, according to a recent systematic analysis by Syed M et al. [37] (2015). In a case report by Ding YJ et al. [38] (2013), the patient initially had nausea and vomiting after using formocresol as a pulp medication, but within 10 minutes of application on the second visit, the patient experienced anaphylactic shock. Formocresol can cause a type-I allergic reaction as seen in magnetic resonance imaging, which revealed brain injury and swollen gyri in the cerebral watershed territory of the left parietal-occipital lobe [38].

However, Dilley and Courts (1981) found no evidence of similar effects in their experimental investigation using rabbits [39]. None of the 128 schoolchildren who were patch tested in a different study by Rölling I et al. [40] (1976) showed any positive reaction following formocresol pulpotomy. The absence of therapeutic relevance of formaldehyde-specific immunoglobulin E was reported by Doi S et al. [41] (2003). Therefore, it has not been proven that formocresol “sensitizes” children.

4.2.4 Formocresol injuries localized to oral and para-oral tissues

When employing formocresol, proper precautions must be taken, especially to prevent contact with any nearby soft tissues; otherwise, there is a risk of the tissue damage [12]. Inappropriate usage of formocresol often results in localized gingival recession, ulcerations, and mucosal burns along with extensive mucosal sloughing throughout the entire affected area [42]. The ulcerative lesion could be severe, and there could be sloughing that resembles coagulative necrosis [43]. The lesions may seem erythematous, edematous, or whitish [43]. Injuries to salivary gland ducts may first result in transient obstructive sialadenitis and ductal opening scarring before becoming permanently obstructed and resulting in chronic sialadenitis. Reduced food intake and a reduced mouth opening may be observed, in addition to pain and edema in the exposed area. In severe situations, the alveolar bone and teeth may also be affected [1].

Burns to the oral mucosa account for the majority of case reports of formocresol injuries in dental offices. However, there is paucity of reports of the effects of formocresol on facial skin. In a case of formocresol exposure, Issrani R et al. [44] (2020) described a patch of darkly stained skin with mild to severe pain and a burning sensation. Conjunctiva injury caused by the unintentional use of formocresol as eye drops has been documented in another instance [45].

4.3.1 Glutaraldehyde

The clinical success rate of glutaraldehyde was reported to be 100% in the study by Havale R et al. [6] (2013), which was better than the clinical success rate of formocresol (86.7%). Glutaraldehyde has a radiographic success rate that ranges from 75.8% to 83.3% [6, 46]. On the contrary, a study by Fuks AB et al. [47] (1991) with 2% glutaraldehyde, showed 18% failure in deciduous molars 25 months after pulpotomy and 45% of teeth showed faster resorption than their controls in 42-month follow-up.

4.3.2 Mineral trioxide aggregate (MTA)

According to recent study, MTA is the most popular choice because of its excellent characteristics, which include preserving pulpal health and promoting healing and pulp regeneration [13, 48]. In five of the six clinical tests comparing formocresol and MTA that Fuks AB (2008) reported, MTA was more successful than formocresol [49]. In studies by Holan G et al. [50] (2005) and Farsi N et al. [51] (2005), success rates in pulpotomized molars with formocresol were 97% and 100%, respectively, after follow-up periods of 38.2 months and 2 years. However, formocresol, MTA, sodium hypochlorite, and ferric sulfate did not significantly vary from one another in a randomized clinical trial conducted by Fernández CC et al. [52] (2013).

4.3.3 Ferric sulphate

Studies by Havale R et al. [6] (2013), Fuks AB et al. [53] (1997) and Fei AL et al. [54] (1991) on pulpotomy of primary teeth have demonstrated that ferric sulfate is more effective than formocresol. Prabhu and Munshi (1997) have reported a 100% clinical and radiographic success rate with ferric sulfate [55]. According to a recent systematic review and meta-analysis, ferric sulfate could serve as an acceptable substitute for formocresol because there is no difference between the two in terms of the clinical and radiographic success rates in primary molar pulpotomies [8].

4.3.4 Calcium hydroxide

According to Markovic D et al. [56] (2005), 47.0% of pulpotomized teeth treated with calcium hydroxide had a dentin bridge above the site of the pulp amputation. Using an alternate hemorrhage control technique, aluminum chloride, Heilig J et al. [57] (1984) performed calcium hydroxide pulpotomies in 17 carious primary molars and suggested that this procedure might be preferable to formocresol pulpotomies. Similarly, Waterhouse PJ et al. [58] (2000) conducted a study to compare the clinical and radiological outcomes following single visit vital pulp therapy techniques, using formocresol and calcium hydroxide and confirmed that calcium hydroxide in its pure, powder form is a clinically acceptable alternative when combined with strict selection criteria for this method of restorative care. In a recent study, Kaya C et al. [59] (2022) compared calcium hydroxide pulpotomies with biostimulation to calcium hydroxide, formocresol, and MTA pulpotomies without biostimulation in primary molars. They found that, clinically, the calcium hydroxide pulpotomies with biostimulation had a similar success rate to the formocresol and MTA group, whereas radiographically, calcium hydroxide pulpotomy with biostimulation showed higher success rate compared to calcium hydroxide but this success was not high as compared to formocresol and MTA. Also, Yildiz E et al. [60] (2014) had found a lower clinical and radiographic success rate of calcium hydroxide as compared to formocresol when used as the pulpotomy material.

4.3.5 Sodium hypochlorite (NaOCl)

According to a study by Vargas KG et al. [61] (2006), the clinical and radiological success rates of pulpotomies with NaOCl were comparable to those of ferric sulfate and formocresol. Kola SR et al. [62] reported similar results (2019). To validate and establish such a conclusion, however, more research with longer follow-up times might be needed before it can be recommended as a suitable alternative to formocresol.

4.3.6 Electrosurgical pulpotomy

Infected radicular pulp tissue has been treated with electrocautery and lasers in addition to the standard formocresol and other pharmaceutical treatments [7]. The use of such techniques was found to be highly successful, as shown by Mack and Dean (1993) [63]. El-Meligy O et al. [64] (2001) showed that electrosurgery pulpotomy causes less tissue reaction histopathologically than formocresol treated teeth. But Oztas N et al. [65] showed that formocresol pulpotomies were histologically superior to electrosurgery (1994). A recent study by Bahrololoomi Z et al. [66] (2008) compared the failure rates of formocresol pulpotomy and electrosurgery on 70 primary molars in children aged 5 to 10 years found no statistically significant difference between the two procedures. Before considering these treatments as alternatives to formocresol pulpotomies, more research is needed due to the conflicting findings from numerous studies.

4.3.7 Laser surgery

Elliott RD (1999) [67] evaluated and compared human primary pulp responses to carbon dioxide laser and formocresol and found no significant differences between the two procedures in their clinical or radiographic findings suggesting that the use of lasers may be beneficial in vital pulpotomy.

4.3.8 Miscellaneous

It has been demonstrated that Biodentine, a calcium-based bioactive cement, exhibited some promising outcomes in the search for newer alternatives for pulp dressing in primary teeth [7, 68, 69, 70]. Additionally, it was determined that White Portland Cement and beta-tricalcium phosphate were superior to formocresol and ferric sulfate [13]. Formocresol or other chemicals commonly used as dressings in deciduous teeth pulpotomies could potentially be replaced by a variety of other materials, including calcium phosphate cement, freeze-dried bone, allogenic bone morphogenetic protein, supersaturated collagen solutions, and allogenic dentin matrix [71, 72, 73]. Although many alternatives to formocresol are available, an ideal agent for pulp dressing in pulpotomies of deciduous teeth has not been established thus far. Until such an agent is found, formocresol, ferric sulphate or MTA may be continued to be used as pulp capping agents in primary tooth pulpotomies [7].

The advantages and disadvantages of alternative materials to formocresol are highlighted in Table 1 [2, 6, 7, 8, 43, 72, 74].