|Year : 2014 | Volume
| Issue : 3 | Page : 114-124
Formocresol, still a controversial material for pulpotomy: A critical literature review
Shashidhar Chandrashekhar1, Jyothi Shashidhar2
1 Departments of Conservative and Endodontics, Modern Dental College and Research Center, Indore, Madhya Pradesh, India
2 Department of Pedodontics, Modern Dental College and Research Center, Indore, Madhya Pradesh, India
|Date of Web Publication||29-Oct-2014|
1663/56, 11th Main Road, Bank Colony, Siddaveerappa Extension, Davangere - 577 004, Karnataka
Source of Support: None, Conflict of Interest: None
This paper reviews the history, clinical success and concerns regarding the safety of formocresol as a primary molar pulpotomy medicament. The alternatives to formocresol are discussed and their advantages and disadvantages are evaluated.
Keywords: Electrosurgical pulpotomy, formocresol, glutaraldehyde, laser surgery
|How to cite this article:|
Chandrashekhar S, Shashidhar J. Formocresol, still a controversial material for pulpotomy: A critical literature review
. J Res Dent 2014;2:114-24
|How to cite this URL:|
Chandrashekhar S, Shashidhar J. Formocresol, still a controversial material for pulpotomy: A critical literature review
. J Res Dent [serial online] 2014 [cited 2019 Dec 14];2:114-24. Available from: http://www.jresdent.org/text.asp?2014/2/3/114/143594
| Introduction|| |
If any field in pediatric dentistry is more controversial than others, it is pediatric endodontics.  Pulp tissue is a highly specialized connective tissue necessary for the immune competence and sensation within a tooth, long after dentinogenesis is completed.  The tissue, located in a specific rigid environment, has a complex blood flow  and is rich in cellular and neural elements. It is very difficult for clinicians to diagnose the level of pulpal inflammation. 
This is the reason why pulp therapy in dentistry, particularly the pulpotomy procedure in pediatric dentistry, has remained a controversial issue. The ideal pulp dressing material after pulpotomy should leave radicular pulp vital, healthy and enclosed within an odontoblastic-lined dentine chamber,  but such material has not been found till now. An effective pulpotomy medicament should show clinical and radiographic success as well as compatibility between pulp and surrounding tissue physiologically. 
Formocresol has been used in dentistry since 100 years and for deciduous teeth pulpotomy since 80 years. The reparative, biologic approach to pediatric pulp therapy is either devitalization approach of formocresol pulptomy or pulpectomy. Formocresol was introduced to treat non-vital permanent teeth in the United States by Buckley in 1904.  In 1930, Sweet introduced the formocresol pulpotomy technique. Formocresol has subsequently become a popular pulpotomy medicament for primary teeth. Initially, the technique involved five visits. Sweet reduced the number of visits over the years, because of economic and behavior management considerations.  Doyle et al.  used a two-visit procedure in their comparison study of formocresol and calcium hydroxide. Within a few years, Spedding et al.  and Redig  reported the results of a 5-min formocresol protocol, and since that time, complete mummification has been abandoned by the profession.
By 1960, a single visit procedure was advocated.  Studies have shown formocresol therapy to have a success rate between 70% and 90%.  Histologic results have been variable in contrast to the high clinical success rate. Formocresol is still considered a gold standard by which all new modalities are compared. 
The composition of Buckley's formocresol is 19% formaldehyde and 35% tricresol, 15% glycerin and 31% water base.  Glycerine is added to prevent the polymerization of formaldehyde to para-formaldehyde. The presence of para-formaldehyde causes clouding of the solution.  One-fifth dilution of Buckley's formocresol can be prepared by adding 30 ml of Buckley's formocresol, 90 ml of glycerol and 30 ml of water. 
| Mechanism of action|| |
Formocresol acts through the aldehyde group of formaldehyde, forming bonds with the side groups of the amino acids of both the bacterial proteins and those of the remaining pulp tissue. It is therefore both a bactericidal and devitalizing agent. It kills off and converts bacteria and pulp tissue into inert compounds.  Its function is to fasten the live pulps, maintaining them inert and facilitating the conservation of deciduous tooth until their physiologic fall. It has a potent antibacterial action that justifies its use in long curative in endodontic treatment.
With formocresol as the pulptomy medicament, a zone of fixation usually is evident where the pulp is in direct contact with the medicament. Coagulation necrosis of the tissue occurs at the amputation site and is supported by the fact that true coagulation necrosis is produced by poisons such as phenol, formaldehyde or mercuric chloride, which denatures the protein of the cells.  It has also been shown that formocresol inactivates the oxidative enzymes in the pulp tissue adjacent to the amputation site. It may also have some effect on hyaluronidase action. Therefore, the protein-binding properties and the inhibition of the enzymes that can break the pulp tissue down together result in 'fixation' of the pulp tissue by formocresol and render it inert and resistant to enzymatic breakdown.  Farther away, where the concentration of formocresol is decreased, there is a zone of poor cellular definition and necrosis. Apical to this is a zone of chronic inflammation, which blends into normal tissue. ,, In contrast, Berger reported complete loss of vitality with fibrous granulation tissue in the apical third of the root canal.  In a study to know the effect of formocresol on polymorphonuclear cells (PMNs), the lysis of PMNs was observed with high concentrations of formocresol. An interesting finding with low concentrations of formocresol was the significant stimulation of PMN adherence. The authors postulate that stimulation of PMNs by pulpotomy medicaments may contribute to the chronic inflammatory changes seen with their use. Initial stimulation followed by depressions is a well-known response of PMNs following activation by various stimuli. Same activation-deactivation phenomenon was observed clearly with formocresol. 
Internal resorption may also result in teeth treated with formocresol might be due to the severe damage to the residual tissue, also destroying its capacity to reabsorb. This may be attributed to inflammation of the residual pulp. On the other hand, pulpotomy treatment with formocresol in monkeys has been associated with the formation of reparative dentin. , Human studies have not reported the finding of reparative dentin in association with the formocresol pulpotomy. , This might be possibly due to the production of reparative dentine on light stimulation like any type of trauma, including formocresol of the pulpal tissue of monkeys. 
| Pharmacokinetics of formocresol|| |
In addition to the clinical response, biologic effects of formocresol should also be studied. Formocresol is toxic to living tissues because of the formaldehyde component. Formocresol applied to vital pulp tissue is absorbed readily into the systemic circulation and distributed throughout the body.  A portion of the absorbed formocresol is metabolized and excreted by the kidney and lungs. , The remaining formocresol is tissue-bound with the liver, kidney and lungs - the predominant sites of tissue binding.
Pharmacokinetics of formaldehyde
Formaldehyde exposure occurs daily as it is present in air, water and food. The World Health Organization (WHO) has estimated daily consumption of formaldehyde to be approximately 1.5-14 mg/day (mean, 7.8 mg/day).  Assuming a contribution of 9.4 mg/day from food, 1 mg/day from inhalation and 0.15 mg/day from water, an adult takes in 10.55 mg of formaldehyde per day.  The estimated formaldehyde dose associated with 1 pulpotomy procedure, assuming a 1:5 dilution of formocresol placed on a no. 4 cotton pellet that has been squeezed dry, is approximately 0.02-0.10 mg. 
Hileman has shown that endogenous levels of metabolically produced formaldehyde range from approximately 3-12 ng/g tissue.  This formaldehyde is produced by amino acid metabolism, oxidative demethylation, and purine and pyrimidine metabolism.  Exogenous formaldehyde is taken up into the human body via ingestion, inhalation and dermal exposure. Inhaled formaldehyde appears to be readily absorbed by the upper respiratory tract, but it is not distributed throughout the body because it is rapidly metabolized.  Ingested formaldehyde is readily absorbed by the gastrointestinal tract and exhibits little subacute toxicity after oral exposure.  Exogenous formaldehyde has a biologic half-life of 1-1.5 minutes and is quickly cleared from human plasma. 
Human cells manage formaldehyde exposure physiologically through multiple pathways of oxidation of formaldehyde to formate. Cytosolic alcohol dehydrogenase, mitochondrial aldehyde dehydrogenase, and glutathione-dependent and glutathione-independent dehydrogenases are important enzymes in the metabolism of formaldehyde in hepatocytes, oral mucosa and nasal respiratory mucosa.  Formate is the principal oxidative product of formaldehyde. Formate is further oxidized to carbon dioxide and water by the action of formyl-tetrahydrofolate synthetase.  Formate might be converted to a soluble sodium salt via alternative pathways and excreted in the urine, or it might be incorporated into biologic macromolecules via tetrahydrofolate-dependent, 1-carbon biosynthetic pathways.  Single C-atoms are released during the metabolism of formaldehyde and formate. These C-atoms deposit in 1 C-atom pool, which in turn is used in the biosynthesis of purine, pyrimidine and proteins.
Histological studies demonstrate the true biological damage after formocresol treatment. Physiologically, with the vascular damage, the balance between osmotic pressure and hydrostatic pressure is disrupted in tissue. As a result, there is absorption of inflammatory fluid insult by pulp tissue and decrease in the osmotic pressure. So hemostatic balance is re-established. ,, When this occurs, the constricted pulp cavity must dissipate the pressure changes. If this does not occur, pressure necrosis of the pulp occurs. In addition, lymphatic and venous vascular flow from the coronal pulp must dissipate this excess inflammatory fluid. This excess is distributed apically and to regional vascular vessels. Therefore, the local insult results in systemic distribution.
Studies report that formaldehyde labeled with radioactive carbon (14C) was apparently distributed among the muscle, liver, kidney, heart, spleen and lungs. The quantities of radiolabeled chemical detected, however, were very small (1% of the total administered dose). , Myers et al.  and Pashley et al.  concluded that [14C] formaldehyde is absorbed systemically from pulpotomy sites and formaldehyde is distributed to distant sites, but did not determine if the labeling of tissues occurred by metabolic incorporation of the [14C] moiety of the labeled formaldehyde into macromolecules.
Pharmacokinetics of cresol
The second active ingredient in formocresol, cresol, has received little attention in investigations of formocresol efficacy. Cresol has poor solubility, so it is assumed that it does not enter systemic circulation.  Cresol is highly lipophilic and has been shown to completely destroy cellular integrity. This would allow deeper tissue fixation by the formaldehyde component of formocresol. , No data exist regarding cresol metabolism or elimination in humans or other mammals, and about environmental sources of cresol to which humans might be exposed.
Benzyl alcohol is a by-product of tricresol oxidation.  Benzyl alcohol is oxidized rapidly to benzoic acid, conjugated with glycine in the liver, and excreted as hippuric acid. It has no carcinogenic or mutagenic potential, and the allowable daily intake, as established by WHO is 5 mg/kg. ,
Concerns about formocresol
Concerns about the safety of formocresol have been appearing in the dental and medical literature for more than 20 years. Formaldehyde, a primary component in formocresol, is a hazardous substance.  National Institute for Occupational Safety and Health in USA states if formaldehyde exposure occurs at a concentration of 20 ppb (parts per billion) or higher, it is instantly dangerous to health and life. 
Studies on formocresol therapy have put the clinical success rate between 70% and 90%.  But variable histologic results were also reported in contrast to the clinical success rate. Instead of preserving vital pulpal tissue, chronic inflammation and necrotic tissue were found. , Another problem with formocresol is its systemic distribution from the pulpotomy site. Pruhs et al. found a relationship between primary teeth treated with formocresol and enamel defects in the permanent successors. The allergenic and mutagenic properties of formaldehyde have been demonstrated in animal models, but not in humans. Cysts have also been found to be associated with the pulpotomized teeth. 
The study suggests that full strength formocresol (48.5% of formaldehyde) absorbed from multiple pulpotomy sites may initiate tissue injury in kidney and liver of experimental animals. The author suggests that a longitudinal study is needed to determine whether the injured kidney and liver cells would recover as there is only cell injury, and no evidence of onset of inflammatory reaction. This study cannot make any direct clinical implications regarding toxicity of formocresol. 
Mutagenicity, genotoxicity and cytotoxicity
Exposure of cells to formaldehyde leads to the formation of DPX (DNA-protein cross-links). The most common types of DNA damage induced by formaldehyde are clastogenic lesions, including sister chromatid exchanges (SCEs), micronuclei and chromosomal aberrations, and deletions. It has been proposed that formaldehyde could induce the development of DPX at distant sites, but no convincing evidence has been obtained from in vivo experimental studies. 
The recent research by Heck and Casanova showed the development of DPX in nasal tissues and upper respiratory tract associated with high dose exposure of formaldhehyde.  DPX does not persist in tissues for more than few hours and undergoes spontaneous hydrolysis or active repair by proteolytic degradation of cross-linked proteins. So role of DPX in formaldehyde-induced carcinogenesis is again questionable. 
Cytogenetic studies of lymphocytes from rodents following formaldehyde inhalation with exposures ranging from 0.5-1.5 ppm for 6 h/day for 5 days failed to detect either chromosomal aberrations or SCEs at any of the formaldehyde concentrations. 
In vitro experiments with a Chinese hamster cell line found that DPX and SCE, as a result of formaldehyde exposure, were associated with cytotoxicity, not mutation.  In addition, no mutagenesis occurred in cultured human lymphocytes below a formaldehyde threshold of 5 μg/mL in the culture medium. 
In one of the dental studies that do not support formaldehyde is a mutagenic, Zarzar et al. performed formocresol pulpotomy on 20 children by using Buckley's original formula. Blood samples were collected from each child immediately before and 24 hours after the pulpotomy. No statistically significant differences were found between the two groups in terms of chromosomal aberrations, chromatid breaks or chromatid gaps. Also, Zarzar et al. concluded that formocresol is not mutagenic. 
Ribeiro et al. reported two studies that assessed the mutagenic potential of formocresol. With a mouse lymphoma cell line, cultured human fibroblasts and a series of formocresol dilutions similar to clinical doses, these authors found that formocresol did not produce detectable DNA damage and should not be considered genotoxic. 
The investigations of root canal sealers that contain formaldehyde and produce cytotoxicity are not comparable with formocresol pulpotomy studies. Because large quantities of formaldehyde are produced from sealers than pulpotomy, large quantities of sealers are used. Root canal sealer remains in root canal and forms part of restoration and may lead to further release of formaldehyde. 
It is summarized that DPX development demonstrated only after a prolonged exposure to formaldehyde at specific contact sites such as nasopharynx. A minute quantity used in pulpotomy for few minutes that will produce distant site genotoxicity is not evidence-based. 
It is concluded that cancer develops after inhalation of air with large concentrations of formaldehyde. The cancer can occur after a long-term direct contact with susceptible tissues. The toxic effects on initial contact sites like ulceration, hyperplasia and squamous metaplasia may subsequently contribute to cancer.  These high-dose responses are unlikely to occur at sites distant from the point of initial formaldehyde contact (such as the bone marrow). Formaldehyde is not delivered to these distant sites. Those who have argued against the continued use of formocresol in pediatric dentistry on the basis that "formaldehyde causes cancer" have failed to recognize this very important distinction. 
Health Canada and the Organization for Economic Cooperation and Development have stated on the basis of CIIT (Chemical Industry Institute for Toxicology Centers for Health Research) research models that "taking into account the extensive information on its mode of action, formaldehyde is not likely to be a potent carcinogen to humans under low exposure conditions." 
Two large American studies from National Cancer Institute (NCI) of epidemiological investigations failed to show any causal relationship between formaldehyde and leukemia. ,
In 2004, International Agency for Research on Cancer (IARC) reclassified formaldehyde as a known carcinogen from human probable carcinogen,  but according to them, it is an agent that can increase the risk of cancer at some doses. They do not undertake the dose response analyses and possible threshold. The possibility that inhaled or ingested formaldehyde might induce cancer at sites distant from the respiratory or gastrointestinal tracts has been investigated in numerous long-term toxicity studies performed in rodents.  Experimental and epidemiologic research do not support the theory that inhaled or ingested formaldehyde might induce distant site toxicity. 
The facts are that formaldehyde occurs naturally throughout the body, there are multiple pathways for detoxification, and only microgram quantities of formaldehyde are applied to pulp tissues during pulpotomy procedures for mere minutes. Considering these facts, exposure of children to the formaldehyde component of formocresol during a pulpotomy is insignificant and inconsequential.
Pulpotomy in dogs demonstrated that histological changes where foreign pulp protein is present, host's necrotic tissues were produced by pulp tissue on reaction with formocresol. The B cells may produce antibodies to foreign pulp protein and host necrotic tissue. Further, non-specific pro-inflammatory mediators and chemotactic cytokines can illicit further immune factor responses. One response is osteogenic activating factor that destroys bone. This has not been quantified in either children or adults. 
Experiment on dogs showed that formocresol produces antigenic activity in pulp tissue.  Rolling and Thulin found no increase in either immune response or allergic reactions in 128 children who had undergone formocresol pulpotomy.  A Canadian study of urea formaldehyde foam insulation from products in the homes of asthmatic subjects found that its long-term exposure had no effect on immunologic responses.  Doi et al. found that there is no clinical relevance of formaldehyde-specific immunoglobulin E. Hence, the suggestion that formocresol "sensitizes" children has not been supported. 
Comparing formocresol with other materials
Formocresol versus glutaraldehyde
In recent years, glutaraldehyde has been proposed as an alternative to formocresol based on its superior fixative properties, self-limiting penetration, low antigenicity, low toxicity and elimination of cresol.  It is a colorless solution that has a mild odor and a boiling point of 183°C to 187°C, is soluble in water, and produces mild acidity on contamination.  Glutaraldehyde is a chemically bifunctional reagent, which forms strong intra- and intermolecular protein bonds, leading to superior fixation by cross-linkage.  Glutaraldehyde produces a zone of tissue fixation where it is in direct contact with the pulp, while apical to this is a zone of normal tissue with few inflammatory cells. , It has been observed that inadequate fixation leaves a deficient barrier to sub-base irritation, resulting in internal resorption. , Penetration into the surrounding peri-apical tissue is limited primarily by protein cross-linkage formation. Thus, systemic distribution of glutaraldehyde is limited.  Glutaraldehyde is less necrotic, dystrophic, cytotoxic and antigenic, is a better bactericide, and fixes the tissue instantly. 
Glutaraldehyde appears to produce tissue fixation without causing tissue necrosis at high concentrations. Although it depresses PMN adherence at intermediate concentrations, it does not seem to stimulate PMN adherence and cause inflammatory tissue damage at low concentrations. 
Prakash et al. concluded that glutaraldehyde is better fixative and less toxic agent than formocresol. In this study, they compared the clinical and radiological effects of formocresol and glutaraldehyde pulpotomies in various exposed vital human primary molars.  The 2% glutaraldehyde compound was promising when compared to ferric sulfate and formocresol in an in vivo study. The only limitations of glutaraldehyde are instability due to short shelf-life and it has to be freshly prepared. In this study, the clinical and radiographic success of formocresol, glutaraldehyde and ferric sulfate were compared as a pulpotomy medicament in primary molars at 3-month intervals over 1 year. Internal resorption was found in all the medicaments. Clinical success was higher than the radiological success. 
One study failed to justify recommendation of 2% buffered glutaraldehyde solution as a substitute to formocresol as failure was observed within 6 months of treatment and failure rate was increased even after and up to 25 months. Internal resorption and external resorption were listed as failures. Resorption rate of pulpotomized teeth was similar to that of other teeth. 
Long-term (36 months) success rates of four different glutaraldehyde preparations (2%-buffered and unbuffered, 5%-buffered and unbuffered) as a pulpotomy agent in pulp exposed primary molars were evaluated. The 5% buffered solution group showed highest success rate, whereas 5% unbuffered solution showed the lowest, but as such there was no significant difference found among the four groups. The canal obliteration was noted in 22 treated teeth. The relative high failure rate in this long-term follow-up indicates that clinicians should be cautious before extensively using glutaraldehyde as pulpotomy agent. 
| Formocresol versus electrosurgical pulpotomy|| |
Another form of non-chemical devitalization developed is electrosurgical pulpotomy.  It is a method of cutting and coagulating soft tissues by means of high-frequency radio waves passing through the tissue cells. The advantages of electrosurgical pulpotomy are similar.  The self-limiting, pulpal penetration is only a few cell layers deep. There is good visualization and homeostasis without chemical coagulation or systemic involvement. It is less time-consuming than the formocresol approach. Electrocautery carbonizes and heat denatures pulp and bacterial contamination. It may not be suitable if apical root resorption has occurred.  Remarkably, Mack and Dean  reported a very high success rate with the technique.
Studies show that there is no significant difference between clinical and radiographic success rates for electrosurgical and formocresol pulpotomies. , But electrosurgery is considered as sensitive technique.  Oztas et al. reported that formocresol pulpotomy technique is histopathologically superior to electrosurgery pulpotomy technique, as they found presence of inflammation, fibrosis, necrosis and resorption.  On the other hand, El-Meligy et al. showed that teeth treated by electrosurgery pulpotomy exhibited less histopathological reaction than formocresol pulpotomy. 
Electrosurgery pulpotomy with either mechanical coronal pulp removal or electrical coronal pulp removal induces formation of reparative dentin. This is in the form of bridging at the pulpal amputation sites or along the canal walls. It indicates the present healthy vital pulp efforts to heal the area of insult. , This technique also increases the fibroblastic activity at the middle and apical portions of roots with early resorption, , as pulp tissue tries to renew itself with proliferation of fibroblasts.
On the basis of the use of electrosurgical current intensity, there is a chance of peri-apical or furcal involvement. Ruemping et al. used low intensity current for electrosurgical pulpotomy during their research so there was no peri-apical or furcal involvement. 
In case of electrosurgery, internal resorption was noted after 4 weeks. This is due to the excess amount of lateral heat that can accumulate, causing necrosis and resorption. Heat transfer through accessory canals on pulpal chamber floor of molars was responsible for internal resorption. Later, intense inflammatory cells were observed at coronal third of pulp canals and complete healing cannot be achieved in the absence of dentinal bridges. 
| Formocresol versus laser surgery|| |
The carbon dioxide laser has wide applications in oral and general surgery procedures involving soft tissue.  The laser emits an infrared beam at a wavelength of 10.6 m, has an affinity for water, and is capable of producing well-localized cautery to soft tissue. Tissue is removed by ablation through conversion of the laser beam to heat.  Based on these characteristics the carbon dioxide laser appears to have promise as an alternative for pulpotomy therapy.
A study conducted to evaluate the response of the human primary pulp to the carbon dioxide laser and formocresol for vital pulp therapy showed that there were no significant differences between the formocresol and laser groups with respect to symptomatic, clinical or radiographic findings. The histologic observations in this study revealed three interesting effects. First, the laser treatment was at least as effective in minimizing post-treatment inflammation as the formocresol treatment. Second, there was no statistically significant recovery from inflammation between the 28- and 90-day observation period in either the laser or formocresol group. Third, there was a strong and statistically significant inverse correlation between the energy used during the respective laser pulpotomies and the degree of inflammation observed at 28 days. 
The histological response of dental pulp after different types of laser irradiation was evaluated in some studies. The results revealed that laser irradiation caused carbonization, necrosis and infiltration of inflammation cells, edema and hemorrhage in the pulp tissue. ,
The pulp can predictably heal itself when the temperature does not raise more than 5.5 o C above physiological baseline. The higher energy created a thicker char layer over the remaining pulp, which in some way had a favorable effect in reducing the initial inflammatory response in residual pulp. 
Laser irradiation was effective for the growth of fibroblast and induced suppressive effects for macrophage. In addition, effects of laser irradiation on vital pulpotomy were investigated. It was observed that laser irradiation induced enhancement of calcification in wound surface and stimulated formation of calcified tissue. These observations indicate that laser irradiation is a useful method for vital pulpotomy. 
| Formocresol versus ferric sulfate|| |
Monsel's solution, which is a 20% ferric sub-sulfate, is widely used as a strong styptic agent in skin and mucosal biopsies.  Ferric sulfate is a non-aldehyde chemical. It controls the pulpal hemorrhage and thus prevents the problems encountered due to clot formation and minimizes the inflammation and internal resorption. Shaw et al. ( 1987) also found reversible damage to the connective tissue adjacent to the sulcular gingiva after application of ferric sulfate. In contact with the blood, ferric ions form a ferric complex and the membrane of this complex seals the cut blood vessels mechanically and provides hemostasis and an agglutinated protein complex, which produces a blood clot that occludes the capillary orifices. The hemostatic properties of ferric sulfate and the favorable pulpal response make it a promising medicament for pulpotomy. 
A clinical research was done by Fie et al. to compare the clinical and radiographic success of ferric sulfate and formocresol as pulpotomy medicaments. They demonstrated that ferric sulfate was clinically and radiographically successful as a pulpotomy medicament in primary teeth. At the one-year recall, the success rate of the ferric sulfate group was actually greater than that of the traditional formocresol pulpotomy group. In this study, samples were small and recall period was short. Although the ferric sulfate technique appeared successful histologically, the long-term effect of this drug on the teeth and the rest of the body was not addressed. 
In this study, they used zinc oxide eugenol as a base material over treated pulp stumps but it is not an ideal choice as eugenol may irritate the underlying pulpal tissue. Since formocresol is said to "mummify" or fix the pulpal tissue in root canals, pulp tissue under this agent may not be affected by the zinc oxide eugenol. Garcia-Godoy et al. found less severe inflammation when zinc oxide eugenol was placed on formocresol-treated pulps.  Ferric sulfate may function passively. Since ferric sulfate is not a fixative agent, the base in direct contact with the pulpal surface may play an important role in the healing process. Bases that are inert may stimulate pulp cell attachment and provide more rapid and less inflammatory wound healing.  The possible combination of ferric sulfate with different base materials is certainly worthy of further investigation.
In case of chronic coronal pulpitis, even though tooth is a good candidate for pulpotomy clinically, inflammation extension makes it questionable for the procedure. At that time, formocresol because of its property of mummifying the remaining pulpal tissue makes the tooth to retain it for a longer time. Ferric sulfate is nonfixative but has bacteriostatic properties and may not act on underlying inflammatory tissue. Thus, it may not be beneficial in similar situation. 
Additional histologic studies are needed to determine pulpal response to this material. Studies should determine the potential effects on underlying permanent teeth and the nature of any absorption and systemic distribution of ferric sulfate from pulpal tissues. 
Jones and Duggal compared the pulpal reactions to ferric sulfate and formocresol pulpotomies in primary molars with inflamed pulps of baboons. This study has shown that both pulpotomy agents produced apparently successful vital pulpotomies, but both were associated with pulp necrosis and apical abscesses at a histological level. No literature has given specific guidelines for histological success after pulpotomy. 
Ideally, healing in primary pulp should be good. The pulps of primary teeth are known to be quite resilient and are cell rich and fiber poor.  The most important part of healing of an exposed pulp is formation of a dentinal bridge. Such finding is rare in the above study as formocresol destroys those cells that produce healing, and the effect of ferric sulfate is unclear apart from hemostatic properties.
This study suggested that the primary teeth appear to be clinically functional and not associated with radiographic changes even though pathological changes can be seen histologically. Both ferric sulfate and formocresol pulpotomies produce favorable clinical results in human primary teeth, which is clear from clinical studies. ,, The highest clinical and radiographic success rate (100%) of ferric sulfate was reported by Prabhu and Munshi.  Another short-term (20 months) study showed 100% clinical and 97.2% radiographic success rate for both ferric sulfate and formocresol. 
There is a study comparing the effects of ferric sulfate and full strength formocresol as pulpotomy agents in primary human molars in a long-term (4 years) follow-up clinical trial, which assessed the succedaneous premolar teeth for any decalcification, abnormal morphology or any other defects as well. They found overall success rate of ferric sulfate was almost similar to formocresol and no delay in eruption of premolars and abnormality were observed. So the authors concluded that ferric sulfate is a nontoxic agent to replace formocresol. 
It has been stated that success rates may be more dependent upon the correct choice of teeth, assessment of bleeding from amputated pulp stumps and adequate coronal seal as a candidate for vital pulpotomies than on other factors. Inconsistencies of technique and microleakage of the restorative material (IRM) may also limit the success of pulpotomy.
In most of the studies, zinc oxide eugenol is used as a sub-base. Zinc oxide is in direct contact with pulpal tissue, which may cause chronic inflammation and necrosis. This may lead to internal resorption. Hume stated that formocresol would fix tissue that may act as a barrier to the eugenol, but with ferric sulfate the clot is the only entity separating the eugenol from vital tissues. 
Some authors have stated that formocresol pulpotomies could be considered clinically successful therapies, as they preserve extremely carious primary molars until their normal exfoliation. , The main objective of pulpotomies must be to maintain the vitality of the majority of the radicular pulp. The authors who advocate pulpotomies should be to keep the pulp of primary teeth vital until their normal physiological resorption, rather than just "maintaining" teeth. 
Formocresol versus calcium hydroxide
Calcium hydroxide was the first agent used in pulpotomies that demonstrated any capacity to induce regeneration of dentin.  The high pH of calcium hydroxide wounds the pulp in a manner that permits the intrinsic reparative cascade to begin. Unfortunately, the stimulus evoked by this compound is delicately balanced between one of repair and resorption. The study by Magnusson demonstrated how often the balance is tilted toward the destructive pathway. 
Schröder emphasized on the importance of avoiding a blood clot between the amputation site and calcium hydroxide for clinical success.  Calcium hydroxide adequately controls pulpal hemorrhage, to permit good contact between medicament and pulpal tissue. This seems to be important in the prevention of internal resorption, post-pulpotomy. 
A study conducted to compare the clinical and radiological outcomes following single-visit vital pulp therapy techniques, using two different materials, formocresol and calcium hydroxide in cariously exposed primary molar teeth. This investigation confirms the clinical efficacy of a one-fifth dilution of Buckley's formocresol as an agent in pulp treatment of cariously exposed, vital primary molar teeth. However, calcium hydroxide in its pure, powder form is a clinically acceptable alternative when combined with strict selection criteria for this method of restorative care. There was a statistically insignificant difference in successful clinical and radiological outcome between the two treatment groups. 
The status of radicular pulp tissue may have more bearing upon the clinical outcome following calcium hydroxide pulp therapy, since this agent relies on the tissue itself being able to recover sufficiently to heal, with or without the formation of a calcific barrier. Therefore, calcium hydroxide may be more technique sensitive than formocresol. The inflammatory status of radicular pulp tissue at the time of treatment, providing effective coronal seal, is thought to be important to a successful outcome.
Markovic et al. reported the presence of a dentine bridge above the pulp amputation site radiographically in 47% of pulpotomized teeth using calcium hydroxide.  Heilig et al. was performed calcium hydroxide pulpotomy in 17 carious primary molars using alternative method of hemorrhage control i.e., aluminum chloride. This study suggests that the aluminum chloride-calcium hydroxide pulpotomy may be a viable alternative to formocresol pulpotomies in the primary dentition. Although these findings encourage continued research, including a long-term follow-up, a histologic study is indicated. 
Formocresol versus mineral trioxide aggregate
Mineral trioxide aggregate (MTA) is a fine hydrophilic powder developed by Mahmoud Torabinejad in Loma Linda University. It consists of tricalcium silicate, tricalcium aluminate, tricalcium oxide, silicate oxide and bismuth oxide.  The US Food and Drug Administration approved MTA in 1998 as a therapeutic endodontic material for humans. 
Torabinejad et al., Bates et al. and Fischer et al. evaluated the sealing ability of MTA in root canals.  MTA is currently being used in pulp therapy and has been shown to provide an enhanced seal over the vital pulp and is nonresorbable. Furthermore, MTA has superior biocompatibility and is less cytotoxic than other materials currently used in pulp therapy.
Previous studies showed that MTA stimulated the release of cytokines and production of interleukin and induced hard tissue formation. Schmitt et al. reported that Tulsa Dental provides MTA as ProRoot. The material can be placed in the tooth with the Tulsa carrier, an amalgam carrier, Messing gun or a hand instrument.  Advantage of MTA is that it needed less time for procedures.  Some of the main disadvantages are discoloration,  costs and accessibility, which may block worldwide distribution of MTA where formocresol is relatively inexpensive and have global accessibility. MTA has also shown to revascularize and promote dentin-like tissue formation in several clinical situations. ,,
A study comparing three pulpotomy agents in preschool children suggested MTA success rates were less than 100%. Success rates of 100% can be attributed to smaller sample size or wider range of patients (5-12 years), which can reduce validity and reliability of results. Younger patients showed high radiographic failure rates after 12 months such as external resorption. This is due to wider pulp canals in younger teeth, which can facilitate the transfer of stimulatory factors. 
A histological study to know the effects of gray and white MTA on amputated pulp tissue, along with formocresol as a gold standard suggests that it preserves and regenerates both hard and soft tissues. The nearly normal pulp architecture was found to be intact and continuous odontoblastic layer was seen. While cases treated with white MTA showed dentine bridge formation along with inflammatory cells and areas of partial necrosis, more clinical and radiographic failures were seen with white MTA. The minor difference in composition between gray and white groups accounts for the differences in pulpotomy success rates. The gray MTA contains tetracalcium aluminoferrite while it is absent in white MTA. 
The clinical success of formocresol is attributed to its bactericidal characters even though it shows poorly calcified secondary dentin bridging along with complete necrosis and inflammatory cells.
The normal consequence of pulp treatment is internal resorption. It was seen in both formocresol and MTA groups but no explanation for MTA was given as this consequence is not seen in MTA cases. 
Six clinical studies comparing formocresol and MTA were presented by Fuks.  It was noted that five out of six of these illustrated that MTA was more successful than formocresol. In the last study they found equal success between the products.  Further, they showed the ability of MTA to elicit dentin bridges beneath the pulpotomy site.
Immunologic testing needs to be performed to know the biological sequelae of MTA. Further studies about its long-term efficacy, biological and clinical use should be done. Nevertheless, the evidence is becoming stronger that MTA is biologically superior and more clinically successful than formocresol. There are additional issues with MTA that need to be rectified. MTA can be difficult to use and requires a learning curve. Recent concern rose about the toxicity of aluminum oxide, which is present in MTA when absorbed systemically. 
| Conclusion|| |
It is highly unlikely that formocresol, when judiciously used, is genotoxic or immunotoxic or poses a cancer risk to children who undergo one or more formocresol pulpotomy procedures. Definitive data to support this hypothesis are lacking, however, such evidence is needed before definitive conclusions can be reached.
In keeping with the accepted therapeutic principles, pediatric dentists who wish to continue to use formocresol should apply the lowest dose possible for the shortest time possible to obtain the desired effect. To that end, a 1:5 dilution of Buckley's formocresol is recommended.
On the basis of the evidence presented in this review, the risk of cancer, mutagenesis or immune sensitization associated with the proper use of formocresol in pediatric pulp therapy can be considered inconsequential. Until a biologic and reparative alternative has been identified that is clearly and reproducibly superior to formocresol, there are no scientific or toxicologic reasons to discontinue its use in pediatric dentistry. When used judiciously, formocresol is a safe medicament.
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