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A review on potential toxicity of dental material and screening their

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A review on potential toxicity of dental material

and screening their biocompatibility

Shahriar Shahi, Mutlu Özcan, Solmaz Maleki Dizaj, Simin Sharifi, Nadin Al-
Haj Husain, Aziz Eftekhari & Elham Ahmadian

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Haj Husain, Aziz Eftekhari & Elham Ahmadian (2019): A review on potential toxicity of dental
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TOXICOLOGY MECHANISMS AND METHODS
https://doi.org/10.1080/15376516.2019.1566424

REVIEW ARTICLE

A review on potential toxicity of dental material and screening their

biocompatibility
€
Shahriar Shahia, Mutlu Ozcan b
, Solmaz Maleki Dizaja, Simin Sharifia, Nadin Al-Haj Husainc, Aziz Eftekharid and
a,e
Elham Ahmadian
a
Dental and Periodontal Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; bDental Materials Unit, Center for Dental and
Oral Medicine, Clinic for Fixed and Removable Prosthodontics and Dental Materials Science, University of Z€urich, Zurich, Switzerland;
c
Specialization Candidate, Department of Reconstructive Dentistry and Gerodontology, School of Dental Medicine, University of Bern, Bern,
Switzerland; dPharmacology and Toxicology Department, Maragheh University of Medical Sciences, Maragheh, Iran; eStudents’ Research
Committee, Tabriz University of Medical Sciences, Tabriz, Iran

ABSTRACT ARTICLE HISTORY

Objectives: A wide range of compounds are utilized in dentistry such as dental composites, resins, Received 12 July 2018
and implants. The successful clinical use of dental materials relies on theirm physiochemical properties Revised 7 December 2018
as well as biological and toxicological reliability. Different local and systemic toxicities of dental materi- Accepted 7 December 2018
als have been reported. Placement of these materials in oral cavity for a long time period might yield
KEYWORDS
unwanted reactions. An extensive variety of materials is used in dentistry including filling materials, Biocompatibility; toxicology;
restorative materials, intracanal medicines, prosthetic materials, different types of implants, liners, and oral health; dentistry; dental
irrigants. The increasing rate in development of the novel materials with applications in the dental materials; toxicity
field has led to an increased consciousness of the biological risks and tempting restrictions of these
materials. The biocompatibility of a biomaterial used for the replacement or filling of biological tissue
such as teeth always had a high concern within the health care disciplines for patients.
Materials and methods: Any material used in humans should be tested before clinical application.
There are many tests evaluating biocompatibility of these materials at the point of in vitro, in vivo, and
clinical investigations.
Results: The current review discusses the potential toxicity of dental material and screening of their
biocompatibility.
Clinical relevance: It is essential to use healthy and safe materials medical approaches. In dentistry,
application of different materials in long-term oral usage demands low or nontoxic agents gains
importance for both patients and the staff. Furthermore, screening tests should evaluate any potential
toxicity before clinical application.

Introduction implants (pure titanium, titanium alloys, zirconium), liners,

irrigants as well as mouthwash (such as antiseptic and anti-
There are some different descriptions for biocompatibility in
plaque rinse) (Vazifehasl et al. 2013; Dizaj et al. 2015; Parnia
the literature. However, in general it refers to the ability of a
et al. 2017; Parnia et al. 2018). The increasing rate in the
material to produce a suitable host response when applied development of the novel materials with dentistry applica-
as intended (Williams 1999). Evidently, biocompatibility can tions has led to an increased consciousness of the biological
be defined as the compatibility of a material with a living tis- risks and tempting restrictions of these materials. The bio-
sue/system by not being toxic, harmful, physiologically react- compatibility of a biomaterial used for the replacement or
ive or including immunological rejection (Kirkpatrick et al. filling of biological tissue such as teeth always had a high
1998; Black 2005). In addition, based on biocompatibility (the concern within the health care disciplines for patients. On
reaction of the tissue to the used biomaterial), dental-used the other hand, dental staff are also at risk of adverse effects
biomaterials can be classified as biotolerant, bioinert, and to the some biomaterials. With some biomaterials, the risks
bioactive. The examples for these classes are summarized in are even higher for staff than patients. For instance, dental
Table 1. resins or rubber products may result to adverse reactions to
An extensive variety of materials are used in dentistry dental staff such as hand and fingertip reactions (Scott et al.
including filling materials (such as composites, amalgam, 2004). Some reports have also shown generalized neur-
polymeric monomers, cements), restorative materials, intraca- opathy after fourteen years of contact and exposure to
nal medicines, prosthetic materials, different types of methacrylates for dental staff (Sadoh et al. 1999).

CONTACT Aziz Eftekhari [email protected] Department of Pharmacology and Toxicology, Maragheh University of Medical Sciences, Maragheh, Iran;
Elham Ahmadian [email protected], [email protected] Dental and Periodontal Research Center, Tabriz University of Medical Sciences,
Tabriz, Iran
ß 2019 Informa UK Limited, trading as Taylor & Francis Group
2 S. SHAHI ET AL.

Table 1. Classification of dental used materials based on biocompatibility (Williams 1981; Albrektsson et al. 1983).
The main characteristic in related
Biocompatibility class Definition in dentistry Examples of dental used materials to bone
Biotolerant Materials that are separated from bone Cements based on poly (methyl methacrylate), Distance osteogenesis
tissue by a layer of fibrous tissue. stainless steels, cobalt alloys
Bioinert Materials that possess the property of Titanium, zirconium, aluminum, carbon Direct contact to bony tissue, direct
establishing chemical bonds with contact to osteogenesis
bone tissue (osseointegration).
Bioactive Materials may show direct contact with Hydroxy apatite, calcium carbonate, calcium Bonding to bony tissue, bonding
the adjacent bone tissue without phosphate, glass ceramics osteogenesis
chemical reactions between the
implant and the tissue.
Poly (methyl methacrylate): also known as acrylic or acrylic glass is a commonly used material in modern dentistry, particularly in the fabrication of dental
prosthetics, artificial teeth, and orthodontic appliances.

Biological and immunological adverse reactions attributed circulating blood after the uptake from saliva and cause tox-
to dental materials are infrequent, and the reported side icity in different organs. Mercury is known to be a neurotoxic
effects are not severe. However, this completely depends on and nephrotoxic agent (Ho €rsted-Bindslev 2004). Lobner et al.
the kind of the materials used and the technique used by reported that amalgam causes neurotoxicity via the liberation
staff. In some rare cases, severe reactions have been pub- of zinc in cortical cell culture, since the toxicity was inhibited
lished. Mjo€r (1992) reviewed the problems and benefits of by a zinc chelator (Lobner and Asrari 2003). In addition, long-
dental restorative materials and their adverse effects. He time occupational exposure to mercury might cause subtle
emphasized that the allergic reactions are the most con- neurobehavioral effects in dental practitioners. Amalgam is also
firmed side effects to dental materials due to their known capable of inducing liver injury. It has been shown that incuba-
allergen components such as transition metals and solutions tion of rat hepatocytes with methyl mercury is simultaneous
such as formaldehyde (Mjo €r 1992). Formaldehyde may form within the depletion of cellular glutathione reservoirs and leak-
as by-product of unreacted monomers from some dental res- age of liver enzymes aspartate aminotransferase (AST) and ala-
ins that may lead to even enhanced tissue responses. nine aminotransferase (ALT) (Ashour et al. 1993).
In general, dental materials are used for replacing dam- Replacing the inorganic structure in dental tissue with res-
aged or defective dental tissues, and so, they should be ins is the initial purpose in application of adhesive systems
chemically stable and inert for the oral cavity. However, as (Peumans et al. 2005). The classification of adhesive systems
we know all materials show some degree of dissolution or was based on their link with smear layer, whereas it is now-
degradation. Then, when the dissolved components from a adays categorized according to the stages in clinical usage
material are toxic, the local or systemic reactions are prob- called total-etched and self-etched adhesive methods. Some
able. Therefore, due to the long-term utilization and durabil- dental adhesives are not polymerized; instead, they are
ity of dental materials in the oral cavity as well as their degraded and separated from resins and form free radicals
contact or exposure with dental staff, there is a real need to which are provocative agents in induction of toxicity (Tadin
ensure their biocompatibility. In this paper, a brief overview et al. 2016).
was performed on the toxicity and biocompatibility of differ- Methacryloyloxy-dodecyl-pyridinium bromide as an
ent materials used in dentistry. important part of adhesive resins has been shown to trigger
toxicity at high concentrations, although in lower concentra-
tion the antibacterial effects have been reported. Easy liber-
Toxicity of dental materials
ation of polymer followed by increased diffusion may stand
Since dental materials are directly in touch with oral cavity, it for unwanted biological reactions (Van Landuyt et al. 2007;
is crucial to have a comprehensive understanding of the bio- Cal et al. 2014). In addition, defective polymerization of
compatibility, toxicity, and physiochemical properties of mater- free resin monomers and dissolutions with saliva or food
ial used in dentistry. The plausible cytotoxicity of different intake within the first 24 h can give rise to cytotoxic
dental materials will be presented below (Kallus and Mjo €r effects on pulp tissue. Immunosuppression, mild-to-severe
1991). Dental amalgam is a mixture of liquid mercury and inflammation of pulp tissue, and apoptotic cell death are the
metal alloy used in dentistry to fill cavities caused by tooth detrimental effects of adhesive resins previously reported
decay (Uçar and Brantley 2017). The cellular and molecular tox- (Moharamzadeh et al. 2007; Ahrari et al. 2010). For instance,
icities of mercury as the main components of amalgam are pic- bis-glycidylmethacrylate (Bis-GMA), hydroxyethylmethacrylate
tured in Figure 1. Criticizers claimed that it has toxic effects (HEMA), urethanedimethacrylate (UDMA), and triethylenegly-
that are unsafe, for both the patient and the staff. They argued coldimethacrylate (TEGDMA) caused cytotoxicity in mouse
that it perhaps show even more toxic effects for the dental fibroblasts after 24–72 h post-exposure in which the mechan-
staff operating it during a restoration (Mutter et al. 2005). The ism of toxicity was mitochondrial malfunction and expression
release of mercury from the restorative dental materials such of inflammatory mediators (Reichl, Esters, et al. 2006).
as composites and amalgam can induce oral damages since it The cytotoxic-free monomers are also appropriate surface
can diffuse into the tooth pulp and gingiva. It has been for cariogenic microorganisms. It has been stated that these
reported that mercury causes toxic effects in human gingival monomers stimulate the growth of cariogenic bacteria such
fibroblast (Reichl, Simon, et al. 2006). Also, it can inter into as Streptococcus sobrinus and Lactobacillus acidophilus.
 TOXICOLOGY MECHANISMS AND METHODS 3

Figure 1. Mercury-induced cytotoxicity and related signaling pathways. Mercury is the main component of amalgam used to fill cavities in dentistry. It induces dif-
ferent signaling pathways leading to cell death, DNA damage, and liver dysfunction.

Besides, TEGDMA promotes proliferation of Streptococcus Although composite resin materials exhibit clinical advan-
mutans and Streptococcus salivarius. These microorganisms tages due to their physicochemical specifications, induction
have vital role in dental caries and initiate cellular mecha- of some toxicities may constrict their application. In a study
nisms involved in pulp damages and allergic reactions conducted by Şişman et al., the cytotoxicity of five bulk fill
(Kleinsasser et al. 2006; Schweikl et al. 2006; Franz et al. composite resins, Filtek Bulk Fill, Tetric EvoCeram Bulk Fill,
2009). Besides, resins result in the expression of cascades of Sonic Fill, X-trafil, and SDR were tested in human dental pulp
proteins involved in the inflammatory reactions. This is in stem cells. The results of this study showed that the viability
tight connection with allergic reactions such as eczema-like of the cells in WST-1 assay was plunged during the incuba-
skin symptoms. In addition, high concentrations of these tion period (Şişman et al. 2016).
materials may display subacute and chronic toxicities which In addition to the release of non-polymerized monomers,
can show noxious effects in different body organs (Alanko the presence of additives and fillers in dental composites has
et al. 2004; Demirci et al. 2008). aroused some concerns. Bisphenol A (BPA) is considered to
Oral soft tissue damages such as gingivitis are among the be one of these additives inducing toxicity (Fleisch et al.
different reactions following the application of restorative 2010). Due to the presence of BPA in food product, it is
materials. Regarding in vivo toxicity screenings of restorative found in saliva even before using a dental composite
materials, it is not unequivocally understood that the cyto- (Downs et al. 2010). BPA is found as an impurity in dental
toxicity is a result of materials or the bacterial plaque accu- resins and polymerizes into solid after chemical or light
mulated on the teeth (Walker 2004). The cytotoxicity related €
exposure (SODERHOLM and Mariotti 1999). Inflammatory
to cement usage has been shown to significantly decrease in effects and toxicities due to BPA led researches to find its
time. This effect is attributed to the buffering impact of the surrogates such as silorane-based composites. However,
saliva and present proteins (Schmid-Schwap et al. 2009). some slight toxicities such as ROS formation and cytokine
Moreover, similar results have been observed in the toxic release have been attributed to silorane (Krifka et al. 2012;
effects of composites in fibroblasts in vitro which were Wellner et al. 2012).
shown to substantially decrease in aged composite models Non-polymerized monomers released from dental resins
in artificial saliva (Goldberg 2008). However, some in vivo prohibit cell proliferation and total polar lipid synthesis. They
experiments pose the safety and biocompatibility of the can even bind to unbound monomers which will mediate
applied composites. Ponce Bravo et al. examined the sub- different cell metabolic events (Goldberg 2008). TEGDMA and
chronic toxicity of commercial MEDENTAL Light-Cure HEMA can suppress heat shock protein expression in human
Composite in rats. The results indicated that no cytological monocytes (Noda et al. 2002). Also, TEGDMA gives rise to
changes in microscopic and also hematological tests were mitochondrial injuries (Lefeuvre et al. 2005). Zhu et al.
observed (Ponce Bravo et al. 2011). reported a novel mechanism associated in the toxicity of
4 S. SHAHI ET AL.

Figure 2. The possible influence of non-polymerized monomers released from dental composite resins in cell function and metabolism (adopted from ref
Schmalz 2009).

TEGDMA. This monomer stimulates autophagy via the activa- interfering with different signaling pathways (Garcıa-
tions of AMPK/mTOR pathway. Different feature of autoph- Contreras et al. 2011). A novel 3D culture in LOD2 cells that
agy occurrence including formation of acidic vesicles and resemble an in vivo-like environment assessed the toxicity of
autophagy vacuoles and LC3-II accumulation was shown dental castings coated with silver nanoparticle. Cell viability
after TEGDMA exposure in human dental mesenchymal cells. tests revealed the materials have a time-dependent toxicity
N-acetyl treatment could inhibit the autophagy and thus the (Zhao et al. 2018).
toxicity of TEGDMA (Zhu et al. 2015). Moreover, other metal-based alloys such as Cu-based alloy
In summary, the mechanism of toxicity has been pro- (Thermobond), Ni–Cr alloys (Remanium CS, Heranium NA,
posed to be related to short-term release of free monomers Wiron 99, CB Soft), and Co–Cr alloy (Wirobond C) used com-
as well as long-term liberation of leachable components as a mercially have been stated to cause toxicity in vitro in which
result of degradations over time. Additionally, ion release Cu ions have more detrimental effects in cell viability.
and growth of microorganisms in the interfacing location of However, Bioherador N alloy had meaningfully less cytotox-
teeth and dental materials are involved in the tissue dam- icity than the other ones (Al-Hiyasat et al. 2003).
ages occurring in situ. Productions of reactive oxygen species There are other dental materials that cause toxicity need-
and depletion of cellular glutathione reservoirs are molecular ing cautions prior to usage. For instance, in pediatric dentis-
mechanisms of probable pulp and gingival apoptosis impli- try, eugenol combined with zinc oxide which is a root canal
cated in resin monomers and also restorative material-based sealer in pulpectomy has been reported to induce toxicity
toxicities. Some additives to dental resins are potential sub- (Hui-Derksen et al. 2013). Also, in combination with carvacol,
strates for cariogenic bacterial strains which can lead to sub- thymol is used to prohibit the proliferation of fungal infec-
sequent secondary caries and degradation of the polymers tions (Markowitz et al. 1992; Mutoh and Tani-Ishii 2011; Vera
lasting in the failure of the restoration (Goldberg 2008). et al. 2012). Disruption of cellular plasma membrane, interfer-
Figure 2 illustrates the possible influence of these monomers ing with ion homeostasis, and induction of oxidative stress
in cell function and metabolism (Schmalz 2009). are the proposed mechanisms implied with eugenol applica-
In spite of the widespread use of alloys as casting materi- tion (Khan et al. 2011; Roberts et al. 2014). Furthermore,
als, their toxicological profile is not comprehensively deter- eugenol has been reported to induce antiplatelet activity
mined yet. Controversial results have been obtained after through inhibition of cyclooxygenase-2 enzyme in human
several tests studying their biological safety (Al-Hiyasat et al. (Raghavendra and Naidu 2009). Eugenol, in a concentration-
2002). The application of nanosilver materials in accordance dependent manner, is capable in cytotoxicity induction in
with dental alloys has gained increasing momentum at the dental pulp fibroblasts of primary teeth (Escobar-Garcıa
same time since they possess both antimicrobial and anti- et al. 2016).
inflammatory properties (Hamouda 2012). However, silver Replacement of missing teeth via implants has made
nanoparticles have been reported to induce cytotoxicity via them reliable treatment surrogate in dentistry (Albrektsson
 TOXICOLOGY MECHANISMS AND METHODS 5

et al. 1988). The physical and chemical properties of implant display some unknown adverse effects, such as instability
material should encompass well biocompatibility, resistance, because of nanocoating or cellular nanotoxicity. The under-
and strength specifications (Parr et al. 1985; Smith 1993). In standing of probable cellular effects and toxicity of nanopar-
addition to implants, there are several materials used for ticles as well as their environmental effects is necessary in
implant coatings that affect the efficiency of clinical applica- this regard (Eftekhari et al. 2018).
tion. These materials should also be examined for any toxic The implant insertion may also expose in risk to bacterial
effects to obtain the successful impacts in practice (Osman plaque (Samiei et al. 2016; Parnia et al. 2017). The reports
and Swain 2015). have shown that dental implants are at an enlarged risk of
In a study conducted by Reigosa et al., the cytotoxicity microbial contamination due to continuously colonization of
and genotoxicity of current titanium-based implants was microorganisms in the oral cavity. Furthermore, owing to the
investigated in osteoblast cells. According to the results of limited blood supply of peri-implant tissues as well as the
neutral red uptake test, alkaline phosphatase enzyme activity, lack of periodontal space at the implant–tissue interface, sus-
and lysosomal stability tests, no significant cytotoxicity was ceptibility of infection is increased in the interface (Derks
reported in the applied implants. Also, comet assay out- and Tomasi 2015). The formation of infection is introduced
comes did not encounter any genotoxicity (Reigosa et al. by oral streptococci and followed by other microorganisms
2008). However, a systematic toxicity assessment at every (Belibasakis 2014). Then, it slowly leads to accumulation of
stage of testing, through in vitro to in vivo, is critical to war- anaerobic bacteria (Koyanagi et al. 2010) that may cause the
rant a longer implant lifetime (Thrivikraman et al. 2014). resorption of circumfluent bone and so may result in implant
Titanium and zirconium are known as inert dental materi- failing (Romanos and Weitz 2012). Nanoparticles have also
als. However, some earlier studies have recognized the been recognized as one of the most effective antibacterial
potential hematologic and metabolic toxicity regarding these agents in different fields. Surface modification of titanium
materials. Furthermore, it seems probable that the occur- using antibacterial possessions of metal nanoparticles can
rence of allergic or toxic reactions to titanium or zirconium decrease the number of bacteria and positively show more
implants may be under testing and has not been reported helpful clinical treatments. However, the unknown cellular
due to a lack of recognition as a possible etiological factor in effects of them are yet in challenge. Coating of implants by
implant failure. Some reports have shown that cationic form metal and metal oxide nanoparticles may lead to toxicity at
of titanium is relatively nontoxic in the amounts and forms higher concentrations of them due to ion release process.
that are normally ingested. Even so, when these metals are This outcome can be high risk for both patient and staff
used as oral implants, they may form an oxide layer with (Dizaj et al. 2014). In addition to patients, the workers who
exposing to oral fluid. Therefore, the formed titanium dioxide most likely come into contact with dental nanomaterials in
(TiO2) or zirconium dioxide (ZrO2) can act a boundary at the the production, research, and development are at the risk of
interface between the oral medium and the metal structure nanomaterial’s toxicity. Nanomaterials may introduce to the
€
(Ozcan and H€ammerle 2012; Chaturvedi 2013). Any separ- staff body through inhalation as most of the dental nanoma-
ation of the oxide layer may lead to corrosion of these met- terials were directly applied in the oral cavity or maxillofacial
als and release of them into oral cavity (Chuang et al. 2005; region. Besides, nanomaterials may also enter with the use
Chaturvedi 2009; Chaturvedi 2013). Besides, this process may of dental tools. Therefore, dental staff and patients may face
also cause to collect titanium/zirconium ions in tissues espe- nanomaterials directly through a grinding or polishing pro-
cially local lymph nodes, and pulmonary tissue. Collection of cedure. The body-entered nanomaterials then may enter into
titanium particles inside the macrophage lysosomes has the bloodstream (or lymph fluid) via absorption through oral
reported to show hypersensitivity reactions (Mitchell et al. mucosa. They may also enter through the digestive tract
1990). In an implant failure study by Frisken et al., two after swallowing. They can be distributed to different organs
implants egress without any infection, and the existence of (liver, spleen, kidneys, heart, lungs, and brain) by systematic
titanium in the lungs was observed to be 2.2–3.8 times pathway. They may also directly translocate to the brain via
higher than normal (Frisken et al. 2002). nerves (Feng et al. 2015).
Coating of bioinert materials with ability to encourage
osseointegration on the titanium implant surfaces in order to
Allergic reactions
improve the stability of them has been reported by different
investigators (Samiei et al. 2016; Parnia et al. 2017). Based on Non-biocompatible dental materials might cause different tis-
the related literature, different types of biomaterials have sue responses, such as local or systemic toxicity and hyper-
been used as particle coatings to the dental implant surface sensitivity reactions. Allergic reactions such as alarming
to progress soft tissue integration and therefore enhance common public health problems are daily increasing in
dental implants success. In recent years, these types of nano- patients using different materials since they remain in the
particles with ability to induce a chemical bond with bone to oral cavity for a long time (Ditrichova et al. 2007).The first
advantage an ideal biological fixation are applied as coating reported allergic reaction occurred in amalgam application in
of dental implants. Indeed, investigators attempt to improve 1928 (Fleischmann 1928). The extent of allergic reactions
bone incorporation of dental implants using nanoparticles as might be low with clinical manifestations such as urticarial,
dental implant coatings. However, the same properties of rash, and swelling. However, it can cause life-threatening
nanoparticles that may progress the functionality may also side effects based on the importance of the issue affected
6 S. SHAHI ET AL.

(Karabucak and Stoopler 2007). In the oral cavity, T-cell-medi- genotoxicity/mutagenicity of dental materials is obliterated
ated hypersensitivity reactions can result in mucosa damage, or at least minimized. For instance, the European Standard
stomatitis, and cheilitis (Ditrichova et al. 2007). Search of lit- "Biological evaluation of medical devices, Part 3: Tests for
erature reveals that amalgam has a robust causative role in genotoxicity, carcinogenicity and reproductive toxicity" (EN
induction of toxicity leading to oral lichenoid reactions in 30993-3, ISO 10993-3:1992) mentions approaches to examine
comparison with other materials (SyeD et al. 2015). Due to the genotoxicity of chemicals (Heil et al. 1996). In addition to
the raised number of patients with allergies, it is important the American Dental Association (ADA) as Specification No.
to have adequate knowledge in this issue. 41 and by the Federation Dentaire Internationale (FDI) as
Regarding the resin-based materials, skin and mucosal Technical Report No. 9, more specified standards were devel-
reactions have been reported (Hume and Gerzina 1996). oped are existent virtually worldwide today and genotoxicity
Eczema and skin symptoms occur at about 12% in patients is the second most important test program in assessment of
and 27% dentists using these materials (Hensten-Pettersen dental material toxicity (Lyapina et al. 2015; Schmalz and
1998). Incomplete formation of the cross-linked polymer Galler 2017).
matrix from the dimethacrylate resin monomers leads to the It is worth to include again that many of these materials
liberation of non-polymerized monomers such as 2-HEMA remain for long periods in the mouth. The genotoxic effects
and triethylene glycol methacrylate (TEGMA). These mono- of distinct dental material such as bleaching agents are vivid,
mers have been implicated in the allergic effects of dental since it contains hydrogen peroxide. The occurrence of oxi-
resins. Dermatosis has been reported to be the most fre- dative stress via the increment of oxidizing agents intimately
quent allergic response (Goldberg 2008). An in vivo study in induces DNA damage and mutations (Ahmadian et al. 2017;
guinea pig has shown that HEMA induces dermatitis, irrita- Ribeiro et al. 2017). The commercial products of dental
tion, and hypersensitivity (Katsuno et al. 1998). Glass ionomer bleaching agents have shown genotoxicity in Chinese ham-
cements and composites stimulate the lichenoid reactions, ster’s ovary and mouse lymphoma cells (Ribeiro et al. 2005;
since they can surge the density of mast cells in oral cavity Ribeiro et al. 2006). Also, toothpastes comprising whitening
(Goldberg 2008). Dental cast alloys that release metal ions to agents have been proved to exert genetic damages in
the oral environment might produce allergic reactions. human gingival cells (Camargo et al. 2014). Dental restorative
However, some other mechanisms including the promotion materials such as bisphenol A has been capable of produc-
of bacterial adherence are also involved in adverse oral reac- tion of DNA adducts via comet assay in different human cells
tions related to cast alloys (Schmalz and Garhammer 2002). in vitro (Huang, Kuan et al. 2015; Huang, Chang et al. 2016).
Allergic response to implants arises from the metal ion Exposure of experimental animals to methyl methacrylate
release or from implant corrosion procedure. The released has increased the number of micro-nucleated cells in bone
ions may lead to complex formation with proteins and as marrow resulting in mutagenicity in vivo (Arau jo et al. 2013).
allergens producing hypersensitivity responses (Hallab et al. The latter can also produce DNA strand breaks in a dose-
2001). The allergic reactions that have been observed with dependent manner in murine macrophages (Li et al. 2012).
titanium implants include edema, redness, urticaria, eczema, The protective role of antioxidants such as melatonin in
and pruritus of the skin or mucosa (Hallab et al. 2001). It has reduction of the aforementioned genetic damages suggests
also reported that the risk of titanium allergy in patients who the pivotal role of oxidative hazard in the mechanism of gen-
show sensitivity to other metals is more predominant. The otoxicity of dental materials (Blasiak et al. 2011; Lottner et al.
allergic reactions related to implants have observed to dis- 2013). Endodontic compounds have also been the subject of
play more serious problems in some cases with the signing extensive studies in the context of genotoxicity in several in
of atopic dermatitis, impaired healing of fractures, pain, vitro experiments. However, more reliable usage and clinical
necrosis, and tolerance that leads to failing of implant. tests will provide a roadmap for future dentistry.

Genotoxicity Screening methods

Induction of DNA damage via an agent is referred to the Selection of biocompatible materials adoptable with pulp
genotoxic effects of the chemical. Due to the reciprocal rela- and other live tissues with minimal cytotoxic effects is an
tionship between genotoxicity and carcinogenesis, it is important issue in dentistry and medicine. Possessing no or
necessary to clarify the potential genotoxic effects of dental very few deleterious effects on oral tissue is the definition of
materials for both patients and staff health care. Dental biocompatible dental material.
materials have been categorized as medical products since Dental materials must be assessed through several toxicity
1995. Thus, it is crucial according to national and inter- and biocompatibility steps before they could be used in
national guidelines that medical devices – either lately devel- clinic. Figure 2 illustrates the example of these tests at three
oped or currently in practice – have been confirmed for their steps. Biocompatibility assays will pinpoint the detrimental
biocompatibility and toxicological profile. effects of materials, estimate the dose of chemicals released,
Genotoxicity is among the important adverse effects of and survey the reactions to this dose.
chemicals. As most dental materials liberate small amounts Systematic approaches to estimate the bioavailability
of several elements into the oral cavity, proper regulations of newly produced materials are a part of toxicological
have to guarantee that the concern about the probable evaluations in early stages of substance development.
 TOXICOLOGY MECHANISMS AND METHODS 7

Figure 3. Different steps in evaluation of the toxicity and biocompatibility of dental materials.

ISO standards due to their key role in meeting legal needs In an agar diffusion test, the test material is basically incu-
for premarketing biocompatibility assessments evaluate the bated on a layer of agar covering a monolayer cell culture
toxicological profiles of materials/substances. Clinical risk where the diffusion of the substance through agar is used to
assessments are carried out by means of ISO 14971 and ISO determine the nonspecific cytotoxicity of materials (Stanford
10993-1. For instances, the instruction for the selection of 1980). In similar techniques, Millipore filter is the surrogate
the suitable techniques to test toxicity of medical devices of the agarose. However, these two methods may not be the
which includes dental materials as well as the techniques ideal test for imitating the oral environment. Dentin barrier
themselves is presented in ISO 10993 series (Schmalz and tests via stimulating the in vivo oral cavity environment
Galler 2017). This standard encompasses 20 different parts at make it a preferable cytotoxicity assay (Swetha et al. 2015).
the moment. In addition to this standard, ISO 7405 is espe- In the next step, biological analysis depends on animal
cially developed for devices used in dentistry (Schmalz and experimentation to a great extent. Before a dental material
Fan 2009). European regulation on registration, evaluation, can be utilized in practice, it must always be assessed com-
and authorization of chemicals (REACH) has several legisla- prehensively in several species of laboratory animals to
tions to have a high level of protection of human health for establish its local and systemic impact in the body (Rowan
consumers, workers, and the environment. Also, the United
1997). Moreover, in vivo tests help to anticipate the potential
States Food and Drug Administration (FDA) Center for
toxic risks that might be encountered in man. Some of these
Devices and Radiological Health regulates the dental materi-
tests have been mentioned in Figure 3.
als and devices marketed in the United States in three
Finally, the ideal methodology for biocompatibility evalu-
classes. However, due to the certain restrictions in determin-
ation is clinical tests in individuals. However, ethical and legal
ing material biocompatibility through preclinical examina-
consideration may restrict this approach in Figure 3.
tions, post-marketing data should complete the picture
through which dentist should report adverse effects.
The first step for evaluation of dental materials as in other
chemicals is in vitro cytotoxicity tests. In addition to the Conclusion
usage of cell viability assays, there are some special terms in It is essential to use healthy and safe materials’ medical
biocompatibility screening of dental materials. As mentioned approaches. In dentistry, application of different material in
in Figure 2, in in vitro tests are used to estimate the plausible long-term oral usage demands low or nontoxic agents gains
toxicity of dental materials. In direct cell contact assays, the
importance for both patients and the staff. Furthermore,
material is directly placed onto cells in mono-layer cultures
screening tests should evaluate any potential toxicity before
and dose–response curves are prepared after different incu-
clinical application.
bation periods. However, these testing situations might not
be clinically relevant, because the cells in the body are not
in direct contact with the materials. So, indirect contact tests
are designed in which there is a barrier between the cells Acknowledgments
and examined substances (Murray et al. 2007). The below- The authors would like to thank Maragheh University of Medical
mentioned assays use barriers to mimic the real situations. Sciences for their moral support.
8 S. SHAHI ET AL.

Disclosure statement Dizaj SM, Lotfipour F, Barzegar-Jalali M, Zarrintan MH, Adibkia K. 2014.
Antimicrobial activity of the metals and metal oxide nanoparticles.
All authors including Shahriar Shahi, Aziz Eftekhari, Solmaz Maleki Dizaj, Mater Sci Eng C Mater Biol Appl. 44:278–284.
Simin Sharifi, Nadin Al-Haj Husain, Elham Ahmadian, and Mutlu Ozcan€
Downs JMZ, Shuman D, Stull SC, Ratzlaff RE. 2010. Bisphenol A blood
declare that they have no conflict of interest. and saliva levels prior to and after dental sealant placement in adults.
Am Dent Hygienists’ Assoc. 84:145–150.
Eftekhari A, Dizaj SM, Chodari L, Sunar S, Hasanzadeh A, Ahmadian E,
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