_______Link: Bis GMA (Insider Othod. Materials, Dec. 2008)
_____7.1 General characteristics
_____Polymers are the base or matrix for many plastics and devices used in orthodontics, many of which are placed in direct contact with soft human tissues, often for years. In contrast to metabolized medicines, the controls imposed on polymers by various governmental agencies are low. As a result, manufacturers are not required to disclose the ingredients or the procedures used in their production, and the specialty journals accept articles that cite commercial names instead of providing pertinent scientific information. Today, chemical compositions are disclosed only if they offer an incentive to the potential buyer. This situation needs to be remedied since some polymers, and especially their additives, are harmful to humans.
_____7.2 Polymer Development
_____Although plastics are generally regarded as a modern invention, there have been “natural polymers,” such as amber, tortoise shells, and animal horns that behaved in a similar manner as today’s manufactured plastics. Although it has been reported that the first man-made plastic, Parkesine, was introduced by Alexander Parkes at the 1862 Great International Exhibition in London, a similar material, vulcanite, was already in use in dentistry. Invented by Charles Goodyear and made by adding sulfur to rubber, vulcanite could be used to make dentures by heating the mixture in a mold. The first attempts to commercialize the new material were not practical because it softened when heated and was partially soluble in water.
_____Traditionally, polymers tailored to fit the needs of industry have been used later in medicine. While over the years many polymers have been tested for their ability to enhance healing, their number has gradually decreased, as many were found to be unacceptable. With the present trend in medicine to substitute hard materials for ones that are less brittle, more biocompatible and tissue-like, polymers have found important applications owing to their capacity to undergo large reversible deformations without the danger of catastrophic failure. Soft lenses, artificial limbs and corneas, cochlear and ophthalmic implants, vascular grafts, prostheses, and the like are used in large numbers.1 The most common products—catheters and intravenous (IV) lines—are used nearly 100 million times a year in the US alone.2 About two million people suffer burns each year, and almost four million diabetics who develop skin wounds are in need of elastomeric implants.3 _____Facial implants include Alar® (Uniroyal, Bethany, Connecticut) cartilage in nostrils, cheeks, chin, lips, in creases above the eye and cheek-lip area, at the dorsum of the nose, in the earlobe, forehead, and glabella frown line, and in the infraorbital and infralabial grooves; most of these implant materials are elastomers.4 While medical plastics represent less than 1% of total plastic consumption, their impact is great; in addition to auxiliary instruments and equipment, polymers can replace skin, tendons, and cartilage and can connect body tissues. For more than 40 years, plastic medical products, from disposable syringes to IV blood bags to heart valves, have helped doctors and nurses save lives. Many of the medical practices that are common today and were not even dreamed of 20 years ago are made possible by plastics.
_____7.3 Polymers in Orthodontics
_____A century and a half after Fauchard’s use of silk, rubber allowed the upgrade of simple ties to gradual movements. Ever since Goodyear created the first synthetic materials used in the mouth, the trend has continued unabated. The polymers used in orthodontics can be divided into three classes according to their various applications:
_____-Ready-to-use, premanufactured devices made in their final form by manufacturers, such as brackets, retainers, impression trays;
_____-Reformable polymers used as connecting framework for a variety of removable or functional appliances;
_____-In situ synthesized polymers, such as impression materials, cured adhesives, and sealant films. Each of these types has its unique qualities that must be treated distinctly.
_____Pre-manufactured polymers. Made in series in a controlled environment, pre-manufactured polymers are properly inspected and offer few surprises. Most of these polymers are used as combinations (blends) or comprise several monomers (copolymers). For hard devices (instruments, brackets or retainers), polymethacrylates, high-molecular-weight polycarbonates and polyurethanes are the materials of choice. For maxillo-facial applications, impression trays, and mouth protectors, the materials of choice are soft and made of low-molecular-weight polyurethanes, vulcanized silicones, or copolymers of polyvinyl acetate with polyethylene, all destined to replace the controversial phthalate-plasticized polyvinyl chloride. For even softer materials like elastomers, aliphatic polyurethanes and (more recently) polyphosphazenes are replacing natural rubber. There is a growing demand for the polycarbonates which are used both for brackets and Invisalign® retainers (Align Technologies, Santa Clara, California). Accepted by the US Food and Drug Administration (FDA), polycarbonates have high impact strength and modulus, they show little elastic deformation under load and are resistant to creep and cold flow. However, they are not as chemically resistant as nylons or polyolefins and are attacked by solvents.
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_____A general source of concern is the trend toward replacing thermoset plastics with thermoplastic materials. The former are more economical because their scraps can be easily re-melted and reused, but the latter are more soluble and prone to decay due to their lack of cross links.
_____Office-processed polymers. Preformed sheets created for specific purpose by manufacturers, these are available for the modern orthodontist’s convenience. Accompanied with step-by-step instructions, these help those who seldom want to spend time in non-clinical endeavors. The most used are made of linear (non-cross-linked) polystyrene, polyurethane, polyacrylates and polymethacrylates, with or without inorganic fillers. These fully polymerized auxiliary devices are subjected in the office to physical transformations, as is the case of the plastic sheets that are formed by heating and molding.
_____In situ-generated polymers. Because of the broad range of their potential applications, in situ-generated polymers require the most attention. Alginate and the less commonly used silicone and polysulfide impression materials suffer both a chain lengthening and some cross-linking in the presence of various inorganic compounds (calcium- and titanium salts and lead oxide, respectively). Mixed in various proportions, the acrylic monomers are polymerized to generate adhesives, restoratives, veneers, and sealants. To initiate the process, heat, chemical reactions, or active light are used and various organic compounds are then added according to the method of initiation. While peroxides are sufficient for the thermally cured acrylates, for those that are cold-cured, tertiary aromatic amines must be added. These enhance the decomposition of the peroxide, releasing a large number of free radicals.
_____To reduce shrinkage—a perpetual battle—while at the same time maintaining viscosity, the standard procedure is to use mixtures of polyfunctional (and thus cross-linkable) acrylic esters. _____These differ as their molecular weight concerns: if lower (as in triethylene glycol dimethacrylate [TGDMA]), these are used to decrease viscosity; if higher (as in the case of bisphenol glycidyl methacrylate [bis-GMA]), these are used to give strength. To enhance bonding, acrylic esters containing hydrophilic groups (hydroxyethyl methacrylate [HEMA]) have only recently been used. Low-molecular-weight polymers of the acrylic- or methacrylic acids are used in glass ionomers; due to their hydrophilic groups, these bond the enamel’s calcium. The addition of copolymerizable chelating agents (N-phenyl-glycine [NPG] to various composites, while quite traditional in dentistry, has found limited use in orthodontics, despite the stable and insoluble complexes achieved when bonding to the calcium ions existing on the teeth’s enamel.
_____7.4 Potential risks
_____While the materials currently used by orthodontists are neither invasive nor metabolized, some may remain in direct contact with the tissues for a period of many years, a potential concern. Regulations in some countries require detailed information about such materials, polymers included: all too often those used in orthodontics are neglected. Most catalogs, advertising pamphlets, and scientific journals refer to the materials used very casually, i.e., only by their commercial name. Even in Germany, a country that hosts the ISO’s technical committee on dental products and which publishes Medizinprodukte-gesetz, the laws governing medical products, manufacturers still present only superficial data and regard the imposed disclosure of information as a mere formality.
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_____Thus, in a recent catalog, one of Germany’s largest orthodontics manufacturers presented a table identical to the one it had published 5 years before to describe the polymers used in its products. In both, seventeen polymeric materials are purported to be components of the devices advertised. Each is accompanied by an identification number that has no reference to any other data in the publication. The most widely used polymers in orthodontics —bis-GMA, and the aliphatic or polyurethane acrylates— do not even appear on the list. Nonetheless, this catalog compares well with that of other manufacturers. To the list of polymers mentioned in that table we have added supplementary information, resulting in Table 1.
_____The superficiality with which the topic is treated corresponds with the faulty terminology and other mistakes that can be found in specialty journals, advertising pamphlets, and even material safety data sheets accompanying products that contain polymers. Thus, for the liquid part of a recently launched glass ionomer, Fuji Ortho LC®, no information is given about the exposure limits of 2-hydroxyethyl methacrylate, 2, 2, 4 trimethyl hexamethylene dicarbonate, and triethylene glycol dimethacrylate, and no toxicity data are provided for these monomers. All ingredients are listed as having no mutagenic, teratogenic, or carcinogenic activity. In addition, no reproductive toxins or sensitization effects are given, in sharp contrast with what will be shown below.
_____One reason for the superficial treatment of polymers in advertising and even in the orthodontic literature is the fact that many of them have a long history of use and the minor differences between the products to which they are added are hidden under various brand names. Indeed, the basic recipe for most adhesives, sealants, restoratives, and veneers used today is quite old; zinc cements, for example, have been known and used for more than 100 years. Bowen’s resin has been based on bis-GMA for almost half a century, and Wilson & Kent’s glass ionomers have been around for 30 years. Because all relevant patent rights have long since expired (the life span of a patent is 20 years), anyone can manufacture and sell related products.
_____Manufacturers may be reluctant to give details about the composition or processing of a polymer out of concern that it would increase chances that they might be sued for health impairment. Indeed, as will be shown below, many can be harmful. According to Greenpeace International, a nongovernmental organization that monitors the environment for the potential damage to human health,5 most are lacking in data. This organization asserts that as of 1981 there were some 100,000 chemicals registered in the European Inventory of Existing Commercial Chemical Sub-stances (ElNECS), and that little is known about the toxicity of about 75% of these. _____Every year variations of these products that may contain inadequately checked chemicals are launched through the support of manufacturers’ lobbies against the environmentalists, between whom governments often serve as referees.
_____In the US in the mid-1990s, dentistry was added to the enforcement of Proposition 65, the Safe Drinking Water and Toxic Act of 1986. In California, 80 dental offices were served with 60-day notices for failing to post Proposition 65 warnings, and the California Dental Association was inundated with inquiries about what the dental offices should do to abide by the requirements.6 In formulating materials for medical applications, the compounder should start with ingredients that are considered safe for such uses.
_____ In the US, this may mean selecting only those ingredients listed as safe for food contact in the lists found in Title 21 of the Code of Federal Regulations (21 CRF) promulgated by the FDA. Compounds for medical devices involving bodily contact must also be biocompatible to prevent adverse bodily reactions. Typically, this means exhibiting no cytotoxicity in cell culture tests of conformance to the protocols of US Pharmacopoeia (USP) Class VI. In addition, the following tests are (unfortunately, just theoretically) required: Ames for mutageneicity, carcinogenicity, mucus membrane irritation (hamster’s pouch), and sensitization on guinea pigs. All of these tests require large funds, and the risk-takers are few: it is far easier to modify the formula a little, change the packaging, and improve or extend the advertising than to conduct research tailored to the specific needs of orthodontics.
_____Are the polymers and related plastics used in orthodontics so harmless as to deserve such light and superficial treatment? Are they maintaining their initial mechanical strength and physical properties throughout treatment? The answer is a resounding NO.
_____While we strive to dump in our environment polymers which will disappear in time, biodegradability means at the same time leaching, with all its health-related consequences. Table 1 shows the biodegradability of several common polymers.
_____According to the FDA’s Products Classification, the dental polymers, including resin-based adhesives and restoratives (resin or glass-ionomer type), are Class II: Class I products require less control, Class III maximum control. Dental sealants, polyacrylamide and carboxy- and polyvinyl-ether maleic anhydride adhesives, however, are considered Class III, the same category as artificial hearts. ISO standards, which also comprise three categories, consider most adhesives Class I and the polymers destined for implants Class lab, in the same category as cardiac monitors.
_____In light of the FDA’s guidelines for industry related to dental composites,7 which require that dental composites (in addition to being non-mutagenic, non-cytotoxic, and non-carcinogenic) “should not produce adverse reproductive and developmental effects,” one may be amazed to learn how the products currently used in orthodontics are faring. Thus, the FDA’s classification (Dental Cements and Dental Composites, ADA/ANSI #66, ISO 7489) indicates that while these devices deserve moderate control, they should not, either directly or through the release of their material constituents, (1) produce significant adverse local or systemic effects; (2) be carcinogenic; or (3) produce adverse reproductive and developmental effects. The evaluation of any new device intended for human use requires data from systematic testing to ensure that the benefits provided by the final product will exceed any potential risks produced by dental cement materials. The ISO standard (ISO-109993, Part 1) uses a test selection that is very similar to Tripartite Guidance previously used by the FDA. It also uses a tabular format (matrix) for laying out the test requirements based on the various factors discussed above. The matrix consists of Consideration and Supplementary Evaluation Tests for Consideration. To harmonize biologic response testing with the requirements of other countries, the FDA has recognized the ISO standard.8,9
_____The reasons for polymer control are many. First, freshly made polymers release ingredients that are harmful. Thus, monomers almost never fully polymerize and consequently the non-reacted component and some of their various ingredients (which should be entrapped and kept in the macromolecule) are allowed to leach. The degree of conversion into the final, presumably insoluble polymer is currently measured with the help of the residual unsaturation (non-reacted double bonds). This amounts to up to 45%, which indicates a conversion of up to 15%.10 While it is true that the monomers used today have several double bonds, and that if only one of these participates in the final macromolecule may be sufficient to immobilize it in the network of the cross linked polymer, it is also true that some monomers remain unchanged or lead to oligomers (short chain polymers of low molecular weight) that are readily soluble. Instead of getting a homogeneous polymer whose chain length is similar, polymerization often leads to a mixture having many long and short chains. The latter, marked with pink in Fig.7.1, are the most prone to leach.
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_____While the maximum accepted weight loss of a restorative material (which, astonishingly, may contain up to 80% insoluble filler) has been recommended to be under 5 mg/mm3 (ISO Standard 4048), amounts as high as 9 mg/mm3 have been reported.11 The elution occurs quite fast: 50% of the leachable species from a dental polymer is found after 3 hours in water, and 75% after extraction with ethanol. The leaching from various dental composites and its effects, which have been exposed over the years, confirm at least a cytotoxic effect.11, 23 The importance of the problem is highlighted in the fact that in addition to the studies directed at the dental polymers, there are journals and books dedicated entirely to the general problem of polymer degradation.23, 24
_____Another reason for concern is the effects of polymer biodegradation. Through exposure to light, air, warm temperatures, and moisture, polymers suffer mechanical and chemical transformations, Fig. 7.2.
_____While some polymers are more resistant than others, enzymes attack the acrylates use in orthodontics to a degree that varies by product25 ; as a result, plaque accumulates26 and both aerobic and anaerobic microbes consume them (Figs 7.3 & 7.4). These microbes attack not only the polymer but also the teeth’s enamel and the metal attachment. Fortunately, this type of attack can be avoided by adding bactericides such as quaternary to the polymer ammonium salts.27
_____7.5 Polymer Toxicity
_____According to Greenpeace, plastics can be ranked according to their hazardous characteristics toward both humans and environment. Thus, polyvinyl chloride, considered the most harmful plastic, is at the top, and the bio-based plastics, the least dangerous, at its base. Still used today in athletic mouth guards, PVC-based orthodontic devices are uncommon. In what follows we will examine the polymers presented in Table 7.1 in this order and use short-cuts for their names.
_____Polyurethanes. Due to their oligomers (see above), unreacted raw materials and additives.28 , polyurethanes (PUR) could be toxic. When subjected to hydrolysis, PUR elastomers depolymerize. The least stable type is the polyether polyurethane.28 Another mechanism that leads to polyurethane decay and cracking is proximity to metals, the corrosion of which could generate a metal ion-induced oxidation (MIO). Attempts to prevent this complex interaction between metal-polyurethane-body have focused on using non-corrosive metals and on coating them with polymers that are less soluble and incorporate antioxidants in them.29 When proper caution is taken, polyurethanes can be successfully used in critical FDA Class III devices, such as the self-contained AbioCor® heart (Abiomed, Inc. Danvers, Mass). Polyurethane elastomers have been proven to be cytotoxic in at least one study.30 Fig. 7.5 shows a worn ligature that has lost in the process 20% of its weight.
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_____The toxic acrylic and methacrylic derivatives of polyurethanes, sometimes used as alternatives to bis-GMA polymers, have undergone less scrutiny and exhibit poorer performances with regard to leaching concerns.31 Their aliphatic structure should, however, place them in the less-controlled polyesters category, as shown by their comparative testing in suppressing macrophage activity.32
_____The polyurethane ligatures used in orthodontics are cytotoxic, as the killed cells that surround them shows, Fig.7. 6.
_____Polycarbonates. Polyesters that theoretically derive from the inoffensive carbonic acid, polycarbonates (PC) are considered much more potentially harmful than their derivation would suggest. The reason is that they are also derivatives of bisphenol A (BPA), into which they are converted during hydrolysis. In the same category are other polyesters that release BPA, such as bisphenol A dimethacrylate (BAD) and bisphenol A diglycidyl dimethacrylate33-35 (bis-GMA), etc. However, in deference to Greenpeace’s classification, the latter will be discussed under the polyesters category.
_____Known chemically as 4, 4’-isopropylidene-diphenol, BPA is currently used in the manufacture of resins and fungicides. Recognized for over 70 years as an estrogenic, the use of its derivatives in health-related fields is controversial. Allegations have been made that it triggers premature puberty in young girls (and possibly cancer) and influences male fertility as a result of its structural analogy to estrogen, Fig. 7.7.
_____True or not, Japan’s environment agency has not allowed the manufacture of polycarbonate bottles, citing fears of BPA contamination. In defense of BPA, a special web site has been launched (www.bisphenol-A.org) by the Bisphenol A Global Industry Group of the American Plastics Council, the Association of Plastics Manufacturers in Europe and the Japan Chemical Industry Association
_____Many baby bottle processors have followed through, switching from polycarbonates to polyether-sulfones (PS). In the US, a study performed at the request of the American Dental Association (ADA) examined some 30 blood samples from dentists who had sealants put on their teeth; no BPA was found.36 In another study,37 only 1 of 12 brands of dental sealants accepted by the ADA leached a trace amount of BPA (5 parts per billion); since then, its manufacturer has changed the formula. Devices made of polystyrene or acrylonitrile-butadiene-styrene (ABS) copolymers have little exposure to human tissues and therefore do not raise much concern.
_____Aliphatic polyesters. Linear polyacrylates and methacrylates, particularly PMMA, have a relatively low toxicity when compared to the aromatic polyesters and especially to those releasing BPA. While the amount of methyl methacrylate released by a PMMA composite denture plate had been determined to be as high as 0.18% from the polymer, its presumable effect is to act only as an allergen.38 Added often to bis-GMA to render it more fluid, triethyleneglycol dimethacrylate (TEDGMA) has been found to leak the most.39 Quite often used in various adhesive formulations is the monomer hydroxyethyl methacrylate (HEMA).
_____The polymers of TEGDMA and 2-hydroxy-ethyl methacrylate have been shown to be more toxic than some mercury compounds to lung cells. 40 Extracts from some composites containing high amounts of TEGDMA and HEMA were found to be extremely cytotoxic,41 and capable of generating adverse systemic effects in patients. Both monomers are known to produce allergies in dental assistants and dentists.17
_____Because it is water soluble, HEM A may cause more problems than the other monomers. It disturbs the human dental pulp cycle,42 suppresses the mitochondrial activity of macrophages,33 and can generate inflammatory reactions within the connective tissues. 43
_____Aromatic polyesters. As noted above (see polycarbonates), the derivatives of BPA are discussed in this less-controlled category both in deference to Greenpeace’s classification system and because the amount of basic monomer (e.g., bis-GMA) is relatively small (high cross-linking = low solubility). 32 According to the Dental Investigation Service of the US Air Force,44 each of the following products contains bis-GMA: AeIite-Flo® (Bisco Dental), Fl Restore® (Den-Mat), Flow-It® (Jeneric-Pentron), Revolution® (E&D Dental), UltraSeal XT Plus® (Ultradent), Star Flow® (Danville Engineering), Versa Flo® (Centrix), and Tetric Flow® (Ivoclar). Since few other flowable resins are used to make dental products, there is a high probability that most of these resins contain bis-GMA.
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_____The aromatic components in the early resins were found to be mutagenic.45, 46 Up to 14% of the total mass of the direct-bonding adhesive can leach out, and the discharge may continue for up to two years. 47, 48 In addition, the monomers and oligomers released by the resins were found to be cytotoxic. 49,50 It is reasonable to deduce that the leaching decreases in the following order, in proportion to the content in the inert filler: sealants>liquid-solid>liquid-paste>paste-paste systems. The cured adhesive is significantly less toxic since it may have up to 80% inert filler. Completely polymerized resins are also described to be insoluble. 51
_____While this may be true in vitro, it should be taken in consideration that all the acrylics used in the mouth are also subjected to the attack of microbes and enzymes. As it is shown in Fig.7.8 and 7.9, samples of thin-polymerized adhesive subjected to a culture of Streptococcus Mutans are severely attacked.
_____Shrinking less and exhibiting a lower solubility in water, polyesters containing aromatic (benzene type) cycles should, however, be controlled as much as the polycarbonates. Indeed, the category comprises most of the polyacrylates and the polymethacrylates used in adhesives. Tests comparing several heat-, cold-, and light-cured acrylic materials under the ISO-standard 10993-5 have shown all of them to be cytotoxic; only the prosthetic acrylic (heat-cured) could be graded nontoxic.52 While the cytotoxicity response of acrylic-based restorative materials cured chemically and with light may not be the same at all time periods, it equalizes after a 24-hour exposure.53 The higher cytotoxicity exhibited by the oxygen-inhibiting layer that forms above the polymer clearly demonstrates a major contribution by the unpolymerized monomers and related oligomers. Interestingly, the bis-GMA-based composites were found to release less basic, aromatic monomer than other ingredients.32
_____In animals, a study performed on a classic estrogen target tissue, rat vaginae, showed a response in some of the animals tested.54 Further studies confirmed that bis-GMA is indeed weakly estrogenic in mice37 and that BPA influences the growth of the rats’ mammary glands.55 Answering such criticisms, a Spanish team supported with in vitro research the results obtained in vivo,56 while trying to determine the relationship of the structure of BPA to estrogenicity.57 The controversy is far from over.
_____Although some studies have concluded that dental resins in general do not represent a significant source of BPA or BAD exposure58 and that even if a weak estrogenic effect is not impossible, the effects are small and the risk assumable,59 the clinician should not become complacent since newer studies are likely to dispute these findings. Indeed, the potential harm produced by the resins commonly used in orthodontics seems to have far-reaching effects. While the layer of low-molecular-weight polymers (oligomers), known as the oxygen-inhibiting layer (OIL), is considered the most cytotoxic and the most active,60 this effect was found to be significant even two years after the initial polymerization.49 No-mix materials as well as sealants exhibit greater toxicity both immediately after mixing and 30 days after mixing.50
_____Glass ionomer and phosphate cements have been found to exhibit effects similar to the composites, except that they are less cytotoxic than the carboxylate cements that contain polyacrylic acid.11 The cytotoxic effect of resin-modified glass-ionomer cements, which contain two types of acrylates (bis-GMA and DEGDMA) in the resin (hydrophobic part) and an oligomer of acrylic acid (in the aqueous part), has been attributed not only to the unpolymerized monomers but also to the heavy metals contained in the glass.61 As newer formulations are used, findings about the toxicity of their ingredients are expected. Thus, recently 4-methacryloxyethyl methacrylate (4-META), an aromatic monomer, has started to be used in the composite formulation, although until recently it was only an additive.62 It was claimed not only to suppress the mitochondrial activity of macrophages, but also to have a residual effect.33
_____An important health-related issue is the polymers’ aqueous extraction in view of removing harmful components. While some researchers claim that the restorative materials’ elution with water for three days52 or merely by boiling63 shows a significant reduction in toxicity, another study has shown that sufficient components that kill or alter cellular function are released even after two weeks of exposure in artificial saliva.19 While lengthy rinsing with an alcohol solution also alleviates the problem,32 the clinician should allow the maximum degree of polymerization attainable, regardless of the cost of longer chair time. To paraphrase J Perkins,64 “speed is a militant force against not only sterilization, but also proper cure.”
_____Aliphatic polymers. Polyolefins such as polyethylene (PE) and polypropylene (PP) and in particular ultra-high molecular weight polyethylene (UHMWPE) are used as fibers in splints: biologically inert by themselves, silane-treated reinforcements did not show health problems after 18 months.65
_____Bio-based polymers. This last, less-controlled category may cause more problems than some of the preceding ones since it comprises, along with the polymers resulting from corn/ starch, those made of natural rubber. The first are used for onplants and implants, while the second is found in the ubiquitous gloves. While the dearth of information about corn- and starch-based polymers leads to the assumption that their use is safe, the complaints regarding latex products abound. Named for its source, the milk of Hevea brasiliensis (latex, from Latin for milk) leads to a polymer that causes problems ranging from urticaria to asthma and from allergic eczemas to anaphylaxis due not only to its constitution but also to its additives (discussed below). More than 19% of the dental personnel examined in a study showed some positive history of hand dermatitis.66 If the latex gloves become contaminated with orthodontic adhesives, the combined toxic effect on cultured cells exceeds that of the washed gloves alone.67 Between 1988 and 1992, more than 1,000 reports of allergic reactions to latex-containing products were received by the FDA, including 15 deaths; as a result, the National Institute for Occupational Safety and Health published an alert in June 1997 recommending the use of non-latex gloves.68 Interestingly, latex gloves have been found to have better barrier properties than the polyvinyl chloride (PVC) used as a substitute.69
_____Cytotoxicity studies of plain and colored elastics and rubber bands have shown that all are cytotoxic.70 The allergen responsible for such reactions has been identified as a protein, profilin, that exists in both fruits and pollen. People allergic to these have a higher risk of developing latex allergy.71
_____7.6 Additive Toxicity
_____Greenpeace did not limit its campaign to the actual plastics, but included the solvents used in their manufacture (e.g. methylene chloride for polycarbonates) and their raw materials (e.g. isocyanates for polyurethanes). In some instances, plastics were condemned not for the polymers but for the additives they contain. Indeed, when referring to the various plastics, usually only the polymers are mentioned, and little information is given concerning the chemistries and additives that enable these products to be as useful as they are. Additives comprise plasticizers, impact modifiers, heat stabilizers, lubricants, biocides, antioxidants, anti-blocking agents, slip agents, light stabilizers, clarifying agents, flame retardants, organic initiators, and blowing and coupling agents as shown in Table 7.3.
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_____Many of these additives can leach into the human body, and even the fillers can leach from cross-linked composites.72 Immersed in water or synthetic saliva, composites leach, in addition to monomers, additives such as ultra-violet stabilizers (TINUVIN P), plasticizers (dicyclohexyl phthalate and bis [2-ethylhexyl] phthalate), initiators (triphenyl stibine), coupling agents (gamma-methacryloxy-propyl trimethoxysilane), and phenyl benzoate. Interestingly, the basic polymerizing monomer (bis-GMA) was not found.32 While most composite additives are cytotoxic, including the inhibitor butylated hydroxytoluene (BHT) and the photo-stabilizer 2-hydroxy-4-methoxy benzophenone (HMBP), little effort is spent in seeking a replacement with less harmful additives.18 Benzoyl peroxide (BPO) and hydroquinone have also been found to be allergenic.73
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_____Additives and their decomposition products are usually more toxic than the polymers to which they are added. In orthodontics, however, with few exceptions, their amount is significantly smaller and therefore often overlooked. In one notable exception, that of plastisols (softened PVCs), plasticizers can often reach over half of the total weight and deserve special attention. Table 7.4 shows some additives used in various plastics and their LD50 values (lethal dose for a 50% kill, given in mg/kg for the oral does in the rat). Whenever no data were found for some special additives, these of the products having a similar structure were used.74
_____Plasticizers. Without plasticizers or softeners, PVC is hard and brittle and so are PMMA plates, dentures, and linings. The best and most commonly used plasticizers are the phthalates, aromatic esters suspected to mimic hormones.16,32,75-79
_____In high dosages, dibutyl phthalate (DBP) acts as a testicular toxicant in three species of young adult laboratory animals, while adult females’ functional reproductive toxicity (i.e., decreased fertility) has been evidenced in rats.80 Such substances can affect the hormonal system of an organism in a wide variety of ways, blocking a hormone’s action and accelerating its breakdown, eventually causing cancer and death. The relative similarity in structure between estrogens and phthalates is shown in Fig 7.10.
_____The publication of the book Our Stolen Future in 1996,81 with a foreword written by then-Vice President Al Gore, stirred emotions as well as controversies. The book fueled a campaign against plastics that had long been sustained by organizations such as Greenpeace, Chemical Impact Project, the World Wildlife Fund, World Resources Institute, and Friends of the Earth. Among its successes is the fact that in all of the construction related to the 2000 Olympic Games in Sydney, no PVC was used.
_____The controversy continues, despite assurances from the American Plastics Council that intermediate products, such as BPA, and plastic additives, such as the phthalates (and especially did [2-ethylhexyl] phthalate [DEHP]) have been used without problems for over 40 years. The use of the latter has received an endorsement from former U.S. Surgeon General Dr. C. Everett Koop82 and the American Council on Science and Health panel, which concluded that “DEHP and DINP (both phthalate esters) are not geotaxis” and that the current human exposure levels in products containing them are “not harmful” It was pointed out that “there is a critical difference between the toxicology and mechanisms for these chemicals between rodents and humans.” According to the FDA, DEHP can be used only as a flow promoter at a level not to exceed 3% weight based on the monomers.83
_____Curing agents. For polymerization of the monomers to occur as desired, a variety of ingredients must be added. In some cases, (e.g, condensations), no curing agents are needed, as the macromolecule results from an interaction of the ingredients (e.g. between an isocyanate and a compound-bearing hydroxyl groups for polyurethanes, or the opening of an oxyrane group containing compound when reacting to an amine for epoxies). In some industrial uses, amines and their derivatives also work as curing agents (i.e. additives, despite the large amount used).
_____To polymerize acrylic monomers without irradiation, initiators such as peroxides are commonly used, with or without tertiary aromatic amines (kickers). In cases where the process is light activated, the additive is a benzoin alkyl ether or a quinone. For polyurethanes, commonly used are metallo-organic compounds, some of which were recently forbidden as ingredients in coatings on boats for being too toxic for the environment.84 Aromatic amines have been shown to be carcinogenic as well as toxic.85
_____Cross-linking agents. Because natural rubber is too weak to be used in the manufacture of many products, including gloves, a series of cross-linking agents delivering sulfur must be added, as per Goodyear’s vulcanization. Among these are compounds such as 2-mercapto-benzthiazole, dithiocarbamates, tetramethyl thiuram disulfide, and sulfenamide. The lethal doses for some representative cross-linking agents were shown in Table 7.4.
_____Inhibitors. To prevent monomers from setting prematurely, compounds that hinder an accumulation of the free radicals that are generated by initiators must be added. Among these are various phenols or their derivatives, such as hydroquinone and butylated hydroxy toluene (BHT). The lethal doses for phenols were shown in Table 7.4.
_____Antioxidants. If exposed to air in moist and warm conditions, polymers such as acrylics, PVC, PC, and PE become subject to an oxygen attack that lower their physical properties. The generated hydroperoxides are compounds that decompose under the influence of metals leading to a premature setting. To protect the polymer against this type of decay, an array of phenols as well as organic phosphites and sulfur-containing compounds must be added. The lethal doses for some representative antioxidants were shown in Table 7.4.
_____Ultraviolet light stabilizers. To prevent decay due to light, amines, or organo-metallic or sulfur-containing compounds, benzophenones, or benzotriazole derivatives (Tinuvin P) must be added.
_____Coloring agents. Subsequent to the banning of toxic cadmium derivatives, organic pigments such as various azo-compounds and the derivatives of naphthol, quinacridone and anthraquinone are now the main additives used to provide the various shades desired by patients. Since some are also used in food, modern coloring agents are of less concern than other types of additives.
_____Biocides. In industry, in addition to the additives needed to provide adequate mechanical properties, antimicrobial agents are added to protect plastics when exposed to dark, moist, and warmer conditions. After consuming organic ingredients, various microbes, fungi, and algae produce enzymes and byproducts that cause the plastic to become brittle, lose tensile strength, smell, and even become toxic. While industrial antimicrobials may contain arsenic or sulfur compounds, medical grades contain only ammonium quaternary salts and micro-capsules capable of freeing silver ions. In most non-medical applications additives must be non-carcinogenic, non-allergenic, and have very low or no toxicity in recommended concentrations: in medical applications additives must also be non-mutagenic, i. e. they must hinder bacteria from easily developing resistance to them, and thus becoming a greater health threat.86