Originally Published MDT October 2009
MATERIALS
Assessing Biological Safety of Metals Associated with Medical Devices
As human exposure to heavy metals increases, the impact these metals are having on morbidity is a growing concern. Methods of evaluating potential toxicity in medical device materials are discussed.
D.E. Albert, A.M. Hoffmann, H. Sy and G.M. Ziegler
NAMSA, Northwood, Ohio, USA
NAMSA, Northwood, Ohio, USA
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Image: iStockphoto
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Evaluating risk from implants
Human exposure to heavy metals has risen dramatically in the past 50 years as a result of an exponential increase in the use of metals in industrial processes and in products. Medical devices are among the products that contribute to the daily exposure that is experienced. Of the contaminants recognised for their toxicity and worldwide distribution, heavy metals are of first concern.
Metals represent a significant component of cardiovascular, orthopaedic and dental implants, but can also be found in plastics where metals such as zirconium, titanium, zinc, platinum, iron, aluminium and magnesium are used as catalysts. A number of studies have shown that metal ions are released by all dental alloys in vitro and in vivo.1,2 There is a direct association with metal ion release and absorption with skin diseases and the manifestation of Type IV sensitisation reactions.
The term heavy metal refers to any metallic chemical element that has a relatively high density and is toxic at low concentrations. Heavy metals are dangerous because they tend to bioaccumulate, that is, their concentration increases in a biological organism over time, compared with their concentration in the environment. Compounds accumulate in living things any time they are taken up and stored faster than they are metabolised or excreted.
Toxic metals, most typically aluminium, arsenic, cadmium, copper, mercury, lead and thallium cause damage at the cellular and molecular levels. Some of these are found in medical devices where they are used as catalysts in polymerisation reactions of polymers and as chemical components of colorants, inks and pigments. Epidemiological data on human cohorts and studies on laboratory animals exposed to heavy metals indicate that these materials can affect several biological systems. The mechanisms of action include altering cell membrane permeability, impairing oxidative phosphorylation, replacing critical metallic components of enzymes or their cofactors, or binding to large molecules and distorting them. Ions released from metals have been associated with local immune dysfunction, inflammation and tissue cell death.3 Acute, high levels of exposure to metal ions typically occur within the first two years following implantation.4 As the population ages and increased numbers of patients need implants with metal components, there is a growing concern about the potential impact on morbidity. Therefore, understanding the role of metal ions in biological reactions and the use of chemical characterisation methods to determine the quantity of metal ions released from devices are two imperatives.
Effective testing methods
The importance of trace metals is addressed in the United States Pharmacopeia (USP) for testing plastics (www.usp.org). Chapter 661 of the USP has a limit test designed to give a qualitative assessment of heavy metals associated with plastics, elastomers and a variety of other materials. This is a qualitative test that demonstrates that the content of metallic impurities does not exceed a specified limit. Metals that typically respond to this test are lead, mercury,bismuth, arsenic, antimony, tin, cadmium, silver, copper and molybdenum. However, the test does not identify the specific heavy metal. Inductively coupled plasma (ICP) spectroscopy can identify and quantify each metallic impurity with higher sensitivity.
Single element detection is typically achieved by ICP-optical emission spectroscopy by emission of a wavelength unique to the element. Compound structures can be examined by use of an ICP-mass spectroscopy detector, which separates charged ions by a mass to charge ratio. ICP provides the ability to analyse many elements simultaneously or in a rapid sequential manner depending on the type of instrument utilised.
In addition to analytical chemical methods to evaluate extracted metals, in vitro biological methods can be used to detect toxicity to metals. In vitro cytotoxicity, which is required for all types of medical devices, is a common screening method that has been reported to be an excellent method for detecting acute adverse biological effects of extractables, including cationic and anionic metal ions.5
Extracts of medical devices
The sample to be analysed for trace elements may be a liquid or a solid (polymer, ceramic, metal). Solid materials must undergo a suitable preparation involving dissolution or extraction. All metals in contact with biological systems undergo corrosion. Implant degradation products have been shown to be associated with dermatitis, urticaria and vasculitis. If cutaneous signs of an allergic response appear after implantation of a metal device, metal sensitivity should be considered.
Cytotoxicity methods using extraction in saline and cell culture media are described in the USP and in ISO 10993, Part 5.6 These highly sensitive test methods are a good first step towards ensuring the biocompatibility of a medical device. The use of cytotoxicity in conjunction with qualitative and quantitative chemistry tests for heavy metals is a good and practical way to evaluate potential toxicity to inorganic chemicals.
When an analytical method is needed to identify the exact chemical ion (metal) that has been extracted from a device, ICP spectroscopic or atomic absorption methods can be used. The value of these two methods is that the specific identification and quantitation of each metal can be reported. This is especially important when trying to evaluate a positive cytotoxicity test result for troubleshooting and for exploring the significance of changes in a material or manufacturing process. The role of ICP certainly must be considered when performing chemical characterisation studies of materials. Its value in determining biological safety and in setting allowable limits for leachable metals
and elements is unquestionable.
and elements is unquestionable.
Toxicological impact of metals
The probability that an adverse effect will arise from exposure to a chemical depends on its inherent toxicity, but also on the amount to which a subject is exposed and the route of that exposure. In general, heavy metals are systemic toxins with specific neurotoxic, nephrotoxic, foetotoxic and teratogenic effects. Heavy metals can directly influence behaviour by impairing mental and neurological function, influencing neurotransmitter production and utilisation, and altering numerous metabolic body processes. There are 35 metals with safety concerns because of occupational or residential exposure; 23 of these are the heavy elements or heavy metals: antimony, arsenic, bismuth, cadmium, cerium, chromium, cobalt, copper, gallium, gold, iron, lead, manganese, mercury, nickel, platinum, silver, tellurium, thallium, tin, uranium, vanadium and zinc.7 As previously noted, these are commonly found in medical devices where they have been used as polymer catalysts and as colorants and ink marks.
All metals in contact with biological systems corrode and the released ions, although not sensitisers on their own, can activate the immune system by forming complexes with native proteins.8 These metal–protein complexes are considered to be candidate antigens for eliciting hypersensitivity responses. Metals known as sensitisers are beryllium, nickel, cobalt and chromium; in addition, occasional responses to tantalum, titanium and vanadium have been reported. Nickel is the most common metal sensitiser in humans, followed by cobalt and chromium.8
Assessing toxicological risk
Human health risk assessments for medical devices are performed by using the principles of ISO 10993, Part 17.9 The assessment method uses a group of interconnected processes that includes hazard assessment, dose response assessment, exposure assessment and risk characterisation.
According to Cassee et al.,10 at levels lower than the no observed adverse effect level (NOAEL) of the chemicals in a combination, they did not clearly affect each other’s toxicity. At or above the toxicity endpoints, the NOAEL of each chemical in similar and dissimilar combinations, some minor effects were observed. The authors concluded that the health risk of these mixtures is entirely determined by the health risk associated with the “most risky chemical” in the mixture.
One of the greatest challenges in medical device chemical characterisation is performing adequate assessment of biological or toxicological risks from extractables that can compromise patient safety. ISO 10993, Part 17 states that “among the risks to be considered are those arising from exposure to leachable substances like heavy metals arising from medical devices.” This standard provides a method for calculating maximum tolerable levels that may be used by “other standards developing organisations, government agencies and regulatory bodies. Manufacturers and processors may use the allowable limits derived to optimise processes and aid in the choice of materials in order to protect patient health.”
Toxicological hazard is a property of the chemical constituents of the materials from which a medical device is made and chemical composition should be considered in relation to hazard identification. Where significant risks arising from hazardous residues are identified by chemical characterisation, their acceptance should be assessed according to established toxicological principles. Biocompatibility tests identified in the ISO 10993 series of standards can provide further assessment of risk.
Collectively, knowledge of the material’s composition including additives and processing aids, prior use of the material(s) in a predicate device or similar device, and biological safety tests should provide predictive evidence of any toxicological hazard to patients. Although ISO 10993, Part 17 can be used to establish allowable limits for individual chemicals, biological safety tests when used to complement the risk assessment can give another measure of assurance.
The increasing need to evaluate
Virtually all aspects of animal and human immune system function can be compromised by heavy metals. Much of the damage produced by toxic metals stems from the proliferation of oxidative free radicals they cause. Biological reactions to metals depend on the quantity of available metal ions released from the materials (corrosion rates). However, single metals and metal mixtures at low levels not considered to be toxic can alter immune system function in human cells.
The use of cytotoxicity in conjunction with qualitative and quantitative chemistry tests for heavy metals is a good and practical way to evaluate potential toxicity to these inorganic chemicals. Chemical characterisation tests that can demonstrate that the level of heavy metals, especially lead, mercury, bismuth, arsenic, antimony, tin, cadmium, silver, copper and molybdenum are less than one part per million should be used to evaluate all materials. ICP spectrometry can provide a fast, reliable, sensitive and accurate screening test for trace elements in model solvents such as purified water, alcohol, dimethyl sulphoxide, serum and biological cell growth media.
As the population ages and increasing numbers of patients need implants with metal components, concern about the affect on morbidity is growing. Therefore, a better understanding of the role of metal ions in biological reactions and the use of chemical characterisation methods to determine the potential quantity of metal ions released from device materials is essential.
References
1. B. Guyuron and C.I. Lasa Jr, “Reaction to Stainless Steel Wire Following Orthognathic Surgery,” Plastic Reconst. Surg., 89, 540–542 (1992).
2. J.S. Covington et al., “Quantitisation of Nickel and Beryllium Leakage from Base Metal Casting Alloys,” J. Prosthetic Dent., 54, 127–136 (1985).
3. A. Au et al., “Nickel and Vanadium Metal Ions Induce Apoptosis of T-Lymphocyte Jurkat Cells,” J. Biomed Mater Res A., 79, 3, 512–21 (2006).
4. Y.J. Kim et al., “Serum Levels of Nickel and Chromium after Instrumented Posterior Spinal Arthrodesis,” Spine, 30, 923–926 (2005).
5. R.F. Wallin and E.F. Arscott, “A Practical Guide to ISO 10993-5, Cytotoxicity,” Medical Device & Diagnostic Industry, 20, 2 , 5–6 (1998).
6. ISO 10993, Biological Evaluation of Medical Devices, Part 5, Tests for In Vitro Cytotoxicity, 2009.
7. W.D. Glanze, “Mosby Medical Encyclopedia, Revised Edition,” C.V. Mosby, St. Louis, Missouri, USA (1996).
8. N. Hallab, K. Merritt and J.J. Jacobs, “Metal Sensitivity in Patients with Orthopaedic Implants,” J. Bone Joint Surg., 83-A, 3, 428–436 (2001).
9. ISO 10993, Biological Evaluation of Medical Devices, Part 17, Establishment of Allowable Limits for Leachable Substances.
10. F.R. Cassee et al., “Toxicological Evaluation and Risk Assessment of Chemical Mixtures,” Crit. Rev Toxicol., 28, 1, 73–101 (1998).
David E. Albert,* MS, DPM, PhD, is Senior Scientist/Consultant at NAMSA Advisory Services, 6750 Wales Road, Northwood, Ohio 43619, USA, tel. +1 419 662 4491, e-mail: dalbert@namsa.com www.namsa.com, Amy M. Hoffmann is Technical Specialist in Chemistry Studies, Harmony Sy, MS, is a Scientist/Research and Development Chemist, George M. Ziegler, BS, is a Research and Development Scientist, all at NAMSA.
* To whom all correspondence should be directed.
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