Guest guest Posted February 8, 2006 Report Share Posted February 8, 2006 Eliminating Mercury Use From IVD Reagents New legislation will challenge IVD manufacturers to find proper mercury alternatives. Ann E. Leonard and Philipp Novales-Li MEDICAL DEVICELINK - Processing Technologies http://www.devicelink.com/ivdt/archive/05/06/003.html A model of thimerosal, a mercury salt that IVD manufacturers use as a preservative in lab reagents. With growing concerns about the quantity of mercury in local environments, several U.S. states have made substantial shifts in their legislative approaches to dealing with the use of mercury in such products as cars, fluorescent lighting, thermostats, and laboratory reagents. Under the auspices of the Interstate Mercury Education and Reduction Clearinghouse (iMERC), some states are demanding the total elimination of mercury use in most products. The first such phaseout deadline for formulated products, including laboratory reagents with more than 250 ppm mercury, took effect in Connecticut on July 1, 2004. Rhode Island's phaseout will follow this year. For years, IVD manufacturers have formulated many of their laboratory reagents using thimerosal, a mercury salt, as a preservative, primarily because of its widely recognized antimicrobial and antifungal activity. Due to the thimerosal concentrations commonly used, many IVD lab reagents squeezed past the first mandated phaseout for products containing more than 250 ppm mercury. However, greater phaseouts for formulated products with more than 50 ppm mercury are already set for 2006 and 2007. Mercury and Thimerosal Background Mercury exposure in the United States did not rise to the forefront of the American consciousness until 1999- 2000, when the American Academy of Pediatrics discerned a link between the rise in autism and the number of inoculations that children under the age of 6 months received. Calculations revealed that by following the recommended inoculation schedule, infants under 6 months would be subjected to a cumulative ethyl mercury exposure that exceeded Environmental Protection Agency (EPA) methyl mercury guidelines.1-3 The other controversy that has found its way to the headlines is the mercury content in commonly consumed fresh-and saltwater fish. Certain fish species, particularly those higher on the food chain such as tuna, sea bass, salmon, and swordfish, are exposed to methyl mercury by eating smaller fish.4 This chain of events begins when mercury vapors from oil and coal combustion at energy plants and from landfill incineration exhaust are released into the atmosphere. Such vapors become rain and infiltrate water systems where they are converted into methyl mercury by sulfate-reducing microbial organisms. After absorbing methyl mercury, these organisms (i.e., benthic organisms, phytoplankton, periphyton) are consumed by smaller fish that are then eaten by higher-order predator fish species.5-7 In the medical industry, most people are familiar with thimerosal, which was first used in the 1930s by Eli Lilly in its diphtheria toxin vaccine.1,2,8 Since then, thimerosal has been used in everything from laboratory reagents and vaccines to topical medicines. However, the associations of mercury use in vaccines with neurological impairment and autism during the past decade have convinced most nations to phase out thimerosal use. Some IVD manufacturers may have abandoned thimerosal to comply with efforts to eliminate its use by countries such as Japan, Sweden, Australia, and Spain. However, those IVD manufacturers that have the resources to make small production lots specifically catering to those countries' regulations may have continued to rely on thimerosal as the primary formulated preservative in most of their products. At present, it is unclear how exposure to different mercurial derivatives affects biological life. Much of the scientific research available is piecemeal, often confined to small populations with unique dietary habits or populations who were the victims of extreme episodes of mercury exposure.4,8,9 Furthermore, the effects of mercurial exposure seem to change throughout the course of life, with neonates being the most vulnerable.1-3,8 More research is needed to elucidate further the physiological differences of various types of mercury exposure and how these differences might change when the exposure consists of multiple mercurial forms. U.S. Mercury Legislation Under the auspices of iMERC, eight northeastern U.S. states (Connecticut, Rhode Island, Massachusetts, Maine, New Hampshire, Vermont, New York, New Jersey) and Washington have embarked on a campaign to eliminate mercury pollution from their environments. iMERC itself is the result of a regional effort to eliminate mercury from northeastern American waste streams, which was fostered by the mercury action plan of the Conference of New England Governors and Eastern Canadian Premiers. The mercury task force representing this group delegated the responsibility of implementing the mercury action plan to the Northeast Waste Management Officials' Association (NEWMOA), a non-profit, nonpartisan organization of regional environmental agency directors. NEWMOA was charged with drafting model legislation with two objectives: eliminating or reducing nonessential uses of mercury in household, institutional, and industrial products and purposes, and reducing the overall amount of mercury-containing waste from household, commercial, and industrial sources through source reduction, segregation, and safe waste management, including recycling. The result was the Mercury Education and Reduction Model Legislation, which drew heavily from current U.S. and Canadian legislation, and was intended to be used as a framework that individual states and provinces could use to draft or amend current mercury legislation. By using an agreed-upon model, resulting legislation would mandate more-uniform programs and policies throughout the U.S. Northeast, and avoid duplication of research and efforts to the benefit of all parties involved.10,11 The Mercury Education and Reduction Model Legislation established 12 initiatives that include the following: notification, bans on certain mercury-added products, phaseouts and exemptions, labeling, disposal ban, collection, disclosure requirements for certain products that healthcare facilities use and that contain incidental mercury, control on the sale of elemental mercury, public education and outreach, universal waste rules, state procurement, and an interstate clearinghouse. All the activities described under each initiative hinge upon the involvement of iMERC, which assists in and coordinates each state's efforts to reduce mercury from its waste streams. Consequently, IVD manufacturers, consumers, waste management officials, and environmental agencies have iMERC as their point of contact for obtaining information and assistance, and for complying with legislative guidelines and mandates. The first encounter that many IVD manufacturers would have had with this legislation was the mercury-added product notification forms that were due to NEWMOA in 2002 and must be resubmitted triennially thereafter. This action fulfilled the legislation's notification component and required manufacturers to declare their mercury-added products, both formulated and fabricated, and account for the total mercury distributed as a result of the sale of such products. The information provided by an IVD manufacturer has been included in a mercury-added product database that is maintained by and available at NEWMOA. If a manufacturer had already eliminated all mercury from its products, it would instead have filed a certificate with NEWMOA declaring that mercury was not added to any of its products.10,11 Complying with Mercury Legislation What does this mean for IVD manufacturers that are still using thimerosal or any other mercury-based fixative or product component? There are only two options: phase out or be shut out. However, if a federal mandate requires thimerosal use or if there are justifiable technical reasons why thimerosal cannot be substituted in a product, manufacturers can apply for an exemption. Such exemptions are granted for up to four years on a state-by-state and product-by-product basis. Continuing to market under an exemption requires complying with both the labeling and collection initiatives. The labeling initiative mandates that appropriate symbols or statements of sufficient size accompany products incorporating mercury-added components. The labeling requirements are exempted for FDA-approved over-the-counter drugs, prescription drugs, and biological products in Connecticut, Maine, Rhode Island, Vermont, and Washington. If an IVD manufacturer's product appears to fall into these categories, it should double-check with NEWMOA first, since the legislation varies from state to state. The collection initiative mandates the use of take-back programs that manufacturers initiate to meet recovery and recycling goals. However, most IVD products (i.e., formulated chemical laboratory reagents) are considered to be consumables and are therefore exempted from the collection initiative.10,11 Complying with the labeling and collection initiatives is just as costly, if not more costly in terms of resources and time, as switching to a more expensive nonmercury preservative and undergoing the requisite contamination testing and engineering change order process. The only other option is to refrain from marketing in those states that participate in NEWMOA. If a phaseout is chosen, IVD manufacturers should file an updated mercury-added product notification form to NEWMOA that states the changes made to previously mercury-formulated products. All NEWMOA states are dedicated to reaching universal compliance with the mercury legislation. First-time failure by IVD manufacturers to comply with the mercury reduction legislation will result in a formal letter of violation. Since NEWMOA does not have any enforcement authority, further actions to address willful noncompliance by manufacturers would occur on a state-by-state basis and be dictated by a particular state's legislation. In 2005, the next mercury-added product notification form will be due for those mercury-added products that were distributed in 2004. With this new information and the data collected in 2002, NEWMOA will have a clearer indication if mercury-containing waste from household, commercial, and industrial sources has been reduced and the mercury action plan's objectives have been met. Mercury and Thimerosal Alternatives Table I. Mercury and thimerosal alternatives. What can IVD manufacturers use instead of thimerosal to provide fail-safe microbial protection and preservation? While manufacturers could consider several mercury alternatives, each comes with its respective pros and cons (see Table I). As with most effective biocidal agents, there is the typical risk of exposure for manufacturing personnel, since most alternatives will cause severe skin and eye burns, and irritation to the nasal and throat passages if there is contact in any concentrated form.12,13 Most alternatives are also suspected to be potential carcinogens or mutagens. Manufacturing personnel must be aware of the potential risks when using such agents, and be provided with the appropriate resources and education to permit their safe use. Nonetheless, most mercury alternatives have been successfully used as preservatives, biocidal agents, disinfectants, and pesticides. They can be found in a range of common medicinal remedies, cosmetics, and over-the-counter products such as shampoos, perfumes, contact lens solutions, and nasal sprays. The most obvious alternatives are those already being used, such as benzalkonium chloride, 2-phenylethanol, its close relative 2-phenoxyethanol, the iso-thiazolanes, and sodium azide. Other alternatives that IVD manufacturers may consider include chlorhexidine diacetate, chloroxylenol, povidone, and triclosan.14 Besides their toxicity in concentrated forms, the problem that arises with mercury alternatives is their susceptibility to degradation in certain formulations. For example, iso-thiazolanes will not survive lyophilization and are degraded at high pH and in the presence of amines. However, an attractive aspect of the iso-thiazolanes is their short half-life (60 days) and biofriendly degradation.12 In addition, using 2-phenylethanol with strong acids and oxidizing agents should be avoided.13 Regarding the microbial effectiveness of such mercury alternatives, while few are superior to thimerosal, most of them are adequate. Researchers have suggested that 2-phenoxyethanol is not as effective as thimerosal against fungi and yeast at low temperatures (26°C), even though both did pass preservative effectiveness tests at this temperature and displayed only biostatic activity at 4°C.15 For hematoxylin, a common pathology reagent that is sometimes prepared with mercuric oxide, a research project recommended using sodium iodate instead, or mercury-free Gill's hematoxylin.16,17 2-phenoxyethanol and benzethonium chloride have also successfully replaced thimerosal in some vaccines used in the United States.2 IVD manufacturers should accompany all incorporations of new preservatives into their products with appropriate antimicrobial-effectiveness testing and standard stability and quality control testing of the reagents before their release. Furthermore, careful completion of such testing regimes will lead manufacturers toward a clearer understanding of whether their product reformulation efforts will necessitate regulatory notification, amendments, and submissions, and require any data for such submissions. Such considerations will depend on the classification and intended use of the IVD products in question. Conclusion The widespread concern about mercury in the environment has lead to many assertions, accusations, opinions, and much controversy around the risk-benefit analysis of using vaccines and consuming certain fish species. The debate over the appropriate use of and tolerable exposure to all forms of mercury (e.g., elemental, organic, and inorganic) will remain unresolved until the different types of mercury that appear in the environment, food, and medicines, and their relative toxicity to biological life, are completely understood. Regardless, at least in the developed nations, the consensus has been drawn and mercury has lost. FDA and the European Union recommend that all children receive only thimerosal-free vaccines, which rely on more-expensive single-dose-puncture vials, and elemental mercury is being removed from manufacturing processes (e.g., chlorine and caustic soda production, gold and silver mining).1-3,7,8,18 Contentious debate continues over EPA regulations on allowable mercury-vapor emissions from fossil-fuel-burning plants, and thimerosal as a preservative is being eliminated, even in products that are not intended for human use.10,11 It will be interesting to see whether the second wave of NEWMOA mercury-added product notification forms that were due in the second quarter of 2005 reveals that IVD manufacturers have reduced their mercury use. References 1. " Policy Reaction to Thimerosal in Vaccines: A Comparative Study of the United States and Selected European Countries " (Ann Arbor, MI: University of Michigan, Child Health Evaluation and Research Unit, 2001 [accessed 18 May 2005]); available from Internet: www.childrensvaccine.org/files/thimerosal_decision.pdf. 2. " Thimerosal in Vaccines " (Rockville, MD: FDA, Center for Biologics Evaluation and Research, 2005 [accessed 18 May 2005]); available from Internet: www.fda.gov/cber/vaccine/thimerosal.htm. 3. LR Goodman et al., " Mercury in the Environment: Implications for Pediatricians, " Pediatrics 108, no. 1 (2005): 197. 4. Sharon L Crenson, " Research of Mercury Contamination Leaves Huge Gaps in Knowledge, " in Environmental News Network [online] October 7, 2002 [accessed 18 May 2005]; available from Internet: www.enn.com/arch.html?id=513. 5. " Wisconsin Mercury SourceBook: Mercury Use in Chemical Manufacturers/Users " (Washington, DC: Environmental Protection Agency, May 1997 [accessed 18 May 2005]); available from Internet: www.epa.gov/glnpo/bnsdocs/hgsbook/. 6. " Wisconsin Mercury SourceBook: Mercury Use in Hospitals and Clinics " (Washington, DC: Environmental Protection Agency, May 1997 [accessed 18 May 2005]); available from Internet: www.epa.gov/glnpo/bnsdocs/hgsbook/. 7. " Safe Mercury Management: State Legislation and Regulations " (Washington, DC: Environmental Protection Agency, 2005 [accessed 18 May 2005]); available from Internet: www.epa.gov/epaoswer/hazwaste/mercury/legislatn.htm. 8. JA , " Vaccines and Mercury, " in American College of Toxicology Newsletter [on-line] March 2003; available from Internet: www.actox.org/newsletters/mar03_vaccines.html. 9. " South Florida Information Access: Projects by Title " (Reston, VA: Dept. of the Interior, U.S. Geological Survey, Center for Coastal Geology [accessed 18 May 2005]); available from Internet: http://sofia.usgs.gov/title.html#M. 10. " Interstate Mercury Education and Reduction Clearinghouse " (Boston: Northeast Waste Management Officials' Association, 1999 [accessed 18 May 2005]); available from Internet: www.NEWMOA.org/prevention/mercury/imerc. 11. " Northeast Waste Management Officials' Association Web site " (Boston: Northeast Waste Management Officials' Association, 1999 [accessed 18 May 2005]); available from Internet: www.NEWMOA.org. 12. " ProClin Preservatives for in Vitro Diagnostic Materials: Efficacy versus Thimerosal and Sodium Azide " (Bellefonte, PA: Supelco, Sigma-Aldrich Co., 1999 [accessed 18 May 2005]); available from Internet: www.sigmaaldrich.com/Brands/Supelco_Home.html. 13. " The Physical and Theoretical Chemistry Laboratory " (Oxford, UK: Department of Chemistry, University of Oxford, 2005 [accessed 18 May 2005]); available from Internet: http://ptcl.chem.ox.ac.uk. 14. " Gojo Healthcare Products " (Akron, OH: Gojo Industries Inc., 2004 [accessed 18 May 2005]); available from Internet: http://healthcare.gojo.com/products/ingredientguide.htm. 15. E Komatsu et al., " Influence of Temperature on the Efficacy of 2-Phenoxyethanol as a Preservative for Absorbed Diphtheria-Purified Pertussis-Tetanus Combined Vaccine, " Journal of Health Science 48, no. 1 (2002): 89-92. 16. " Mercury Sources and Alternative Health Care " (Lowell, MA: Sustainable Hospitals Project, 2003 [accessed 18 May 2005]); available from Internet: www.sustainablehospitals.org. 17. " Removing Mercury from Hospital Labs " (Lowell, MA: Sustainable Hospital Project, 2003 [accessed 18 May 2005]); available from Internet: www.sustainablehospitals.org. 18. J , " Too Much of a Bad Thing: As U.S. Companies End Mercury Use, Questions Mount over the Need to Limit World Access to the Surplus, " Chemical and Engineering News 80, no. 30 (2002): 22-34. Ann E. Leonard, PhD, is a regulatory affairs coordinator at Abbott Vascular Devices (Redwood City, CA) and can be reached at ann.e.leonard@.... Philipp Novales-Li, DMedSc, PhD, DPhil, is director of scientific and regulatory affairs at BioGenex Laboratories Inc. (San Ramon, CA) and can be reached at philippn@.... Copyright ©2005 IVD Technology Comments about this article? Post them in our Members' Discussion Forums. Quote Link to comment Share on other sites More sharing options...
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