June 2005 article - Eliminating Mercury Use From IVD Reagents

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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

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