Safety and Efficacy of Oligodynamic Silver: A Rebuttal to “Silver Products for Medical Indications: Risk-Benefit Assessment 1996”

Dana F. Flavin, MD, MS

Foundation for Collaborative Medicine and ResearchGreenwich, CT

Abstract

Background:

The FDA often cites the authoritative work of Fung and Bowen1, which reviews the

toxicology and efficacy of a wide variety of silver-based medicinals. These authors have

breached the fundamental tenets of metal toxicology by applying the non-corresponding

sets of generic physical and chemical attributes of colloidal silver proteins to all forms of

silver, instead of acknowledging distinct speciations of colloidal silver-based medicinals.

The inaccuracies from their report are negatively impacting on new technological

advancements, that have resulted in the development of oligodynamic silver, an

unadulterated, pure form of silver hydrosol showing none of the toxicological

complications reported from the unrefined protein or salt colloids of silver.2 Its

antimicrobial action seen at nanomolecular levels, affects the majority of microbiological

pathogens, even the new emerging Multi-Drug Resistant (MDR) organisms.

Carl Nageli 1893 first identified the oligodynamic effect (from the Greek oligos=few, and dynamis=power to best describe how extremely low metal ion {e.g. silver and copper} concentrations beyond definitive chemical analysis exert potent biocidal actions. Webster’s Dictionary gives further definition to the biocidal properties of extremely low metal ion concentrations as follows: Ol-i-go-dynamic adj [ISV olig + dynamic, orig. formed as G oligodynamisch] 1 :active in a very small quantities <an ~ germicide> 2 a :produced by very small quantities <~ action of finely divided silver in disinfecting water> b :of or relating to the action of such quantities(*). Thus, the term oligodynamic is only applicable to extremely low concentrations of metal ions (Ag+)(*). The lethal actions of heavy metal salts are only obtained from much higher concentrations. This distinction underscores why heavy metal salts are considered metal poisons (*).

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Objectives: It is imperative to differentiate between the new forms of refined silver

colloids and those silver products that are chemically complex salts and proteins which

can lead to excess accumulation in the body and in the environment.

Conclusions: The Fung and Bowen paper is no longer applicable in relation to the new

nanotechnology available in the development of picoscalar silver hydrosols. Regulatory

application of their conclusions is preventing the further development and application of

life saving silver medicinals.

Introduction

The question of the safety of silver products in medicine has resulted in a

tremendous opposition from concerned health officials in every area of regulation for the

protection of the public.3 Potential and known toxicities related to adulterated forms of

silver, silver salt and protein bound compounds have been recorded over decades. The

most toxic effects relate to discoloration of the skin, a benign medical condition known as

Argyria4, which results from the inability of macrophages to remove such highly complex

silver salts and other silver compounds, which bind heavily to proteins and thiols.5, 6

Nitrated silver, when in contact with chlorides, has been shown to have direct toxicity to

bacteria and therefore it was always applied diluted in sterile water for disinfection of the

eyes in newborn babies.7 The most important aspect of the safety of silver as an

antimicrobial agent is its form, or speciation. Silver at picoscalar particle size in a pure

hydrosol suspension actually forms the safest and most efficacious antimicrobial

substance. Nanotechnology has finally achieved an oligodynamic form of silver that can

eliminate multi-drug resistant pathogens. Oligodynamic refers only to extremely low

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concentrations of pure metal ions.8, 9 The difference between this safe oligodynamic

silver antimicrobial and the antimicrobial silver salts has to do with both dosage and

speciation. These salts of silver are effective antimicrobials10, 11, however, they must be

present at considerably higher concentrations, which can lead to Argyria. This is not seen

with the new oligodynamic silver hydrosol suspensions. The effective dosage of

oligodynamic silver is simply too low to cause any toxicological effects. In addition, the

pure speciation of the silver eliminates the development of toxicity by avoiding

accumulation.

Physical and Chemical properties of Silver:

Like copper and gold, silver shows a considerable tendency to form coordinated

covalent compounds such as when it reacts with NH3 or amines to form the complex ion

Ag(NH3)2+ or [Ag(RNG2)2)]+ and with sulfhydryl (SH) groups to form a very slightly

ionizable AgSR compound. Silver ion has a remarkable affinity for SH (thiols) groups

1

REFERENCES? Fung MC, Bowen DL. Silver products for medical indications: risk-benefit assessment. J Toxicol Clin Toxicol. 1996; 34(1):119-26.2 Shinogi M, Maeizumi S. Effect of Pre-induction on Metallothionein on Tissue Distribution of Silver and Hepatic Lipid Peroxidation. Biol Pharm Bull 1993; 16:372-4.3 Gaul Le, Staud AH. Clinical spectroscopy. JAMA 1935; 104: 1387-1390.4 Hill, WR, Pillsbury, DM. Argyria: The Pharmacology of Silver, Baltimore, MD: Williams & Wilkins Co., 1939:169.5 White JML, Powell AM, Brady K, Russell-Jones R. Severe generalized argyria secondary to ingestion of colloidal silver protein. Clinical & Experimental Dermatology May 2003; Volume 28, 3:254.6 Brandt D, Park B, Hoang M, Jacobe HT. Argyria secondary to ingestion of homemade silver solution. Journal of the American Academy of Dermatology, August 2005, Volume 53, Issue 2, Supplement 1, 105-107.7 Roe AL, Collosal Argentum and its Ophthalmic Uses. Brit Med J, January 16th, 1915; 3:104.8 Crede KSF, Ber Klin Wochenschr, 1901; 38:941.9 Goetz A, Tracy RL, Harris FS. Oligodyanmic Effect of Silver. Chapter 16. In: Silver in Industry, edited by L. Addicks, Reinhold Publishing Corp., NY, 1940; p.402.10 Marshall CR, Killoh GB. The Bactericidal Action of Collosols of Silver and Mercury. Brit Med J, January 16th, 1915; 1:102-3.11 Morris M. The Therapeutic Effects of Colloidal Preparations. Brit Med J, May 12th, 1917; 1:617.

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but can also react to form stable bonds with chloride ions, amino, imidazole, phosphate,

and carboxyl groups12. It also reacts with CN- to form [Ag(CN)2]- complex ion.

Silver occurs most often as Ag2S together with lead and nickels and is recovered

during the purification of these metals. The most common oxidation states of silver are

Ag1+ and Ag2+. For Ag2+ complexes only planar structures with the coordination number

4 are known whereas Ag1+ complex compounds can have the coordination numbers 2, 3,

4, and 6 giving respectively linear, trigonal, tetrahedral and octahedral structures. The

Ag1+ structure of silver hydrosol has been shown to have the greatest antimicrobial

activity at or near the picoscalar level13 due to the fact that it enjoys the greatest surface

presentation (~6km2 per gram Ag). 14, 15 The surface presentation of Ag2+ is such that it

must be used at higher concentrations to achieve the same antimicrobial activity which

also increases its toxicological properties within the body.

The antiseptic activity of silver compounds results from the reaction of Ag1+ with

proteins of the microorganism. Chambers et al have shown that the activity of a specified

amount of silver is related to the concentration of Ag1+ ion, which is in an unbound state,

rather than to the chemical or physical nature of its source.16 Goetz et al showed that

insoluble compounds of silver, or even metallic silver, can affect microorganisms by

releasing traces of this pure Ag1+ ion.Error: Reference source not found

12 Petering HG, Pharmacology and Toxicology of Heavy Metals: Silver, Pharmac. Ther. A.1976;1; 127-130.13 Morones JR, et al. The bactericidal effects of silver nanoparticles. Nanotechnology. 2005;16:2346-53. 14 Gordon E, Holtorf K. Promising cure to URTI pandemics including the avian flu (H5N1): Has the final solution to the coming plagues been discovered? Part II. Townsend Letter. 2006 April; #273.15 Russell AD, Path FR, Hugo WB. Antimicrobial activity and action of silver. Prog Med Chem.1994; 31:354.16 Chambers CW, Proctor CM, Kahler PW. Bactericidal effect of low concentrations of silver. J.Am.Wat.Wks.Ass.1962; 54:208-216.

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In general, silver salts have difficulty achieving biologically meaningful

concentrations of Ag1+. Therefore, the efficacy of silver salts speciation is dependent on

its release of Ag1+ as its solubility product. The oligodynamic state which is achieved in

the purest silver hydrosol form does not require its being released from any salt as it is

already in the free Ag1+ form in water. The salt form of silver, however, has a reduced

surface area and bactericidal activity because of restricted dissociation into Ag1+. Error:

Reference source not found Acél17 was perhaps the first to observe that the oligodynamic action of

silver was due to liberated Ag1+ as opposed to metallic (neutral) Ag. Eichorn et al 18

emphasized that the charge significantly facilitate electron displacement. The nano- or

picoscalar pure Ag1+ particles have a tremendous advantage of affecting a greater surface

area. That, along with the total concentration of silver Ag1+ increases the order of

magnitude in its respective therapeutic index.

The advantage of pure Ag1+ hydrosol substances is its ability to adsorb and

penetrate into the greatest possible biological area with the lowest possible effective dose.

The oligodynamic metal charge effectively pulls electrons away from the surface of a

pathogen and weakens the molecular bond, rendering it susceptible to cleavage.19 The

smaller the size of the silver particle, the more biologically active it becomes. The only

antimicrobial portion from earlier, cruder colloidal silvers was from the unbound, non-

salt picoscalar silver (as pure Ag1+) in a hydrosol suspension. The Ag1+ was the only

active antimicrobial component of in vitro and in vivo systems. Error: Reference source

not found, Error: Reference source not foundThe activity of biocatalysts like the pure silver hydrosol is

directly proportional to the adsorption power upon a biological surface. 20 Kopaczewski

19 Rochart C, Uzdins K. Katadyn (silver preparation): clinical application. Schweiz Med Wochenschr. 1947; 77: 1100-4.

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concluded that the net colloidal particle size meant a great deal to the oligodynamic

effectiveness of any colloidal silver preparation and that only the finest dispersed

particles of silver had the desired antiseptic effects.21

Silver-based drugs are formulated from (a) silver salts and compounds or (b)

silver suspensions. There are dozens of silver-based drugs in each of these

classifications.22, 23 Each individual silver-based drug has unique and substantially

different physical and chemical properties which have been defined as its respective

speciation.24, 25 For example weakly absorbed metals and metals associated with insoluble

sulfides vary greatly in their associated risks for toxicity.26

There are two distinct categories of silver speciation: solutions and suspensions.

There are respectively two subgroups of silver-based drugs that form solutions and at

least 5 subgroups to silver-based drugs that form suspensions, each with their distinct

specific properties. The colloidal silver products are comprised of insoluble silver

particles that never dissolve but form suspensions with five classifications of mediums. 27,

28, 29, 30, 31 The silver salts and compounds form true silver solutions, which can never be a

pure silver hydrosol suspension.

Historical Uses:

22 Wood, HC, et al., “The Effects of Selected Metals on Marrow Cells in Culture,” Chem. Biol. Interactions, 1974; 9:217.23 Pilcher JD, Sollmann T. Organic, Protein and Colloidal Silver Compounds: Their Antispetic Efficiency and Silver-Ion Content as a Basis for Their Classification. The Journal of Laboratory and Clinical Medicine, 1923;301-10.24 Grier N. “Silver and Its Compounds,” p.385; In: Disinfection, Sterilization and Preservation, S. Block, edit., Lea & Febiger, Philadelphia, PA, 1983.25 Goodman LS, Gilman A. The Pharmacological Basis of Therapeutics, First Edition, The Macmillan Co., NY, 1941.26 Sedlak DL. Analytical Techniques for Determining Metal Speciation in Polluted Waters. In: Transport, Fate and Effects of Silver in the Environment, Anders W. Andren and Thomas W. Bober, editors, published by University of Wisconsin, 1997;5.

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Paracelsus, a Swiss alchemist, recommended the use of silver for diseases of the

nervous system in the early 1500’s. By the late 1800’s in America, silver in the form of

silver nitrate was used to prevent blindness from pathogens contaminating the eyes of

newborns during childbirth and is still used today. In 1893, Carl Nagéli first identified

that extremely small pure silver (Ag1+) particles could exert powerful anti-bacterial

effects at extremely low concentrations. He called this the oligodynamic effect from the

Greek oligos = few and dynamis = power. At that time it was beyond definitive chemical

and physical analysis.8 Articles on the efficacy of silver as an antibiotic began to appear

in such journals as Lancet and The British Journal of Medicine in the early 1900’s

emphasizing its therapeutic success in cases of encephalitis, septicemia and others. Silver

was even administered intravenously during those times, saving patients’ lives.32, 33, 34

The first comprehensive attempt to evaluate the efficacy and variety of silver

medicinals was published by the department of pharmacology of the medical school of

Case Western Reserve University, Cleveland, in 1923 by Pilcher and Sollmann.Error:

Reference source not found They successfully showed the greater efficacy of colloidal

silvers compared to salts and compounds, emphasizing that the smaller particle size of

colloids enhanced their activity against pathogens, not realizing at the time that the

disassociations ration of pure Ag1+ was the most important factor in their antiseptic

properties.

With the introduction of penicillin in the early 1940’s, the medical

establishment’s interest in silver waned, particularly due to the documented side effect

32 Duhamel BG. Electro Metallic Colloids, Etc. The Lancet, January 13th, 1912.33 Sanderson-Wells TH. A Case of Puerperal Septicemia Successfully Treated with Intravenous Injections of Collosol Argentum. The Lancet, February 16th, 1916; p.258.34 Fuller AW. Epidemic Encephalitis of Severe Type. The Lancet, July 24th, 1926; 2: 172.

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seen in some patients of Argyria, a permanent discoloration of the skin. This condition

was found in some patients using inferior compounds of silver salts or homemade

putative colloidals of silver having little if any oligodynamic properties. Most of these

patients were using large doses of these inferior silver forms over a considerable length of

time.Error: Reference source not found

Silver exposure:

In 1991, the EPA published the oral daily reference dose (RfD) of silver exposure

at 5 micrograms/kg/day with a critical dose estimated at 14 micrograms/kg/day for the

average person 35 (1 no.10). This data was not based on pure Ag1+ silver studies but

rather on estimates drawn on various silver compounds and the toxicity resulting from

such high dosages of these complex silver compounds over a period of time. A dosage of

EPA RfD is not applicable to a pure Ag1+ but applies solely to the complex silver salts

and silver proteins. The EPA guideline is inconsistent with milk consumption, which may

contain up to 54 micrograms/liter of silver, resulting in a child of 10 kg easily surpassing

the critical dose of silver according to the EPA RfD.

18 Eichorn GL et al. Interaction of metal ions with biological systems with special reference to silver and gold. Proceedings of the First International Conference on Gold and Silver in Medicine, Bethesda, MD, 13-14 May. Washington, DC: The Silver Institute, 1987, 4.20 Bodansky M. Introduction to Physiologigcal Chemistry. John Wiley & Sons, Inc., NY, 1934;22-3.21 Kopaczewski W. The Pharmacodynamics of Colloids. In: Colloid Chemistry – Theoretical and Applied, edited by J. Alexander, The Book Department, The Chemical Catalogue Co., Inc., NY, 1928; Vol. 2, p. 962.27 Wood HC, et al., The Dispensatory of The United States of America, Centennial (22nd) Edition, J.B. Lippincott Co., Philadelphia and London, 1937.28 Grier N, “Silver and Its Compounds,” p.385; In: Disinfection, Sterilization and Preservation, S. Block, edit., Lea & Febiger, Philadelphia, PA, 1983.29 Goodman LS, Gilman A. The Pharmacological Basis of Therapeutics, First Edition, The Macmillan Co., NY, 1941.30 Goodman LS, Gilman A. The Pharmacological Basis of Therapeutics, Second Edition, The Macmillan Co., NY, 1956.31 Pilcher JD, Sollmann T. Organic, Protein and Colloidal Silver Compounds: Their Antispetic Efficiency and Silver-Ion Content as a Basis for Their Classification. The Journal of Laboratory and Clinical Medicine, 1923; p.301-10.

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The highly variable silver concentration in silver products needs to be evaluated

for each individual compound. These compounds must be reevaluated as to the ease or

difficulty with which they are removed from biological and ecological systems.

Oligodynamic silver is active at such low levels that it cannot cause toxicity to the

environment nor biological systems as it is not bound to any salt or protein which would

decrease efficacy and compromise its removal from any biological or ecological system.

Due to modern technology, utilizing electrolytically removed pure silver Ag1+, a high

concentration of picoscalar oligodynamic silver Ag1+ hydrosol suspension becomes

possible, and due to the absence of anions, results in a formulation as gentle as water.36

Current Promotion:

There are many forms of silver products sold as dietary supplements to consumers

through health food stores, natural pharmacies and the internet. These products are

regulated by FDA under the guidelines established by the Dietary Supplement Health and

Education Act (DSHEA) of 1994. These products consist of colloidal silver, silver

proteins, ionic silvers, silver solutions and silver hydrosols. Many manufacturers are

unaware of the sophistication of the technology necessary for the development of pure

forms of silver (Ag1+). The newest products utilizing extremely advanced nanotechnology

have far surpassed the other older forms of colloidal silver in their efficacy, safety and

maximum therapeutic index at nanoscalar levels not achieved in the older compounds.

Regulatory History: Efficacy

Mild silver proteins as antiseptic ingredients were removed in 1992 from FDA’s

monograph for over-the-counter (OTC) medications as a result of inadequate efficacy

data available at that time. The Agency for Toxic Substances and Disease Registry

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(ATSDR) in 1990 carefully listed the older varieties of different silver medicinals

elaborating on the toxicities peculiar to each. However, there have been no toxicity

parameters for the new oligodynamic Ag1+ in a hydrosol suspension. Pure oligodynamic

silver has been tested (Feng et al in 2000) extensively for its antibacterial efficacy on

both gram negative and gram positive bacteria.37 They were able to elaborate on the

changes in bacteria via x-ray microanalysis and its effect in inactivating DNA replication

in these bacteria. This followed dozens of articles elaborating on the efficacy of

oligodynamic silver against most strains of bacteria, including those thought to be

resistant to other forms of silver medicinals. Those previously thought to be resistant

proved sensitive to pure silver hydrosol Ag1+ . 38 The list includes: Acinetobacter

baumani, Citrobacter freundii, Entamoeba histolytica cysts, Enterobacter cloacae,

Enterobacteriaceae (some strains), Escherichia coli (J62, C600, R1 & S1), Klebsiella

pneumoniae, Mycobacteria, Pseudomonas aeruginosa, Ps. Stutzeri (AG256, AG259,

JM303), Ps. Putida CYM318, Proteus mirabilis, Salmonella typhimurium,

Staphylococcus aureus, Thiobacillus ferro-oxidans, Thiobacillus thio-oxidans, Vegetative

B. Cereus Spores.

Most Fungi have also proven to be extremely sensitive to the antimicrobial

actions of silver ions 39, 40, 41 including: Actinomyces viscosus, Alternaria dianthi,

Alternaria oleracea, Alternaria solani, Aspergillus flavus, Aspergillus fumigatus,

Aspergillus niger, Botryobasidium (Rhizoctonia) solani, Botrytis cineria, Botrytis

paenoiae, Candida albicans I, Candida albicans II, Candida globata, Candida krusei,

Candida parapsilosis, Candida tropicalis, Candida utilis, Chlamydospores – Tilletia tritici,

Erwinia amylovora, Erysiphe graminis, Fungi Imperfectii, Heterodera marioni, Monilinia

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fructicola, Mucor pusillus, Ophiobolus graminis, Pestalotia stellata, Phlyctenular

Conjunctivitis, Phycomycetes, Phytophthora infestanis, Ringworm of the body, Rhizopus

nigricans, Saccharomyces cereevisiae, Saprophytes, Sarcina aurantiaca, Sclerotinia

americana, Sclerotinia fructicola, Septoria apii, Sporosarcina ureae, Tinaea versicolor,

Torulopsis glabrata, Uromyces caryophyllinus, Xanthium glabaratum, Yeast). The

mechanism of toxicity to fungi is apparently related to the absorption of silver ions

through the cell surface of fungi thought to be related to the changes in functions of

cytoplasm membranes.42

The efficacy of oligodynamic silver Ag1+ has also been shown to have an

inhibitory affect on viral replication in vitro and in vivo against HIV43, 44, 45, 46, 47, 48, 49, 50, 51

and Herpes virus hominis (HSV).52, 53, 54, 55, 56, 57, 58 Earlier data showed sensitivity of the

following viruses to silver medicinals: Adenovirus, bovine rotavirus, Cerebro-spinal

Meningitis, Conjunctivitis, Coxsackie virus type B-3 (CB-3), ECHO virus, ECHO virus

type 6 (EC-6), Enteroviruses, Haemophilus influenzae, Influenzae Influenzae A, Measles

virus (MV, Nagahata strain), Poliovirus 1 (Sabin strain), Polio virus type 1 (Po-1),

Pseudorabies virus, Reovirus type 1, Rhinovirus type 1A, Shingles Small pox, Vaccinia

virus (poxviruses), Varicella-zoster virus, Vesicular stomatitis-Indian virus, and Warts). 59

Clinical Toxicology: Safety

The safety information from EPA’s data for metallic silver includes The Oral

Reference Dose (RfD) and the Lowest Observed Adverse Event Level (LOAEL). The

data is calculated from earlier publications on skin discolorations (Argyria) from the

1930s. The lowest I.V. dose resulting in Argyria was at 4 grams of silver arsphenamine

containing 1 gram of metallic silver. Conversion of the I.V. dose to oral dose was based

11

on oral retention factor of 0.04. 60 This is the method for arriving at 25 grams of silver for

a lifetime period. The speciation of the silver product, however, plays a major role in

determining whether the silver used is toxic or harmless. Speciation refers to salt

(compound) versus colloid and the dissociation constant. Each individual silver-based

drug has unique and substantially different physical-chemical properties which are

defined as its speciation.61, 62 These differences in speciation describe the distinct physical

and chemical properties of a specific metal’s fate, transport, and toxicity as it occurs

respectively, uniquely and separately in differing: (1) compounds, (2) salts, and (3)

suspensions. 63

There are in existence many speciations of silver-based drugs that have been

listed in official and unofficial Pharmacopoeia monographs including The Dispensatory

of the United States of America (USP), The British Pharmacopoeia (BP), The National

Formulary (N.F.), The New and Non-Official Drug Registry (N.N.R.), and others in The

Council on Pharmacy and Chemistry of the American Medical Association.64, 65, 66, 67

The two distinct categories of silver speciations are solutions and suspensions.

These categories are further subdivided into two subgroups of solutions, and at least five

subgroups to silver based drugs that form suspensions. The former two categories are:

(1) silver salts and the compounds that form true silver solutions, and (2) colloidal silvers

which are comprised of insoluble particles in suspensions, which are further subdivided

into five classifications of suspension mediums.68, 69, 70, 71, 72

64 Wood HC, et al. The Dispensatory of The United States of America, Centennial (22nd) Edition, J.B. Lippincott Co., Philadelphia and London, 1937.65 The Era Key to the USP XI & NF VI, Fifth Edition, revised by Lyman D. Fonda, The Haynes & George Co., Inc., New Jersey, 1939.66 Council on Pharmacy and Chemistry of the A.M.A., Epitome of the Pharmacopoeia of the United States and the National Formulary with comments, American Medical Association, Chicago, IL, 1940.67 Hill WR, Pillsbury DM. Argyria: The Pharmacology of Silver, The Williams & Wilkins Co. Baltimore, 1939;169.

12

The solubility of these compounds varies tremendously. Their efficacy as an

antimicrobial is only related to the concentration of pure Ag1+ in the suspension. For this

reason, only nanoscalar particles of the pure oligodynamic silver hydrosol (Ag+) are

necessary to achieve antimicrobial efficacy.

Argyria is definitely a problem with silver salts and with non-oligodynamic

colloidal silver products, but not the nanoparticles of pure oligodyanamic colloidal silver

or silver hydrosol. Particles measured on the nanoscale and smaller are easily removed

from the dermis, thus not capable of resulting in Argyria as reported from the older salts

and complex compounds of silver and colloidal silver.73,74 The complex compounds,

however, including the silver salts, appear to be the basis of all reports of silver toxicity

in higher life forms.75, 76, 77,Error: Reference source not found These large complex silver compounds

cannot be efficiently removed from the skin and end up remaining bound in the dermal

layers and within the mucous membranes78, with the highest concentration in the skin,

liver, and adrenal glands.79, 80, Error: Reference source not found, Error: Reference source not found Although the

deposition of the silver compounds in the skin is uniform, the discoloration is most

prominent in sun exposed areas because of an increase in the melanin production as well

as a reduction of the elemental silver. The discoloration of the skin is usually permanent

but benign with a few isolated reports on neurological deficits, renal problems and

hepatic complications.Error: Reference source not found This is most likely the result of

selenium and vitamin E deficiencies. Error: Reference source not found, 81, 82 The reported

toxicological effects are not seen with the new speciations of pure oligodynamic silver

hydrosol because they are at both a dosage and purity that does not result in deposition in

tissues. They are also not bound to salts or other compounds that would hinder their

13

removal from the membranes.Error: Reference source not found, Error: Reference source not found, Error:

Reference source not found

Therefore, toxicological evaluations of silver products must be done through

evaluation of the individual products and their specific speciation in order to have

accurate substantial data for safety and regulatory purposes.

Conclusion:

Government regulators are still using the paper by Fung and Bowen as a

major reference for evaluating the toxicity of all silver medicinals although the authors

simply combined all silver products for purposes of safety evaluation. They did not take

into consideration the differing speciations and variations in chemistry, physical

properties, dissociation constants, transport, biological effects and toxicology. Fung and

Bowen inappropriately “bundled” a wide spectrum of silver-based medicinals’ physical

and chemical attributes when discussing silver medicinals, and furthermore did not

adequately delineate either the (A) numerous and distinct categories of silver-based

medicinals, or – in most instances – (B) clearly define which specific speciation of silver-

based medicinal they were discussing. Their conclusion, often cited by critics of silver-

based medicinals, effectively confuses and blurs the relevant issues surrounding

pharmacokinetics, pharmacodynamics, toxicity and therapeutic index pertaining to each

respective silver species. The erroneous conclusions in the Fung and Bowen paper are a

grave error for any regulated substance regardless of whether it is a metal, trace element,

or new pharmacological agent.

14

Individual silver compounds in solution must be evaluated against the colloidal

suspensions carefully and separately to eliminate those potentially toxic substances, but at

the same time to allow pure silver medicinals, which, because of their oligodynamic state

and picoscalar size, render them safe as antimicrobial agents. This new refinement of

colloidal silver falls into a completely different category of chemistry that no longer

poses a concern for safety to patients or the environment. Unlike silver salts, new 35 US Environmental Protection Agency: Reference dose for chronic oral exposure of silver. Washington, DC, Chemical Screening and Risk Assessment Division. CASRN 7440-2204, 1991.36 Rentz EJ. Viral Pathogens and Severe Acute Respiratory Syndrome: Oligodynamic Ag+ for Direct Immune Intervention. Journal of Nutritional and Environmental Medicine (June 2003) 13(2), 109-118.37 Feng et al. A Mechanistic Study of the Antibacterial Effect of Silver Ions on Escherichia coli and Staphylococcus aureus. J Biomed Mater Res, 2000 March; 52:662-8.38 Clement JL, Jarrett PS. Antibacterial Silver. Metal Based Drugs, ed. By Frank Shaw, III, August 17th-20th, 1994; 1(5-6):472.39 Berger TJ, et al. Antifungal Properties of Electrically Generated Metallic Ion. Antimocrob Agents Chemother, 1976; 10(5):856-60.40 Grier N. Silver and Its Compounds. In: Disinfection, Sterilization and Preservation, S. Block, edit., Lea & Febiger, Philadelphia, PA, 1983; 379.41 Berger TJ, et al. Antifungal Properties of Electrically Generated Metallic Ion. Antimocrob Agents Chemother, 1976; 10(5):856-60.42 Golubovich VN, Khovrychev MP, Raotnova, IL. Binding of Silver Ions by Candida utilis Cells. Mikrobiologiia, Jan-Feb 1976; 45(l):119-22.43 Antelman M. United States Patents: 5,017,295; 5,073,382; 5,078,902; 5,089,275; 5,098,582; 5,211,855; 5,223,149; 5,336,416; 5,336,499; 5,772,896.44 Antelman M. Multivalent Silver Bacteriocides. Precious Metals, 1992; 16:151-63.45 Antelman M. Anti-Pathogenic Multivalent Silver Molecular Semiconductors. Precious Metals, 1992; 16:141-9.46 Dean W, et al. Reduction of Viral Load in AIDS Patients with Intravenous Mild Silver Protein - Three Case Reports. Clinical Practice of Alternative Medicine, Spring, 2001.47 Oka H, et al. Inactivation of Enveloped Viruses By A Silver-Thiosulfate Complex Metal Based Drugs, 1994; 1(5-6):511.48 Antelman M. Silver (II, III) Disinfectants. Soap/Cosmetics/Chemical Specialties, March, 1994;52-9.49 Hussain S, et al. Cystine Protects Na, K-ATPase and Isolated Human Lymphocytes From Silver Toxicity. Biochem., Biophys. Res. Comm., 1992; 189:1444-1449.50 Aiken C. Dec 16, 1997; In vitro MIC Test Against HIV-1, published account via email, AA-90 Results, Vanderbilt University, School of Medicine.51 Zhong-Yin Z, et al. Zinc Inhibition of Renin and the Protease from Human Immunodeficiency Virus Type 1. Biochemistry, 1991, Sept 10; 30(36):8717-21.52 Grier N. Silver and Its Compounds. In: Disinfection, Sterilization and Preservation, S. Block, edit., Lea & Febiger, Philadelphia, PA, 1983; 380.53 Shimizu F, Shimizu Y, Kumagai K. Specific Inactivation of Herpes Simplex Virus by Silver Nitrate at Low Concentrations and Biological Activities of the Inactivated Virus, Antimicrobial Agents and Chemotherapy, July 1976; 10(l):57-63.54 Thurman RB, Gerba CP.The Molecular Mechanisms of Copper and Silver Ion Disinfection of Bacteria and Viruses. CRC Critical Reviews in Environmental Control, 1989; 301.55 Coleman VR, Wilkie J, Levinson WE, Stevens T, Javetz E. Inactivation of Herpesvirus hominis Types 1 and 2 by Silver Nitrate In Vitro and In Vivo. Antimicrob. Agents & Chemother., 1973; 4:259.56 Russell AD, Hugo WB. Antimicrobial Activity and Action of Silver. Prog Med Chem, 1994; 31:354.

15

nanotechnology has allowed the development of a pure silver hydrosol that is not bound

in the dermis or mucous membranes; and therefore, it does not cause the primary side-

effect associated with impure silver compounds: Argyria. It is our responsibility as

physicians, scientists, and regulators to recognize this new innovative non-toxic form of

oligodynamic silver that is extremely effective in eliminating destructive pathogens at

nanomolecular levels. It is imperative to keep this pure form of silver separated in

regulatory, safety, and efficacy data from those inferior compounds that are potentially

hazardous.

The Fung and Bowen paper is inadequate for evaluation and determination of

safety and efficacy for silver products based on the newest nanotechnology available for

manufacture of the new speciations of silver. Regulatory agencies have an obligation to

improve and update the tools upon which they rely for evaluation of safety and efficacy

57 Chang TW, Weinstein, L. In vitro Activity of Silver Sulfadiazine Against Herpesvirus hominis. J Infect Dis, July 1975; 132(1):79-81.58 Tokumaru T, Shimizu Y, Fox CL. Antiviral Activities of Silver Sulfadiazine in Ocular Infection. Res Commun Chem Pathol Pharmacol, May 1974; 8:151-8.59 Thurman RB, Gerba CP. The Molecular Mechanisms of Copper and Silver Ion Disinfection of Bacteria and Viruses. CRC Critical Reviews in Environmental Control, 1989; 301.60 Furchner JE, Richmond CR, Drake GA. 1968. Comparative metabolism of radionuclides in mammals – IV. Retention of silver – 110m in the mouse, rat, monkey, and dog. Health Phys. 15:505-514.61 Pilcher JD, Sollmann T. Organic, Protein and Colloidal Silver Compounds: Their Antispetic Efficiency and Silver-Ion Content as a Basis for Their Classification. The Journal of Laboratory and Clinical Medicine, 1923;301-10.62 Grier N. Silver and Its Compounds. p.385; In: Disinfection, Sterilization and Preservation, S. Block, edit., Lea & Febiger, Philadelphia, PA, 1983.63 Sedlak DL. Analytical Techniques for Determining Metal Speciation in Polluted Waters. In: Transport, Fate and Effects of Silver in the Environment, Anders W. Andren and Thomas W. Bober, editors, published by University of Wisconsin, 1997;5.68 Wood HC, et al. The Dispensatory of The United States of America, Centennial (22nd) Edition, J.B. Lippincott Co., Philadelphia and London, 1937.69 Grier N. Silver and Its Compounds. p.385; In: Disinfection, Sterilization and Preservation, S. Block, edit., Lea & Febiger, Philadelphia, PA, 1983.70 Goodman LS, Gilman A. The Pharmacological Basis of Therapeutics, First Edition, The Macmillan Co., NY, 1941.71 Goodman LS, Gilman A. The Pharmacological Basis of Therapeutics, Second Edition, The Macmillan Co., NY, 1956.72 Pilcher JD, Sollmann T. Organic, Protein and Colloidal Silver Compounds: Their Antispetic Efficiency and Silver-Ion Content as a Basis for Their Classification. The Journal of Laboratory and Clinical Medicine, 1923; p.301-10.

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of silver based substances; otherwise we may lose viable tools for addressing essential

therapeutic interventions, particularly in an era of ever-increasing Multi-Drug Resistant

pathogens. Acknowledging the safety and efficacy of these new silver hydrosols is

critical to regain a beneficial medicinal substance that is desperately needed in our fight

against evolving resistant pathogens.

17 Acél D, Biochem Z, 1920; 112: 23-32. In: Russell, AD, Path, FR, Hugo, WB, Antimicrobial Activity and Action of Silver. Prog Med Chem, 1994; 31:353.73 Simonetti N, Simonetti G. Electrochemical Ag+ for Preservative Use. Applied and Environmental Microbiology, Dec 1992; 58(12):3834-3836.74 Crede, KSF, Ber Klin Wochenschr, 1901; 38:941.75 Handbook of Chemistry and Physics, ed. David R. Lide, CRC Press, Boca Raton, Fl., 2000; Section 4, p.27.76 Grier N. Silver and Its Compounds. p.386-90; In: Disinfection, Sterilization and Preservation, S. Block, edit., Lea & Febiger, Philadelphia, PA, 1983.77 Addicks L. Silver in Industry, Reinhold Publishing Corp., NY 10940; p.403.78 Pariser RJ. Generalized argyria: clinicopathiologic features and histochemical studies, Arch Dermatol.1978; 115;373-377.79 Tanner LS, Gross DJ. Generalized argyria, Cutis 45. 1990; 237-239.80 Gulbranson SH, Hud JA, Hansen RC. Argyria following the use of dietary supplements containing colloidal silver protein, Cutis 66. 2000;373-374.81 Wagner PA, Hoekstra WG, Ganther HE. Alleviation of silver toxicity by selenite in the rat in relation to tissue glutathione peroxidase. Proc Soc Exp Biol Med. 1975; 148: 1106-1110.82 Bunyan J, Diplock AT, Cawthorne MA. Green J. vitamin E and stress: 8. Nutritional effects of dietary stress with silver in vitamin E deficient chicks and rats. Br J Nutr. 1968; 22:165-182.

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