MINERAL CHELATION FACTS ON CHELATION IMPACT ON REPRODUCTION AND COMPOSITION OF GAIN JOEL F MANGALINDAN DVM

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1 MINERAL CHELATION FACTS ON CHELATION IMPACT ON REPRODUCTION AND COMPOSITION OF GAIN JOEL F MANGALINDAN DVM Clinical Nutrition Practitioner

2 MINERALS - constitute very small fraction of body weight and diet - vital components of wide variety of body form and functions - from bones to muscles to all organ and tissue enzyme functions DESCRIPTION - present in animal and plant tissues in "naturally chelated " form; attached to organic components like sugars, proteins, vitamins and other organic acids - traditional source of animal mineral supply

3 - intensified animal productivity increased animal mineral requirement and intensive/monoculture feed crop production depleted soil mineral content to such a levels that traditional sources can not meet requirement Extensive Intensive > inorganic mineral supplements used to fill gap

4 RECENT STUDIES HAVE SHOWN THAT INORGANIC MINERAL SUPPLEMENTS ARE NOT ABSORBABLE AS EXPECTED (<20% bioavailability) > VERY HIGH LEVELS OF UNABSORBED MINERALS IN THE MANURE/EFFLUENTS >SIGNIFICANTLY CONTRIBUTE TO FOULING UP OF SOILS AND WATER BODIES BY EFFLUENTS

5 SCIENCE CAME UP WITH AN EFFECTIVE YET ECONOMICALLY VIABLE SOLUTION MINERAL CHELATION

6 FATE OF INORGANIC MINERALS IN THE DIGESTIVE SYSTEM

7 STOMACH In a normal stomach, the ph is Acid ph is necessary for the activation of gastric enzyme pepsinogen to pepsin, responsible for the initial digestion of proteins. ph NUTREX Current Nutrition Technology Exponents

8 Fe 2+ FeSO 4 Low ph SO 4 2- Inorganic Mineral compounds dissolve in the acidic ph in the stomach and dissociate into the metal and non-metal components. These are the forms that pass onto the intestines. NUTREX Current Nutrition Technology Exponents

9 LIVER PANCREA S INTESTINES STOMACH In the first part of the small intestines (duodenum), bile from the liver/gall bladder enters, and causes ph to rapidly elevate to alkaline (ph 7-7.2). The alkaline ph in the intestines is necessary to activate the other enzymes for digestion secreted by the pancreas.

10 Fe 2+ High ph Phosphates MAGMA formation (80-85%) In the highly alkaline intestines (>ph7) free metal ions of the dissociated metal along with other anions precipitate and form insoluble and inabsorbable magma *. *causes gut disturbances Inabsorbable!!! Intestinal Wall

11 Vitamins Fe 2+ Iron-Vitamin Complex Free metal ions also are attracted to and bind with vital nutrients like vitamins (esp. Vit C and A) and some reactive fibers forming a strong inabsorbable complex, in effect directly reducing vitamin bioavailability INABSORBABLE!! Intestinal Wall

12 Fe 2+ Bacterium (E.coli &/or Salmonella sp.) Intestinal Wall Growth and colonization of GI tract by harmful, diarrhea causing bacteria like E.coli & Salmonella sp. are elemental iron dependent. Ionic iron (from disassociated inorg. Iron) actually feeds bacterial need and supports colonization

13 SUMMARY : INORGANIC MINERAL INTERACTIONS IN THE DIGESTIVE SYSTEM Inorganic mineral salts disassociate at gastric ph (2-4), and precipitate at ph 5. More than 85% of minerals fed form precipitates at intestinal ph of Interact with vitamins (especially Vit C and A) significantly reducing vitamin bioavailability Highly active Buffering of gastric acid > elevated gastric ph > reduced protein digestion (ex. 1% calcium carbonate in diet increases the gastric ph from 3 up to 5) Mineral precipitates form viscous magma which inhibit intestinal absorption processes and initiate intestinal distress Inorganic iron supports growth of harmful intestinal bacteria Increasing the dose of one in an attempt to correct a deficiency or for other purposes negatively affects absorption of the other/s

14 Interaction of Inorganic Minerals in a Biologic Environment

15 INCREASING THE DOSE OF PARTICULAR INORGANIC MINERALS TO MEET/ CURE DEFICIENCY SYMPTOMS OR FOR ANTI-DIARRHEAL OR AGP MIMICKING REASONS MERELY INCREASES THE NEGATIVE EFFECTS The mode of action of high doses of zinc oxide and copper as antidiarrheal or as AGP like, is by inhibiting iron absorption by infectious microbes and thereby inhibiting their multiplication. But at the same time iron absorption by the animal is also inhibited - likely to be more harmful than beneficial INTERACTIVE EFFECTS OF EXCESS SUPPLEMENTATION EXCESS Calcium depresses phosphorous, zinc and iron absorption Phosphorous depresses calcium, zinc, manganese and iron Zinc depresses copper, iron and calcium absorption Iron depresses phophorous and calcium absorption Copper depresses iron and zinc absorption *Lewis, Morris & Hand. Small Animal Clinical Nutrition.1992

16 - RATED TRUE* ABSORBABILITY OF COMMON INORGANIC MINERAL SUPPLEMENTS Iron, as Ferrous sulfate 4-20% Copper, as copper sulfate 10-15% Manganese, as manganese sulfate 6-15% Zinc, as zinc sulfate 5-13% Selenium, as sodium selenite less than 0.5% Chromium, as chromium chloride less than 0.5% ========================================================================================================= *As absorbed and retained, monogastrics Adopted fr: Minerals, Nutrient Req. for Swine, USNRC Release 98 Anderson R. 1996, J. of Trace Elements in Exp. Med., USDA ARS Standard Mineral Bioavailability estimates are expressed as a percentage of a recognized standard and do not refer to percentage absorbed and retained. Absorbed and retained mineral as a percentage of intake is usually under less than 50% of the intake. (Minerals; Nutrient Requirement for Swine. USNRC release 1998)

17 UPON ABSORPTION OF MINERAL IN THE SMALL INTESTINES - TO PORTAL CIRCULATION TO LIVER MINERAL POOL FOR PROCESSING PRIOR TO RELEASE TO THE BLOODSTREAM

18 DEPENDING ON THE TISSUE NEEDS, in the liver: IONIC METALS ARE CHELATED TO FINAL FORM LIGANDS (specific amino acids & vitamins) METALS ALREADY ATTACHED/CHELATED TO NON- FINAL FORM LIGANDS ARE DETACHED AND METAL GOES TO POOL - EX. ZINC METHIONINE METALS ALREADY CHELATED TO FINAL FORM AMINOACIDS ARE COMPLETED PRIOR TO RELEASE TO THE BLOOD STREAM FINALLY TO THE TISSUE REQUIRING THEM

19 SOLUTION REACTIVE APPROACH - Inhibit interaction with gastric ph other organic materials - avoid precipitation at intestinal PH - add acidifiers LOGICAL/BIOLOGICAL APPROACH - Imitate NATURAL CHELATION of minerals

20 MINERAL CHELATION - Chemically attaching minerals, using a catalyst (AN ENZYME), to an organic acid (called a LIGAND) such as amino acids, sugars, fats, vitamins, etc., For the purpose of preventing interaction with gastric acids, intestinal ph, vitamins and other organic acids and improving absorbability and bioavailability Example: catalyst Amino acid iron - Amino acid Iron-amino acid chelate ligands supply the 2 electrons and bonding process utilizes an enzyme catalyst forming a coordinate covalent bond A WET PROCESS AS WHAT OCCURS IN NATURAL CHELATION

21 R R C r Coordinate Covalent Bond R NUTREX Current Nutrition Technology Exponents

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23 Effects of Chelation 1. Chemically binds the positive valence of the metal to the negative valence of the ligand > resulting complex is non- reactive to ph changes and to other organic materials (vitamins, phytic acid, etc) in the gut 2. Helps preserve vitamins and other nutrients which will otherwise be precipitated with the minerals and rendered inabsorbable 3. The mineral assumes the inherent solubility and absorbability of the ligand IN EFFECT - the intestines absorb the ligand and with it the Mineral 4. Drastically improves bioavailability of the minerals

24 LIGAND SELECTION CRITERIA 1. Must be highly soluble and absorbable in a wide ph range 2. Must produce a stable bond with the metal 3. Must not react with other organic materials and to ph changes in the gut 4. Must be one, two or all of the components of the FINAL FUNCTIONAL FORM of the metal in the body faster utilization and maximized bioavailability

25 FINAL FUNCTIONAL FORMS OF MINERALS IN THE BODY Metalo-organic chelates as existing in the body are made up of one, two or all of the three aminoacids glycine, cysteine and glutamic acid - plus a vitamin as cofactor. Chromium, for example, in the final form of Glucose Tolerance Factor(GTF), is composed of Cr + glycine + cysteine + glutamic acid + nicotinic acid Selenium, as Glutathione Peroxidase (GPX) is composed of Se + cys (+ gly/glut) + Vit. E.

26 DEFINITIONS AAFCO 1987 Metal-amino acid chelate - Product resulting from chelation of a metal salt with amino acids with a mole ratio of 1 mole of metal with 1 to 3 moles of amino acids to form coordinate covalent bonds. The average weight of the hydrolyzed amino acids must be approximately 150 and the resulting chelate must not exceed 800. Metal (mineral) proteinate - Product resulting from chelation of a metal salt with amino acids and/or partially hydrolyzed protein

27 METAL CHELATES USING EDTA, NTA and gluconates AS LIGANDS provide effective chelation BUT animal bodies have been shown to be unable to extract the metals from the chelates, such that even if absorbed into the blood, such chelates are apparently excreted intact. (Bates et.al.1972) KEY WORDS FOR MINERALS AND CHELATES: SOLUBILITY BIOAVAILABILITY - ABSORBABILITY, TISSUE RETENTION & UTILIZATION

28 DRY BLENDS & COMPLEXES - Metals and ligands simply mixed together - relies on natural physical attraction between the (+) valence of the metal with the (-) valence of the ligand (as in a magnet) - forms a SIMPLE IONIC BOND - physical bondings weak and break in acidic gastric medium - incomplete bondings - still partly reactive > lower absorbability - falsely passed on/sold as chelates - minor improvements over inorganic minerals and do not provide the benefits of true chelates - usually described as "mineral complex" - ratio of metal content over ligand is usually below or well beyond what is chemically prescribed/possible for the specific chelate (ex. 15% iron proteinate with 15% iron but only 20% CP) - usually come with a precaution Do not use with organic solvents as such complexes invariably separate upon exposure to such solvents

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30 Yeast based CHELATES yeast grown in culture media (solid state or fermentation vat method) with high metal and methionine concentrations the bioavailability of the metal chelate, being inside the yeast cell is subject to the digestibility of yeast cell wall (typically <20%) the bio-uptake of the metal by the yeast is subject to the biologically toxic concentration level of the metal (and therefore the product s maximum possible metal concentration) which is typically an LD50 of below 0.1% (0.01% to 0.08%)

31 METAL (i.e. Zn, Cr, Se) METHIONINE CHELATES The amino acid METHIONINE although a choice ligand like other amino acids, does not form any part of the final functional form of metals. Thus, it needs to undergo the process of detaching, then reattaching of the metal to final form ligands in the liver before it is finally available for use by the body just like other inorganic minerals

32 Comparative Solubility of Inorganic Minerals in Increasing ph Range

33 Comparative Absorption of Inorganic Minerals and True Chelates

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35 COMPARATIVE CHARACTERISTICS Inorganic True Chelate Gastric buffering highly active buffer non-buffering Vitamin binding active binder non-binding Reactivity with other organic acids highly reactive non-reactive Reaction to intestinal ph precipitates non-precipitative Stability in wide ph range unstable stable Mineral bioavailability** 0.5%-20% >90% High Dose impact on other minerals inhibition non-inhibitory Dose comparison high very low Cost Effectiveness* negative positive *Feed consumption, growth rate and carcass weight in No-Inorganic Trace Mineral/Vitamin supplemented ration were higher than in Inorganic Trace-Mineral/Vitamin supplemented rations (Deyhim & Teeter 1993 & 94:Fang, Deyhim, Teeter 1995) **Iron from Iron chelate 68-81% as bioavailable as in iron sulfate (Lewis et.al. 1995) **A 250ppm zinc chelate supplement gave equal improvements in performance as 2,000ppm inorg. zinc (Ward, et.al., 1996)

36 THE EVOLUTION OF MINERAL - AMINO ACID CHELATE In Better equipment and newer processes enabled economical full use of single amino acids as ligand - further development of the proprietary 3 stage chelation process assured complete chelation a) enzyme catalyzed wet chelation process b) allowed use of final functional form composite amino acids to trivalent metals like chromium (i.e glycine, cysteine and glutamic acid ligands for chromium as final form GTF) c) creates a coordinate covalent bond which effectively resists uncoupling effects of gastric ph resulting to unparalleled solubility, absorbability and maximized mineral bioavailability

37 MINERAL- AMINO ACID CHELATES, 3 stage chelation process - "state of the art" in terms of process, stability and bioavailability

38 COMPARATIVE TRUE BIOAVAILABILITY OF DIFFERENTMINERAL FORMS Form Bioavailability Mineral- amino acid chelate >90% Mineral-picolinates/saccharides/ other organic ligands <60% Mineral - yeast/methionine <35% Dry blends <20% Inorganic minerals very poor (0.5-15%) adapted From: Anderson, 1996; Olin,1994;Underwood,1997; Fang 1997

39 **Iron from Iron amino acid chelate is 4-5 times more bioavailable as iron sulfate (Lewis et.al. 1995) **A 250ppm zinc amino acid chelate supplement gave equal improvements in performance as 2,000ppm inorg. zinc (Ward, et.al., 1996) *Feed consumption, growth rate and carcass weight in No- Inorganic Trace Mineral/Vitamin supplemented ration were higher than in Inorganic Trace-Mineral/Vitamin supplemented rations (Deyhim & Teeter 1993 & 94:Fang, Deyhim, Teeter 1995)

40 SUMMARY OF COMPARATIVE EFFECTS OF CHELATED MINERAL AND CONVENTIONAL INORGANIC MINERAL SUPPLEMENTATION A. ON SOW PRODUCTIVITY AND PIG GROWTH Inorganic chelated Ave. response Wean to 1st service 6.5 days 5.0 days -23.3% Ist service conception 81.0% 90.0% +10.4% Prewean mortality 14% 8.0% -43.8% Weaned pigs/litter % Weaning wt, lbs % ADG to 105 kg % Source: Seedstock May/June 96 B. ON BROILER PRODUCTIVITY AND GROWTH No Mineral supp. Inorganic min. supp. Chelated min. supp. + vitamins + vitamins + vitamins Gain gms Feed consumption gms Gain/feed Dressing % Carcass wt gms Breast Yield/100 birds Carcass kg Breast kg Source: Fang, Deyhim and Teeter 1995 C. ON LAYER PRODUCTIVITY Higher egg mass Longer Peak lay Thicker egg shell Longer egg shelf life Lower culling % Source: Agri/TLCP data Phil ; Bonomi et.al 1992

41 PHIL. DATA 2004 Egg retention of Selenium using Different Forms of Selenium Supplement (samples 30 days from start of supplementation) Dose Na. selenite Selenomethionine Selenium Selenium yeast amino acid chel. 0.1ppm neg neg 0.76 u/g of egg 0.3ppm neg 0.21 u/g 1.18 u/g DRIP LOSS IN BROILER CARCASS (% of carcass) 12 hr hang, ambient temp. 0.1ppm >3.89% na >0.92% 0.3ppm >3.61% na >0.97%

42 Intestinal Wall Iron amino acid chelate can not be used by bacteria as their siderophores can not attach to the iron, thus effectively limiting bacterial multiplication and colonization and resultant diseases Studies on E.coli population in the jejunum of piglets have shown that inorganic iron supplemented piglets have more than 80 times the E.coli count than pigs supplemented with NUTREX Iron Amino Acid Chelate. *Bain and Almeda, UPCVM, UPLB 2005

43 DIFFERENTIATING TRUE CHELATES FROM DRY BLENDS AND INORGANIC MINERALS THRU SPECIFIC ASSAY PROCEDURES The standard mineral assays detect and measure the total free/reactive metal ion in the sample i.e. The amount of reactive metal present in inorganic mineral and incompletely bonded dry chelate. It cannot measure non-reactive metals in true chelates. The AAS detects and measures all the metals present in the sample, free or bound, inorganic, organic, dry blend and true chelates. AAS can not differentiate Inorganic from true chelates, and may not be sensitive enough to measure true chelates Inductively CoupledPlasma (ICP) is a specific test for true chelates, and can differentiate inorganics/complexes from chelates.

44 2 ND TEST to differentiate true chelate from complexes, blends and simple proteinate mixtures HPLC - High Performance Liquid Chromatography true AMINO ACID chelates will have signature SINGLE PEAK profiles. INORGANIC MINERALS WILL NOT SHOW PROFILES WHILE complexes, blends and simple mixtures will SHOW MULTIPLE PEAK HPLC profiles Current SPECIATION ASSAY TEST - ICP OES and ICP MS developed to distinguish between true amino acid chelates from complexes/dry blends/metal salts MOST CURRENT SPECIATION TEST HPLC ICP MS COUPLING

45 HIGH PERFORMANCE LIQUID CHROMATOGRAPHY (HPLC) PROFILE SAMPLE SELENIUM AMINO ACID CHELATE 1%

46 MINERAL ABSORPTION, AND THE ATTAINMENT OF MINERAL SUPPLEMENTATION IMPROVEMENTS, ARE ENTIRELY DEPENDENT UPON THE FORM (Anderson et.al 1996;Olin, et.al, 1994) THUS, THE HIGHER THE TRUE BIOAVAILABILITY, THE MORE PREDICTABLE THE EFFECTS AGRIaccess 4 th generation MINERAL AMINO ACID CHELATES 3 stage chelation process USING FINAL FORM COMPOSITE amino acids - the "state of the art" in mineral chelation - unequalled true bioavailability % HIGHER ABSORBABILITY AND TISSUE RETENTION than other mineral forms - predictable effects - cost effective and cost competitive

47 RECOMMENDED DOSE RATE NUTREX AMINO ACID CHELATES cu amino acid chelate Fe amino acid chelate zn amino acid chelate mn amino acid chelate mg amino acid chelate se amino acid chelate cr amino acid chelate dose active/kg of feed 1.5 mg/kg 11 mg/kg 7 mg/kg 5 mg/kg 12 mg/kg 0.1 ppm 200 ppb * increase by 25% for young animals except Se and Cr

48 USING THE BIOAVAILABILITY based RECOMMENDED DOSING* Mineral amino acid chelates actually costs less than inorganic minerals on a per ton of feed basis * Dose of Mineral Amino acid chelate which will produce equal to or better ABSORPTION/plasma levels/retention and Performance rates COMPARED TO the EQUIVALENT STANDARD inorganic mineral dose

49 Chromium amino acid chelate Selenium a.a. chelate Iron a.a. chelate Copper a.a. chelate Zinc a.a chelate Manganese a.a chelate Magnesium a.a chelate Available as: individual chelates - pure and premix custom blends mineral packs ICP ASSAYED AND HPLC PROFILED FEED GRADE AND WATER SOLUBLE

50 AGRIaccess Current NutritIon Technology Exponents MAKE THE MOST OUT OF FEED!