ࡱ> wyvY GbjbjWW ۻ==QC1]NNNNNNN(*F?o$ ^NHNNHHH"NNNNNNHfHNN$~&" OHES Newsletter 1/99 EDITORIAL Manganese - the Essential Element Manganese has been frequently described as both the abundant and the essential element given its widespread occurrence on all the continents and on the ocean-bed; its vital role in providing high strength and toughness to steels and, in complete contrast, its crucial role in maintaining good human health at all stages of life. This particular edition of the newsletter is devoted to a review of the problems posed by the apparent confusion existing between different branches of US regulatory authorities when the essential nature of manganese in maintaining good health is contrasted with the suggestion of possible adverse effects of excessive manganese intake. As Professor Greger makes clear, the heart of the problem lies in the failure of two groups with differing viewpoints on the standards to be defined, to consult each other and to find a common basis for action. This situation is elegantly described as "incongruent". The tabulation of the various dietary sources of manganese and the wide variation of the relative concentration of manganese in various foodstuffs provides a new insight for observers of the manganese scene. In addition, many of the vitamin supplements, which are recommended to the public as part of a widespread effort to encourage greater personal responsibility for the maintenance of good health, also contain specific additives of manganese, together with the oligo-elements. The article points out that there is a specific need for the development of better biomarkers which can provide unequivocal evidence for both the state of manganese deficiency and that of excessive exposure. Armed with such biomarkers, and combined with modern scanning techniques, it should be possible for clinicians to provide accurate data from which valid standards can be formulated. Such efforts would provide the sound scientific evidence, acceptable to all concerned parties, on which regulators can legitimately base their proposals. IMnI warmly approved these initiatives and looks forward to the development of this fascinating area of nutritional science. A recent positive development regarding a Canadian government decision to lift a ban on the use of an organic manganese-containing compound in fuel is also reported in this edition. IMnI is taking a positive and pro-active stance in preparing information dossiers on various aspects of manganese usage and the possible impact of these applications on human health and the environment. We believe that regulations based on the best available and scientifically sound information provide a framework within which industry can successfully operate. These dossiers will provide working tools for industry, enabling them to have access to best developed practices and to maintain a sensible dialogue with the relevant authorities. Our annual conference in Biarritz in June this year will provide the occasion for presenting these tools to our members. V. Trelut, Chairman, OHES Committee/ C.D. DesForges, Executive Director January 1999 WHY IS THERE CONFUSION ABOUT NUTRITIONAL AND TOXICOLOGICAL STANDARDS FOR MANGANESE ? Nutritional and Toxicological Standards for Manganese Nutritionists and toxicologists in the past established standards defining deficient or toxic oral intakes of nutrients with little consultation of each other. Differences in how the two groups define standards (Table 1) and limited data have resulted in incongruent nutritional and toxicological standards for manganese. The Food and Nutrition Board of the National Research Council in 1989, in the absence of good biomarkers did not establish a Recommended Dietary Allowance (RDA) for manganese. Instead they based the Estimated Safe and Adequate Daily Dietary Allowance (ESADDII) for manganese on typical  intakes of manganese and data from short-term balance studies. The ESADDI for manganese is 2-5 mg Mn/day. The US Environmental Protection Agency (US EPA) used an estimate of manganese levels in vegetarian diets to calculate the Reference Dose (RfD) for manganese in food. The RfD for manganese in food is 0.14 mg Mn/kg x day or 10 mg Mn/day for a 70-kg individual. In contrast, the EPA employed data from a Greek epidemiological study to calculate the RfD for manganese in water based on the observation of more neurological symptoms in individuals over 50 years of age who lived in areas in which drinking water contained 1.8-2.3 mg Mn/L. Assuming that a 70-kg individual would consume 2 L of water daily, the EPA calculated the LOAEL for water to be 4.2 mg Mn/d (0.06 mg Mn/kg x day).  Table 1: Definitions of US Nutritional & Toxicological StandardsRecommended Dietary Allowance (RDA)Levels of intake of nutrients that are judged by the Food and Nutrition Board of the National Research Council (NRC) to be adequate to meet the nutritional needs of practically all (ie, 97-98%) healthy personsEstimated Safe & Adequate Daily Dietary Intake (ESADDI)Ranges of intake of nutrients that are judged by the Food and Nutrition Board of the NRC to be safe and adequate but for which there were insufficient data to estimate an RDA in 1989.Lowest Observed Adverse Effect Level (LOAEL)Lowest exposure at which statistically or biologically significant increases in the frequency or severity of adverse effects is seen between the exposed population and its appropriate control group.Reference Dose (RfD)Amount of daily exposure to a substance by a human population that is likely to have no appreciable deleterious effects during a lifetime as judged by the Environmental Protection Agency (EPA). An RfD is calculated as: RfD = LOAEL/(UF x MF) UF (uncertainty factor) reflects how sure experts are that the experimental data are applicable to practical situations; 10 is often used. MF (modifying factor) is generally 1 These standards could thus be interpreted to mean that an individual consuming a "safe" amount of manganese in diet (5 mg/day) would be in danger of "excessive" exposure to manganese (>4.2 mg/day) if most of the manganese came from water. Incongruent standards of this sort can lead to bad policy decisions in regard to toxic clean-up and food fortification. Oral Manganese Exposure Recommending optimal intakes of manganese is difficult because scientists are not sure of typical manganese intakes. Various surveys showed that adults eating Western-type diets consumed from 0.7 to 10.9 mg Mn/day. The variations in manganese intake primarily reflected differences in food choices. Major sources of dietary manganese are whole grains, nuts, legumes, and tea. (Table 2). Residents in some areas may consume as much as an additional 5 mg Mn/day in water. Until recently, dietary supplements were not a major source of manganese.  Table 2: Dietary Sources of Manganeseg Mn/gAnimal ProductsBeef, ground & cooked0.14Cheese, cheddar0.29Eggs, scrambled0.25Ham, canned0.17Milk, whole or skim0.04Tuna, canned0.15Legumes & NutsBean, pinto & lima, cooked5.1-6.0*Peanut butter18.2*Peas, green, boiled2.8Pecans46.8*Grain ProductsBread, rye8.9Bread, white enriched4.6Bread, whole wheat20.6*Oatmeal, cooked9.3*Rice, white, cooked5.9*Fruits & VegetablesApple, raw0.32Banana, raw2.2Beans, snap, boiled3.1Broccoli, cauliflower & corn, boiled1.2-1.8Pineapple, canned10.4*Potato, peeled & boiled1.3Spinach, cooked5.3*Sweet potato, baked in skin6.6*Tomato, raw0.9OtherBeer0.09Candy, milk chocolate3.4Coffee, regular beverage0.34Soda0.01Tea, beverage2.1* * Provides more than 0.5 mg Mn per standard serving Now many commercially available "1-a-day" vitamin and mineral supplements provide 1-5 mg Mn daily if taken as directed. Scientific Basis for Assessing Oral Manganese Exposure Manganese excretion and balance Inadequate knowledge of manganese metabolism limits the ability of scientists to set standards. For example, data from human metabolic balance studies are insufficient to define manganese requirements. In carefully controlled, short-term metabolic studies, human subjects achieved positive balances in regard to manganese when fed diets containing 2.5 to 15.0 mg Mn/day and achieved negative balances when fed diets containing 0.01 to 13.9 mg Mn/day. The wide range of manganese intakes at which negative manganese balances were achieved reflected a number of factors, including past manganese intakes of subjects and dietary levels of calcium, phosphorus, iron and phytate. Similarly, neither urinary nor biliary excretion of manganese appeared to be good indications of long-term manganese exposure. Metabolic studies have provided some useful insights, however. Based on isotope studies, it has been estimated that adult humans absorbed 5.9% of ingested manganese, but variations among subjects were large. Growing rats can absorb 8.7% of their manganese intake but lose 37% of the absorbed manganese through gut secretions, with biliary manganese levels being significantly elevated 1-hour after an oral dose of manganese. Thus animals appear to be protected against manganese toxicity - primarily by low absorption and/or rapid elimination of manganese by the liver. Tissue manganese concentrations Tissue manganese levels are the most used biomarkers of manganese exposure because manganese concentrations in the tissues of laboratory animals have been found to be sensitive to both low and high intakes of manganese. Women had elevated serum manganese concentrations after consuming 15 mg supplemental Mn daily for 25 days. Animals and humans are especially sensitive to high levels of manganese exposure if the manganese is provided by parenteral solutions and/or if liver function or biliary secretion is impaired. However, serum manganese concentrations are not perfect biomarkers, as it has been found that blood manganese concentrations were not elevated among subjects exposed to elevated levels of manganese in water, even though the subjects exhibited an increased number of neurological symptoms possibly related to excessive manganese intake. What are the symptoms of manganese deficiency and toxicity Another limitation faced by experts trying to establish optimal exposures to manganese is that the levels of oral intake of manganese associated with adverse effects (both deficient and toxic) are debatable. Many of the symptoms of manganese deficiency, for example, growth depression, reproductive failure, reduced blood HDL cholesterol levels, and impaired glucose tolerance, are not specific to manganese deficiency. Skeletal abnormalities in livestock (characterised by enlarged joints, deformed legs, and lameness) are fairly unique to manganese deficiency but have not been recognised in humans. Typical responses (eg, growth depression, reproductive failure, and anaemia) to chronic oral exposure to excess manganese are also not specific. The consequences of chronic inhalation of excess manganese, observed in some manganese miners, include a severe psychiatric disorder resembling schizophrenia and irreversible neurological disorder resembling Parkinson's Disease. Early neurological responses to excess manganese exposure are less specific, including hyperirritability, inco-ordination, and altered responses to a battery of neurofunctional tests. The most specific early signs of excess manganese exposure appears to be high intensity signals from the globus pallidus region of the human brain, in T-1 weighted magnetic resonance imaging (MRI) scans of brains. Patients infused with manganese-supplemented parenteral solutions and/or patients with compromised liver or biliary function and at least one arc welder, with long-term exposure to high levels of atmospheric aluminium, have displayed similar changes in MRI scans. The abnormal imaging was reduced after manganese was removed from the parenteral solutions in several cases. How can we measure the presence of manganese in humans One group of biomarkers that might indicate the beneficial effects of manganese is the activity of manganese-dependent enzymes. Unfortunately, most manganese-activated enzymes are not reduced during manganese deficiency. Two specific enzymes, glycosyl-transferases and xylosyltransferases, may be the exception. Monitoring nutritional status in regard to manganese of osteoporotic women using these enzymes as biomarkers, would be interesting. It has been observed that women showed less spinal bone loss when calcium supplements were fortified with manganese, zinc and copper. Research to improve how these enzymes are measured is necessary. Two manganese metalloenzymes (arginase and mitochondrial superoxide dismutase (MnSOD)) have some potential as biomarkers of manganese exposure. Arginase activity has been found to be reduced in the livers of manganese-deficient rats, but its usefulness as a biomarker in clinical situations is debatable because it can be affected by a variety of  factors, for example, diabetes, liver disease, ingestion of a high protein diet. MnSOD is not an ideal biomarker either, but appears to be sensitive to a range of manganese intakes. MnSOD activity is usually depressed in the hearts and often the livers of manganese-deficient rats. This reduction in MnSOD activity in the hearts of rats has been related to increased oxidative damage in their heart mitochondrial membranes. The activity of MnSOD in lymphocytes of young women were sensitive to moderate supplements (15 mg Mn/day for 90 days). Unfortunately, MnSOD activity can be affected by a variety of factors that induce oxidative stress (ethanol, interleukin-1, tumour necrosis factor, and ingestion of high levels of polyunsaturated fatty acids). Conclusions Defining nutritional and toxicological standards for manganese is problematic because there are no perfect biomarkers for assessing inadequate or excessive manganese exposure. However, serum manganese concentrations in combination with lymphocyte MnSOD activity, appear to be the best way to monitor insufficient manganese intake. Serum manganese concentrations in combination with brain MRI scans appear to be the best way to monitor excessive exposure to manganese The use of these biomarkers in clinical studies and epidemiological studies, in which manganese exposure from food, water, pharmaceuticals, and air is measured carefully, should yield the type of data needed to formulate valid standards. This research would be of great value to all concerned parties. ( Professor Janet Greger Department of Nutritional Sciences University of Wisconsin, USA fax +1 608 262 5860 A list of references on this subject can be obtained from IMnI secretariat. Good News for MMT The following article appeared in the Chemetals Newsletter in 1998 : "In July, the Canadian government announced an end to the ban it had imposed only last year on the gasoline additive methylcyclopentadienyl manga-nese tricarbonyl (MMT). The government said it did not have the scientific evidence to back claims made by automakers that MMT can gum up the onboard diagnostic systems that control car emissions, nor to back up claims that MMT poses hazards to human health. The government will pay Ethyl US$13 million for lost profits and costs, and Ethyl is to drop its suit against Canada in consequence. Ethyl's subsidiary, Ethyl Canada, was the sole importer and manufacturer of MMT in Canada." Ethyl had sued the government under the North American Free Trade Agreement, which links the United States, Canada and Mexico. Four provinces led by Alberta had also challenged the ban under Canada's Agreement on Internal Trade (AIT), designed to promote commerce between provinces. Environment Minister Christine Stewart said the government would nonetheless review studies that are under way now, and if they proved health or environmental risks, MMT would be banned under environmental law. The use of MMT in the United States has been permitted since 1995 after a U.S. Court of Appeals found there was no basis for an Environmental Protection Agency ban. It is worth noting that an absolute ban on the use of lead in petrol in Europe comes into effect in 2000. MMT will be one of the candidate materials to take its place as a fuel additive. IMnI ANNUAL CONFERENCE - JUNE 1999 The Board of IMnI at a meeting held in Paris on January 20, approved the draft content of the OHES sessions which will form an integral part of the Annual Conference/General Assembly to be held in Biarritz from June 9-12, 1999. The IMnI Chairman Graeme Hunt and Chairman-elect Jos-Antonio Rivero wish to encourage all members to attend these sessions which will deal with the challenges facing our industry in the years to come. C.D. DesForges / Executive Director January 1999 Copyright 1999 No part of this publication may be reproduced in any form whatsoever without obtaining IMnI's prior written consent. 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