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The Safe Use of Nutritional Supplements April 2011 Dr Alan Stewart MRCP www. stewartnutrition. The Safe Use of Nutritional Supplements April 2011 Dr Alan Stewart MRCP www. stewartnutrition. co. uk

Are Nutritional Supplements always Safe? • Supplements of vitamins, minerals and other nutrients are Are Nutritional Supplements always Safe? • Supplements of vitamins, minerals and other nutrients are taken by 40% of UK adults • Studies involving high dose supplements or their prolonged use have revealed adverse effects • The risks of supplement use need to be more well known • Practitioners and the supplement industry need to address the issue of supplement safety

Nutritional Supplements: Responsibilities • Safety is central to FSA, DEFRA, EFSA & Do. H Nutritional Supplements: Responsibilities • Safety is central to FSA, DEFRA, EFSA & Do. H policies Food Standards Agency is responsible for food supplements • Professional and Authorizing Bodies Training of nutritionists is overseen by the National Occupation Standards, Nutritional Therapy Council and British Association for Applied Nutrition & Nutritional Therapy who set standards for training and practice • UK Supplement Industry – formulation, manufacture & marketing Health Food Manufacturers’ Association www. hfma. co. uk “ To promote high standards of product manufacture and presentation to ensure consumer safety. . ” Council for Responsible Nutrition UK www. crn. org. uk “members all agree to abide by voluntary quality standards to ensure consumer safety and confidence. ” • Medicines Health Regulatory Authority Accepts reports of adverse reactions to nutritional supplements

Nutritionists Training and Safety Standards • National Occupation Standards for Nutritional Therapy CNH 8. Nutritionists Training and Safety Standards • National Occupation Standards for Nutritional Therapy CNH 8. Knowledge and Understanding “ 16. ways in which individual safety may be compromised by inappropriate treatment and how to minimise such risks “ https: //tools. skillsforhealth. org. uk/competence/show/html/id/2805/ • Nutritional Therapy Council Core Curriculum for accredited nutrition courses. 2. 1. 3 Micronutrients (L 3 -7) “ 4. Explain the signs and symptoms associated with micronutrient/ orthomolecular compound deficiency, imbalance and toxicity. ” 2. 2. 2 Treatment and Scope of Methods of Nutritional Therapy “ 3. Discuss the purpose, range and limitations of different methods of nutritional therapy” • British Association for Applied Nutrition & Nutritional Therapy Mission statement. “ 2. Promote high standards of education, training, practice and integrity in the nutrition profession”

Distribution of Nutrient Requirements Assumes a Gaussian (normal) distribution Dietary Reference Values: Dept of Distribution of Nutrient Requirements Assumes a Gaussian (normal) distribution Dietary Reference Values: Dept of Health 1991 • LRNI “An amount enough for only the few people in a group who have low needs” • EAR “About half will usually need more than the EAR and half less” • RNI “An amount of the nutrient that is enough, or more than enough, for about 97% of people in a group”

Nutrient Intake and Risk to Health WHO Vitamin and Mineral Requirements in Human Nutrition Nutrient Intake and Risk to Health WHO Vitamin and Mineral Requirements in Human Nutrition 2004 • • EAR Estimated Average Requirement RNI Recommended Nutrient Intake LRNI Lower Reference Nutrient Intake an amount enough for only a small % of population UL Tolerable Upper Intake Level at which no evidence of toxicity is demonstrable

Paracelsus: the Father of Toxicology Theophrastus Phillipus Auroleus Bombastus von Hohenheim 1493 -1541 • Paracelsus: the Father of Toxicology Theophrastus Phillipus Auroleus Bombastus von Hohenheim 1493 -1541 • “All things are poison and nothing is without poison: only the dose makes a thing a poison. ” • “Alle Dinge sind Gift und nichts ist ohne Gift: allein die Dosis macht, das ein Ding kein Gift ist. ”

Use of Nutritional Supplements in UK National Diet and Nutrition Surveys • • • Use of Nutritional Supplements in UK National Diet and Nutrition Surveys • • • Supplement categories are reported with slight differences between surveys Females are usually bigger consumers of supplements than males Most iron and multivitamins with iron are consumed equally by females and males

Proportion of Adult Males with low Intakes from Food, and Food + Supplements < Proportion of Adult Males with low Intakes from Food, and Food + Supplements < LRNI

Proportion of Adult Females with low Intakes from Food, and Food + Supplements < Proportion of Adult Females with low Intakes from Food, and Food + Supplements < LRNI

How Do Nutritional Deficiencies Develop? Adapted from Brin M. Journal of the American Medical How Do Nutritional Deficiencies Develop? Adapted from Brin M. Journal of the American Medical Association 1964; 187: 762 -766 • State of Adequacy • State of Negative Balance: 1. Poor Intake 2. Reduced absorption 3. Increased losses 4. Increased requirement 5. Altered metabolism – illness, alcohol, drugs, toxins, genetics • Decline in Tissue Stores • Loss of Function: 1. Symptoms 2. Physical Signs 3. Organ Failure • Death

How the Two Forms of Malnutrition Develop Deficiency Excess • State of Adequacy • How the Two Forms of Malnutrition Develop Deficiency Excess • State of Adequacy • State of Negative Balance: • State of Positive Balance: • Decline in Tissue Stores • Increase in Tissue Stores • Loss of Function: • Death 1. Poor Intake 2. Reduced absorption 3. Increased losses 4. Increased requirement 5. Altered metabolism illness, alcohol, drugs, genetics 1. Symptoms 2. Physical Signs 3. Organ Failure 1. Increased Intake 2. Increased absorption 3. Reduced losses 4. Reduced requirement 5. Altered metabolism illness, alcohol, drugs, genetics increased sensitivity to nutrient 1. Symptoms 2. Physical Signs 3. Organ Failure

Risk Methodology and Supplement Safety Adapted from FAO/WHO Environmental Health Criteria 240 (2009) and Risk Methodology and Supplement Safety Adapted from FAO/WHO Environmental Health Criteria 240 (2009) and 1995/1997/1998 www. fao. org/docrep/008/ae 922 e 03. htm 2. Risk Communication 1. Risk Assessment 3. Risk Management

Risk Methodology and Supplement Safety Adapted from FAO/WHO Environmental Health Criteria 240 (2009) and Risk Methodology and Supplement Safety Adapted from FAO/WHO Environmental Health Criteria 240 (2009) and 1995/1997/1998 www. fao. org/docrep/008/ae 922 e 03. htm 2. Risk Communication Patient Professionals Authorities Industry Public 1. Risk Assessment 3. Risk Management Possible Adverse Effects Dose-Response Effect Exposure Assessment Modifying Factors Policy Options Accept/ Minimize/Remove Implement Options Monitor and Review

Methodology: 1. Risk Assessment • Possible Adverse Effects Expert reports, data from trials, case Methodology: 1. Risk Assessment • Possible Adverse Effects Expert reports, data from trials, case reports US Supplements Label Database • Dose-Response Effect Data mainly from trials and epidemiological data • Exposure Assessment Sources – food, supplements, water, industrial etc. . UK National Diet and Nutrition Surveys, UK Committee on Toxicity – intakes from all sources • Modifying Factors Age, smoking, asbestos, alcohol, disease of excretory organs – liver and kidney, drugs, genetic factors etc…

Major Reports on Supplement Safety • Safe Upper Levels for Vitamins and Minerals Expert Major Reports on Supplement Safety • Safe Upper Levels for Vitamins and Minerals Expert Group on Vitamins and Minerals, FSA Safe Upper Levels and Guidance Levels May 2003 www. food. gov. uk/multimedia/pdfs/vitmin 2003. pdf • Review of Dietary Advice on Vitamin A Scientific Advisory Committee on Nutrition Sept 2005 http: //www. sacn. gov. uk/pdfs/sacn_vita_report. pdf http: //www. sacn. gov. uk/pdfs/Vitamin_A_Report_and_Annexes. pdf • Tolerable Upper Intake Levels for Vitamins and Minerals Scientific Committee on Food, European Food Safety Authority Feb 2006 http: //europa. eu. int/comm/food/fc/sc/scf/index_en. html • Mortality in Randomized Trials of Antioxidant Supplements for Primary and Secondary Prevention Bjelakovic G et al JAMA. 2007; 297: 842 -857 Mar 2007 www. cochrane. org/reviews/en/ab 007176. html • Dietary Reference Intakes (and ULs) Book (+ Tolerable Upper Intake Levels) Otten JJ et al Institute of Medicine http: //www. nap. edu/catalog/11537. html 2006

UK Expert Group on Vitamins and Minerals 2003 • Safe Upper Levels, SULs derived UK Expert Group on Vitamins and Minerals 2003 • Safe Upper Levels, SULs derived from human data 8 • Guidance Levels, GLs 22 derived from animal/incomplete human data • Based on a 60 kg female • “. . are the doses of vitamins and minerals that susceptible individuals could take daily on a life-long basis, without medical supervision. ” • Total Safe Intakes = food + water + supplements for retinol and some trace elements

Defining a Toxic Intake Levels usually derived from population intake, case reports or trial Defining a Toxic Intake Levels usually derived from population intake, case reports or trial data • NOAEL/LOAEL: No/Lowest Observed Adverse Effect Level • Tolerable Upper Intake Level (UL) = NOAEL/LOAEL/Uncertainty Factor

Setting Safe Upper Levels Hathcock J, Shao A. J. Nutr. 2008; 138: 1992 S-1995 Setting Safe Upper Levels Hathcock J, Shao A. J. Nutr. 2008; 138: 1992 S-1995 S Tolerable Upper Intake Level (UL) = NOAEL/LOAEL Uncertainty Factor, UF Uncertainty Factors selected by Institute of Medicine • Manganese = 1 • Vitamin D = 1. 2 • Vitamin A and Zinc = 1. 5 • Selenium and vitamin B 6 = 2 • Folic acid = 5 • Vitamin E = 36

Definitions of Safe Levels • UK Safe Upper Levels (SULs) Guidance Levels (GLs) “are Definitions of Safe Levels • UK Safe Upper Levels (SULs) Guidance Levels (GLs) “are the doses of vitamins and minerals that susceptible individuals could take daily on a life-long basis, without medical supervision. ” Single figure, applies to adults only, based on 60 kg female Total Safe Intakes (TSIs) are set for retinol and some trace elements • US Tolerable Upper Intake Levels (ULs) Range of figures depending upon age and sex “is the highest average daily nutrient intake level likely to pose no risk of adverse effects for nearly all people in a particular group” Based on total intake from food, water and supplements • EU Tolerable Upper Intake Level (UL) “the maximum level of total chronic daily intake of a nutrient (from all sources) judged to be unlikely to pose a risk of adverse effects”. ULs vary with age and sex and exclude “those under medical supervision and certain disease states” but includes “sensitive individuals”

Adverse Nutrient Reactions: Classification • Acute Toxicity Minor – gastrointestinal upset – Mg, Fe, Adverse Nutrient Reactions: Classification • Acute Toxicity Minor – gastrointestinal upset – Mg, Fe, Zn, Severe – large amounts of vitamins A, D, C • Chronic Toxicity Osteoporosis – vitamin A Nervous system – vitamin B 6, Mn, Cu Liver disease – Fe, Cu, vitamin A, beta-carotene Metabolic Effects – hypercalcaemia, renal stones, induced deficiency • Cancer Induction – antioxidants may act as pro-oxidant Growth Rate – zinc, vitamins A and B • Adverse Pregnancy Effects Fetal development/growth – Fe, vitamins A, C and E • Minor and Idiosyncratic Adverse Effects Dermatological – beta-carotene, vitamin B 12, n-3 EFAs and others

Sources of Nutrients • Food and Beverages All nutrients • Fortified Foods Vits A, Sources of Nutrients • Food and Beverages All nutrients • Fortified Foods Vits A, D, E, C, B group, Ca, Fe and a few trace elements • Supplements All nutrients • Water Mains supply – Ca, Mg, Cu, Bottled – Mg, Na Non-mains supply – Ca, Mg, Cu, Fe and Mn • Air and Industrial Exposure Mn (60, 000 with exposure in UK – HSE estimate) Other trace elements • Drugs and Other Iodine (disinfectants, amiodarone, thyroxine) Ca/Mg (antacids), Cu (bracelet), Zn (dental fixative) Retinol (dermatological preparations), vit K (mouth wash)

UK Population Exposure Assessment The National Diet and Nutrition Surveys • Four surveys covering UK Population Exposure Assessment The National Diet and Nutrition Surveys • Four surveys covering ages 1. 5 yrs to >85 yrs • Random samples of the British population with approximately 2, 000 subjects in each. The very ill, pregnant women and those of no fixed abode were not included • Field-work conducted between 1990 and 2001 • Collected information on: - 4 -7 day weighed dietary intakes - supplement and drug use - laboratory measures of nutrient status - alcohol intake and smoking - tests of liver and kidney function (elderly only) - BP and BMI • The surveys provide detailed information about the prevalence of nutritional deficiencies and excess and some of the associated risk factors

Supplement Safety: Nutrients of Greatest Concern Percentage Contribution to Total Intake from Supplements: NDNS Supplement Safety: Nutrients of Greatest Concern Percentage Contribution to Total Intake from Supplements: NDNS data • The above are the nutrients most likely to be associated with a variety of adverse effects. No intake data on selenium

Nutrients of Concern and Recommendations for Safe Daily Intakes HFMA UK FSA UK Holford Nutrients of Concern and Recommendations for Safe Daily Intakes HFMA UK FSA UK Holford EFSA EU US Io. M 1997 2003 2004 2005/9 2006 Retinol ug (TSI) /F>50 2300 800 (1500) 15, 000 (3000/1500) (3000) Retinol ug Pregnancy None Nutrient Beta-carotene mg [smokers/asbestos] 20 Vitamin C mg Selenium ug (TSI) (3000) 7 [Avoid] ? 2000 1000 5000 200 350 500 300 (400) Manganese mg (TSI) 15 4. 0 (12. 2) 50 (11) Mn >50 yrs (TSI) 0. 5 (8. 7) No recommendation 2 5 (10) Copper mg ( TSI) 5 1 (10) Zinc mg (TSI) 10 [Avoid ] (2000) 25 Vitamin B 6 mg (TSI) No conclusion 40 100? (100) Folic Acid ug 400 1000 ? 1000 (1000) Thiamin mg 100 120 No limit None set

Use of Nutritional Supplements in UK National Diet and Nutrition Surveys • • • Use of Nutritional Supplements in UK National Diet and Nutrition Surveys • • • Supplement categories are reported with slight differences between surveys Females are usually bigger consumers of supplements than males Most iron and multivitamins with iron are consumed equally by females and males

Safety of Vitamin A: SACN Sept 2005 • Total Safe Intake, TSI 1500 ug/day Safety of Vitamin A: SACN Sept 2005 • Total Safe Intake, TSI 1500 ug/day • UK adult diet provides on average 700 ug/day • Supplements should usually be limited to 800 ug/day none in pregnancy • % population intakes >TSI - adults (19 -64 yrs) M 9%, F 4% - elderly (65+ yrs) M 11%, F 10% • High intakes can occur from: - food – liver, very high dairy - supplements multivitamins and cod liver oil

Safety of Vitamin A: SACN Sept 2005 • Acute Toxicity: – rare >50, 000 Safety of Vitamin A: SACN Sept 2005 • Acute Toxicity: – rare >50, 000 ug/day - liver failure, death • Chronic Toxicity: - pregnancy (limb deformity) - osteoporosis - hair loss, dry skin - hypercalcaemia • Recommendations to: - Farming Industry - Food Supplement Industry • Supplement Industry: - overages of <30 -65% according to CRN/HFMA - only 50% of cooperated in a subsequent survey

Reported Retinol content of Liver in UK Publications Mon Manual of Nutrition HMSO, Co. Reported Retinol content of Liver in UK Publications Mon Manual of Nutrition HMSO, Co. F Composition of Foods HMSO/RSC

Retinol Content of Supplements Safe Upper Level 800 ug/day • • • Cod Liver Retinol Content of Supplements Safe Upper Level 800 ug/day • • • Cod Liver Oil 10 mls 1, 800 ug Holford Multivitamin 1, 200 ug Health. Span Multi 50+ 1, 000 ug H and B ABC Plus Senior 1, 050 ug Solgar Solovit 750 ug Biocare Adult Multi Vit+Mins 600 ug • • Continental Multivitamins Solgar Multivitamins – many Seven Seas Premium CLO in Norway reduced by None 70%

Retinol Status of the British Population (estimates) Plasma Retinol Levels NDNS Data Collected 1990 Retinol Status of the British Population (estimates) Plasma Retinol Levels NDNS Data Collected 1990 -2001

Serum Retinol and the Risk of Fracture [Swedish men aged 49 -51 yrs, 30 Serum Retinol and the Risk of Fracture [Swedish men aged 49 -51 yrs, 30 year cohort study] Michaelsson K et al NEJM 2003: 348: 287 -294 Dark line = mean and 95% CIs

Retinol Intake and Fracture Feskanich D et al. JAMA 2002; 287: 47 -54 • Retinol Intake and Fracture Feskanich D et al. JAMA 2002; 287: 47 -54 • Nurses’ Health Study in the USA • 72, 337 predominantly white postmenopausal women 18 yr follow-up • High intakes of retinol >2000 ug/day vs <500 ug/day; fracture RR 1. 89; 95% CI 1. 33 to 2. 68

Serum Vitamin A and Hip Fracture. NHANES I prospective analysis of follow-up data Opotowsky Serum Vitamin A and Hip Fracture. NHANES I prospective analysis of follow-up data Opotowsky et al Am J Med 2004; 117(3): 169 -74 • 2799 women age 50 -74 years in the US • No linear relationship between serum retinol and risk of hip fracture • Fracture risk was increased in the: lowest quintile – HR 1. 9 (95% CI: 1. 1 -3. 3) highest quintile – HR 2. 1 (95% CI: 1. 2 -3. 6) • Both low and high serum retinol may be associated with an increased risk

Serum Retinoids and Beta-Carotene as Predictors of Hip and Other Fractures in Elderly Women Serum Retinoids and Beta-Carotene as Predictors of Hip and Other Fractures in Elderly Women Barker et al J Bone Miner Res 2005; 20: 913 -920 • Prospective study of 2606 British women median age 75 years followed up for a median duration of 3. 7 years • Subjects were part of a bisphonate trial • 312 incident osteoporotic fractures and 92 incident hip fractures • The risk of osteoporotic fracture was slightly less in the highest quartile of serum retinol • Multivitamin or cod liver oil use was associated with a significantly lower risk of any fracture • “We suggest that there is not sufficient evidence to support the elimination of retinol supplements or restriction of dietary intake of pre-formed retinol or beta-carotene on the basis of skeletal risk” • However, this was not a representative survey ……

Barker et al study comparison with NDNS population Barker et al J Bone Miner Barker et al study comparison with NDNS population Barker et al J Bone Miner Res 2005; 20: 913 -920 • Subject exclusion criteria: hypocalcaemia neutropenia abnormal LFTs renal impairment • Serum retinol and 25(OH)D correlated r = 0. 12, p <0. 001 • * Weight difference cases vs controls (p <0. 01) • Conclusion: CLO/Multivitamins are safe in elderly women if – none of the above and not overweight/obese i. e. non-normal population • However many will have an increased risk as they age Parameter Mean 95% CIs Cases 61. 7* 60. 6 -62. 9 Controls 65. 4* 64. 6 -66. 1 NDNS 65 -84 yrs 65. 5 43. 0 -91. 0 Cases 1. 95 1. 88 -2. 02 Controls 2. 00 1. 96 -2. 05 NDNS 65 -84 yrs 2. 20 1. 2 -3. 5 Cases 40. 0 38. 3 -42. 0 Controls 41. 9 40. 8 -43. 0 NDNS 65 -84 yrs 52. 5 15. 0 -110. 0 Weight kg Serum/plasma Retinol umol/l Serum/plasma 25(OH) vit. D nmol/l

Renal Function and Plasma Retinol: NDNS 65+ Correlation between deteriorating renal function and plasma Renal Function and Plasma Retinol: NDNS 65+ Correlation between deteriorating renal function and plasma retinol

How Common are Abnormal Liver Function Tests? NDNS 65+ Prevalence: Plasma Alkaline Phosphatase >110 How Common are Abnormal Liver Function Tests? NDNS 65+ Prevalence: Plasma Alkaline Phosphatase >110 IU/L Plasma Gamma-Glutamyl Transferase >50/32 IU/L • Abnormal LFTs may occur in 10% - 30% of UK adults • Common causes: - Alcohol excess - Obesity - NAFLD - Hepatitis B and C - Drug-induced - Auto-immune liver disease • Elevated Alkaline Phosphatase - cholestatic liver disease - increased mortality • Elevated Gamma GT - usually alcohol excess • Abnormal LFTS - potential accumulation Mn, Cu - altered vitamin A status - reduced 25(OH) vit. D

Retinol: Liver Disease • Reduced Hepatic Content in Liver Disease Leo and Lieber. NEJM Retinol: Liver Disease • Reduced Hepatic Content in Liver Disease Leo and Lieber. NEJM 1982; 307: 597 -601 • Elevated Plasma Retinol with high Alcohol Intake 20% increase in plasma DNSBA 1989 • Supplements Increase Plasma (Liver) Alkaline Phosphatase Use of 7, 576 ug/day for 3. 8 yrs was associated with a 7% increase Cartmel B et al AJCN 1999; 69: 937 -43 • Liver Damage with High Doses >15, 000 ug/day Sheth A et al J Am Diet Assoc 2008; 108(9) 1536 -7 • Hepatitis C - Poorer Response to Interferon in those with high total intake of retinol Loguerico C et al Am J Gastro. 2008; 103(12) 3159 -3166

Hepatic Vitamin A content and Liver Disease Leo and Lieber 1982 Hepatic Vitamin A content and Liver Disease Leo and Lieber 1982

Vitamin A: Liver Disease and Alcohol DNSBA 1989 alcohol consumption and plasma retinol in Vitamin A: Liver Disease and Alcohol DNSBA 1989 alcohol consumption and plasma retinol in British Adults

Effect of 21 day Alcohol Abstinence and Supplement Programme on Vitamin A and Carotenoids Effect of 21 day Alcohol Abstinence and Supplement Programme on Vitamin A and Carotenoids (serum levels umol/l) Geugeun S et al JACN 2003, 22(4): 303 -310. 106 Alcoholic French subjects. Supplement: beta-carotene 6 mg, Vitamin C 120 mg, Vitamin E 30 mg, Zinc 20 mg, Selenium 100 ug

Elevated Serum Vitamin A and Metabolic Syndrome Graham T et al NEJM 2006; 354: Elevated Serum Vitamin A and Metabolic Syndrome Graham T et al NEJM 2006; 354: 2552 -2563 • Retinol Binding Protein transports retinol and thyroxine • Produced by the liver, choroid plexus and adipose tissue • RBP 4 is produced by adipocytes and is the main carrier protein for retinol in serum • Elevated RBP 4 is associated with abdominal obesity, raised TG levels, decreased HDL levels and systolic hypertension • Serum RBP 4 correlates with insulin resistance in obese and pre-diabetic subjects • Serum RBP 4 and serum retinol levels are moderately correlated

Diet and Response of Hepatitis C to Interferon Loguerico C et al Am J Diet and Response of Hepatitis C to Interferon Loguerico C et al Am J Gastro 2008; 103: 3159 -3166 • The response of patients with HCV-hepatitis to standard treatment is ~60% • The response is significantly better in younger people, with early disease, who are not obese, drink less alcohol and differs with the viral genotype • The patient’s diet may also be a factor • Intake of some micronutrients may increase and others reduce the chance of successful outcome to therapy • Because multiple statistical analyses were made no firm conclusions about micronutrient intake and disease progression can (yet) be made

Diet and Response of Hepatitis C to Interferon Loguerico C et al Am J Diet and Response of Hepatitis C to Interferon Loguerico C et al Am J Gastro 2008; 103: 3159 -3166 • • • 1084 with HCV-related chronic hepatitis in Southern Italy 24 -48 wk trial Patients with HIV, HBV-hepatitis or other major illness were excluded 432 Treated with interferon + ribavarin. 246 responded; 186 didn’t respond Non-responders were likely to be >50 yrs, BMI >25 kg/m 2 and alcohol ++ 7 -day diet diaries were used to calculate nutrient intake Intakes were also compared with 2, 326 healthy blood-donor controls Nutrient Daily Intake P value Controls Responders Non-responders Respond vs Non-Respond Alcohol g 26 15 32 0. 01 Zinc mg 11. 7 13 8 0. 01 Vitamin B 3 mg 14. 4 18 11 0. 05 Iron mg 12. 4 10 17 0. 01 Vitamin A ug 730 725 1220 0. 001

Vitamin A Excess: Case Histories Pl. Retinol Age & Daily Intake: 1 -2. 8 Vitamin A Excess: Case Histories Pl. Retinol Age & Daily Intake: 1 -2. 8 umol/l Sex Supplements Presenting Problem Cause 4. 45 umol/l 83 F 800 ug More in past Headaches, severe osteoporosis, alcohol 2 u/day Self 3. 74 umol/l M 58 ~ 800 ug Renal impairment, obese, None for 4 months hypertension, alcohol 4 u/day Self 3. 04 umol/l M 63 3, 500 ug Fatigue, obesity, low alcohol Doctor 3. 5 umol/l M 60 Nil Overweight Hypercalcaemia Ate liver weekly 4. 54 umol/l M 56 Nil Overweight 107 kg, T 2 D, liver eater, alcohol+, Na valproate Multiple 3. 81 umol/l F 26 ~400 ug Cornelia De Lange, 40 kg epilepsy, Na valproate Multiple

Retinol: OC Pill, HRT and Pregnancy • The OC Pill and HRT These cause Retinol: OC Pill, HRT and Pregnancy • The OC Pill and HRT These cause a small, probably insignificant, rise in serum retinol • Pregnancy and Lactation Requirement Increases The Reference Nutrient Intake, rises from 600 ug/day to 700 ug and in lactation to 950 ug/day. A diet rich in dairy foods and vegetables should be emphasised • Retinol is needed for growth and particularly in utero and infancy for full lung and kidney development. The full consequences of deficiency in the infant might only be observed later in adult life • Pregnancy Safety CMO (1990) and SACN advise pregnant women to avoid liver and retinol supplements as an excess (3, 000 ug/day) can cause limb deformity. Beta-carotene supplements are considered to be safe. • However the pattern of vitamin A intake has changed dramatically

Vitamin A Intakes in Younger Women: Mean values ug/day Food-sourced Pre-formed Retinol • • Vitamin A Intakes in Younger Women: Mean values ug/day Food-sourced Pre-formed Retinol • • All Sources - Retinol Equiv. All Sources = retinol + carotene from diet + supplements The fall in liver and full-fat dairy consumption over the last two decades has greatly reduced the intake of pre-formed retinol especially in young women The impact of this on pregnancy and infant health is not known The rise in obesity and alcohol intake in women might influence vitamin A metabolism, requirements and the suitability and safety of supplements

Clinical Picture of Chronic Retinol Excess Positive Balance Reason or Clinical Picture Intake High Clinical Picture of Chronic Retinol Excess Positive Balance Reason or Clinical Picture Intake High from liver, fortified foods, supplements Absorption ? Increased in fast beta-carotene converters Losses Reduced in renal impairment Requirement Reduced in elderly Metabolism Reduced storage in liver disease and alcohol XS. Increased RBP 4 if obese, T 2 D or ? Na valproate. More susceptible to osteoporosis if vit D deficient Stores Increase in serum, liver and CSF levels Symptoms Headache, fatigue if hypercalcaemia Signs Raised CSF pressure, dry skin, hair loss, abnormal liver function tests, bone changes – loss of height Organ Failure Osteop. #, pregnancy deformity, ? cancer growth

Treatment of Retinol Excess/ Elevated Plasma Retinol • • • Stop high intake –supplements, Treatment of Retinol Excess/ Elevated Plasma Retinol • • • Stop high intake –supplements, foods (liver & fortified foods) Reduce weight if obese or abdominal obesity Assess liver and renal function and plasma calcium Limit alcohol if excessive or abnormal liver function tests Reduce weight if overweight especially if T 2 D or liver disease Assess osteoporosis risk and vitamin D status and treat Assess other nutrients excess or deficiency (zinc) and treat Review drug treatment (oc pill, tetracycline, sodium valproate) Advise against pregnancy Reassess after 2 -3 months

Beta-carotene and Health • A carotenoid with anti-oxidant activity; 1/6 -1/12 converted to retinol Beta-carotene and Health • A carotenoid with anti-oxidant activity; 1/6 -1/12 converted to retinol • Cleveage of ingested beta-carotene occurs by action of monooxygenase enzyme in gut wall and liver. Activity of enzyme is genetically determined and zinc is a co-factor • >5 portions of fruit and vegetables provides ~ 3. 0 mg/day Average UK intake of 2. 7 portions provides 1. 8 mg/day providing approximately 33% of male and 40% of female total vitamin A intake • Supplements of beta-carotene provide 1 -3% of total intake in adults • Plasma beta-carotene lower in smokers of both sexes and male, not female, alcohol consumers • Dietary intake and plasma level correlate negatively with risk of many cancers and heart disease • 4 Major trials of beta-carotene (ATBC, CARET, PHS, HPS) • Beta-Carotene Metabolites enhance DNA damage Possible difference between synthetic and naturally-occurring forms van Helden YG et al. Free Radic Biol Med. 2009; 46: 299 -304

Elevated Plasma Beta-carotene and Health • Plasma beta-carotene levels are higher in women than Elevated Plasma Beta-carotene and Health • Plasma beta-carotene levels are higher in women than men • Plasma levels are higher in infants and some young adult women • Plasma beta-carotene levels are lower in male alcohol consumers but slightly higher in female moderate alcohol consumers • High intake from diet or supplements can lead to: - carotenoderma (harmless - may be associated with amenorrhoea) - corneal deposition (harmless) - mild liver damage in alcoholics (supplements) - increased risks of cancer and possibly vascular disease (in trials of high-dose supplements) • Hypercarotenaemia/ carotenoderma can also be caused by: - hypothyroidism - coeliac disease - protein deficiency/malnutrition - zinc deficiency

Physicians’ Health Study USA • 22, 071 male physicians • 50% never smokers, 11% Physicians’ Health Study USA • 22, 071 male physicians • 50% never smokers, 11% current smokers • 2 x 2 factorial design • Beta-carotene 50 mg on alt. days (BASF, reduced bioavailability) and Aspirin • No effect on lung cancer or mortality • Relatively high baseline beta-carotene levels than in other trials

CARET Trial USA Omenn GS et al. JNCI 1996; 88: 1550 -59 Druesne-Pecollo N CARET Trial USA Omenn GS et al. JNCI 1996; 88: 1550 -59 Druesne-Pecollo N et al. Int J Cancer Oct 28 2009 EPub. • 18, 314 men and women 14, 254 smoking men and women, 4, 060 asbestos-exposed men • 30 mg beta-carotene and 25, 000 IU 7567 ug retinol/day • Serum beta-carotene rose from 170 ng/ml to 2100 ng/ml • Supplement group increased rates of death all causes [1. 17] lung cancer [RR 1. 46] cardiovascular disease [RR 1. 26] • Beta-carotene may increase the risk of a fatal MI Rapola et al Lancet 1997; 349: 1715 -20 • It was not possible to differentiate between the effects of retinol and beta-carotene

ATBC Trial Finland • 29, 133 male smokers; average 36 pack-years • 2 x ATBC Trial Finland • 29, 133 male smokers; average 36 pack-years • 2 x 2 factorial design • 20 mg beta-carotene/50 IU alpha-tocopherol/day for 6. 5 years • Vitamin E: no effect lung cancer [RR 0. 98] • Beta-carotene: no effect lung cancer [RR 1. 18; 95% CI 1. 03 -1. 36] and mortality [RR 1. 08; 95% CI 1. 01 -1. 16] • Risk higher in heavy smokers >20 cigs/day [RR 1. 25; CI 1. 07 -1. 46], light smokers 5 -19 cigs/day [RR 0. 97; 95% CI 0. 76 -1. 23] • Alcohol consumers (>11 g ethanol/day) increased non-small cell lung cancer • Baseline intake and serum beta-carotene were inversely related to lung cancer risk

Asbestos in the News 2008 and …. . http: //news. bbc. co. uk/today/hi/today/newsid_7700000/7700020. stm Asbestos in the News 2008 and …. . http: //news. bbc. co. uk/today/hi/today/newsid_7700000/7700020. stm • In UK >200, 000 cases of industrial asbestos-related lung disease • Presentation peaks in 2012 with: - chronic lung disease - lung cancer - mesothelioma. www. lunguk. org British Lung Foundation • Chronic low-level exposure of public sector workers, teachers, nurses and other hospital staff. BBC 30/10/2008 • Lung cancer and mesothelioma risk in those with industrial or low level exposure may be increased by supplements of retinol/betacarotene

Beta-carotene: UK Supplements • EVM (2003) set Safe Upper Level set at 7 mg Beta-carotene: UK Supplements • EVM (2003) set Safe Upper Level set at 7 mg per day “. . as a matter of prudence, smokers and those heavily exposed to asbestos should not take beta-carotene supplements. ” • Beta-Carotene (Healthspan) 15 mg/day Advice on website “most nutritionists recommend 15 mg per day for optimal health”. “There is no evidence that vitamin and mineral supplements in reasonable doses are harmful (except when smokers take large doses of beta-carotene)” no mention of asbestos Dr TS on Healthspan website, undated, (accessed 11/3/2010) • NICE (2007) Management for Post Myocardial Infarction “take no supplements containing beta-carotene” www. nice. org. uk/nicemedia/pdf/CG 48 Full. Guideline. pdf • Cardioace (Vitabiotics) 4 mg of beta-carotene/day No mention of contraindications on product page. • Beta-Carotene 15 mg/day available from many companies

Beta-carotene: US position Institute of Medicine of the National Academies 2006 “. . beta-carotene Beta-carotene: US position Institute of Medicine of the National Academies 2006 “. . beta-carotene supplements have not been shown to aid in the prevention of major chronic disease “ “ supplements are not advisable other than as a provitamin A source for the prevention and control of vitamin A deficiency in at-risk populations. ”

Treatment of Beta-Carotene Excess/ Carotenoderma • Stop supplements especially if smoker or asbestos exposed Treatment of Beta-Carotene Excess/ Carotenoderma • Stop supplements especially if smoker or asbestos exposed • Limit foods – carrots, dark green leafy vegetables, fortified foods • • • Assess liver, thyroid function and coeliac disease as appropriate Check dietary intake of protein and zinc and advise on diet Measure plasma zinc if appropriate and advise on diet/supplements Check menstrual status and ? family history of carotenoderma Limit alcohol if excessive, overweight or abnormal liver function tests Reassure patient about harmless nature especially if a young female Review drug treatment (oc pill) Reassess after 2 -3 months Very elevated levels could take >6 months to return to normal

Manganese: UK Position • • • • Adult intakes average 2. 77 – 3. Manganese: UK Position • • • • Adult intakes average 2. 77 – 3. 42 [95% CI 1. 05 -8. 11] mg/day Food sources: grains (50%), tea, beans, blackberries; supplements 3% Deficiency rare but may occur in those fed parenterally Glucosamine preparations contain 2 to 8 mg per day [34 -45 mg] GL 4. 0 mg (TSI 12. 2 mg) but 0. 5 mg (TSI 8. 7 mg) if >50 yrs 1. 03% to 4. 86% of dietary manganese is absorbed Absorption is approximately doubled in iron deficiency (low serum ferritin) or by low dietary non-haem iron and little by anaemia Absorption requires Divalent Metal Transporter, DMT 1, in the gut wall Any excess of Mn is excreted via the bile, if liver function is normal Up to 1. 5 mg of Mn may be retained per day; half-life is 12 -36 days Manganese excess in the brain can occur as a result of cholestatic liver disease and is associated with fatigue; it may not be reversible High Mn concentration in platelets ? raised in thrombocythaemia Iron deficiency and abnormal liver function are common in UK

Manganese Excess – is the UK population at risk? Committee on Toxicity (COT) of Manganese Excess – is the UK population at risk? Committee on Toxicity (COT) of Chemicals in Food, Consumer Products and the Environment: 2006 UK Total Diet Study of Metals and other Elements • Para 64. “Dietary supplements provide up to 10 mg/day, which if added to the high level dietary exposure results in a total intake of 290 ug/kg body weight/day in a 60 kg adult, representing 145% of the EVM guidance value. ” • Para 65. “The Committee concluded that there was insufficient information to determine whethere are risks associated with dietary exposure to manganese”.

Manganese: Environmental Exposure I • HSE estimate 60, 000 workers have industrial exposure: metalworkers, Manganese: Environmental Exposure I • HSE estimate 60, 000 workers have industrial exposure: metalworkers, welders, those in fertiliser and cosmetics industries • Manganese salts are used as a flux in welding, Mn fumes can cause lung inflammation, pneumonia and be absorbed resulting in neurological effects; assessed by Purdue Pegboard Test • Replacement for lead anti-knock in petrol is MMT methylcyclopentadienyl manganese tricarbonyl provides 10 mg Mn/l • Blackberries contain ~ 15 mg/kg but variable range (1 -153 mg/kg) MAFF Multi-element survey of wild edible fungi and blackberries 2000 www. food. gov. uk/multimedia/webpage/maffinfo/2000/maff/2000199 • Mn is occasionally found in well water or water/soil from mining areas and exposure to these sources can cause health problems • The Committee on Toxicity (UK) consider that Mn toxicty might be a problem in children and others, if there is increased bioavailability from some foods or beverages, or if high doses are taken www. ? ? ?

Purdue Pegboard • Developed at Purdue University • Standard test of manual dexterity assess Purdue Pegboard • Developed at Purdue University • Standard test of manual dexterity assess both hands • Used to assess workers suitability for manual tasks e. g in electronics industry • Dexterity declines with age

Manual Dexterity and Plasma Manganese/Iron Ratio? (Standardized Composite Index Purdue Pegboard) • • • Manual Dexterity and Plasma Manganese/Iron Ratio? (Standardized Composite Index Purdue Pegboard) • • • Data derived from 323 subjects; controls(106), low-exposure (122) and high exposure (95) workers in a smelting plant in China p. MIR expressed as xxx of Mn /yyy of Fe Cowan DM et al. Neurotoxicology. 2010; 30(6): 1214 -22

Manganese Toxicity: Non-Industrial Reports Neurology • Fatigue in patients with liver disease and high Manganese Toxicity: Non-Industrial Reports Neurology • Fatigue in patients with liver disease and high blood Mn and MRI changes • Neurological problems related to drinking water Mn conc. (1. 8 -2. 3 mg/l)* • High total intakes of iron and manganese increased risk of PD • Impairment of postural balance and high hair Mn (mean 4. 4 ug/g)* Fotron DM et al. Gut 2004; 53: 587 -592 Kondakis XG et al Arch Environ Health 1989; 44: 175 -8 Powers KM et al Neurology 2003; 60: 1761 -1766 Standridge JS et al J Occup Environ Med 2008; 50: 1421 -9 Reproduction • Reduced sperm motility and concentration with high blood Mn • Lower Infant Birth Wt assoc. with high (>4. 0 ug/dl) or low maternal blood Mn Wirth JJ et al Epidemiology 2007; 18: 270 Zota AR et al Epidemiology 2009; 20: 367 -73 Child Development • Reduced child intelligence and high hair Mn (Mean 471. 5 ppb)* • Reduced child intelligence and high blood Mn (1. 4 ug/l) and high blood Pb Wright RO et al Neurotoxicity 2006; 27: 210 -6 Kim Y et al Neurotoxicity 2009; 30: 564 -71 * Increased environmental exposure e. g. proximity to mining/metal works

Clinical Picture of Chronic Manganese Excess Positive Balance Reason or Clinical Picture Intake High Clinical Picture of Chronic Manganese Excess Positive Balance Reason or Clinical Picture Intake High from diet, water, supplements and industry Absorption Increased in iron deficiency Losses Reduced in cholestatic liver disease or jaundice Requirement Reduced ? in elderly Metabolism Altered in some genetically determined neurological disease Stores Increased in serum, whole blood, Globus Pallidus region of the brain Symptoms Fatigue, poor co-ordination Signs Reduced tapping speed Organ Failure Parkinson like disease, reduced sperm count, poor pregnancy outcome

Manganese: Glucosamine Supplements FSA GL 4. 0 mg/day but 0. 5 mg/day if >50 Manganese: Glucosamine Supplements FSA GL 4. 0 mg/day but 0. 5 mg/day if >50 yrs • Enzyme cofactor in cartilage • Two US trials Glucosamine plus Manganese 34 - 45 mg/day No adverse effect in young subjects over a short period Leffler CT et al Mil Med 1999; 164(2); 85 -91 Das A et al Osteoarthrits Cartilage 2000; 8(5): 343 -50 • US Cosamin DS, Mn 9. 0 mg/day • UK Gl’amine /Multis contain 1 -5 mg • High Dose Supplements Nutri many products <60 mg/day Health Plus Zinman 9 mg/day ZMC 15 mg/tablet Lamberts 5 mg x 3/day* * with warning Daily provision: Multivitamin and mineral 0. 5 mg Glucosamine + Chondroitin* 3. 5 mg * 2010 Tesco have agreed to reduce the Mn content to 0. 5 mg

Manganese Excess: Case Histories Manganese Age & Suppl. Sex Intake mg/day Presenting Problem Cause Manganese Excess: Case Histories Manganese Age & Suppl. Sex Intake mg/day Presenting Problem Cause 58. 6 nmol/l Pl. (9 -40) F 58 Nil Cholestatic liver disease, fatigue Self use. Raised Alk Phos 44. 1 nmol/l Pl. (9 -40) F 80 2 mg/day Thrombocythaemia Self use. Platelets have high Mn content WB 220 nmol/l (80 -200) M 71 14 mg/day OA Knees Self-use of canine supplement! WB 230 nmol/l (80 -200) F 60 70 mg/day 4 x ZMC + other Spasticity R Foot Nutritionist using hair Motor neurone analysis. disease variant Liver normal Plasma/whole blood

Treatment of Manganese Excess • Identify cause (food, supplements, industrial, well water) and stop Treatment of Manganese Excess • Identify cause (food, supplements, industrial, well water) and stop • Limit foods – tea, tinned pineapple, ? blackberries, ? home-grown • Assess anaemia, platelet count and liver function – alkaline phosphatase, inflammation and refer to specialist if abnormal • Assess neurological status – poor co-ordination or gait or reduced tapping speed; refer to neurologist for MRI scan • Limit alcohol if excessive, overweight or abnormal liver function tests • Assess status of other trace elements, zinc, copper and iron and treat any other deficiencies/excesses • Consider giving zinc 10 mg x 2/day to reduce manganese absorption • Reassess after 2 -3 months, re-measure manganese – whole blood and plasma zinc and copper • Elevated levels could take >6 months to return to normal and brain content is unlikely to fall

Vitamin C: UK position • Adult intakes average 50 -100 mg /day + that Vitamin C: UK position • Adult intakes average 50 -100 mg /day + that from supplements • Food sources: fruit and vegetables, potatoes, food additive • Increases absorption of non-haem iron • Mild deficiency common in elderly, smokers or very poor diet • Many preparations provide 500 -1000 mg - up to 3 g/day • GL 1000 mg (haemochromatosis – 500 mg in US) • At high doses ~20% is absorbed; excess may act as a laxative • Any excess is excreted in the urine some changed to oxalate • High doses may increase risk of renal oxalate stones in those who are predisposed • I. V. use can precipitate haemolysis in those with deficiency of Glucose-6 Phosphate Dehydrogenase (Africans/Mediterraneans)

Vitamin C: Oestrogen Metabolism • EVM set Safe Upper Level set at 1 gm Vitamin C: Oestrogen Metabolism • EVM set Safe Upper Level set at 1 gm per day (2003) • Increased Plasma Ethinyloestradiol in OC pill users Effect of 1000 mg per day retarding oestrogen catabolism Back DJ et al BMJ 1981; 282: 1516 • Possible increased risk of Breast Cancer in WHI Study Supplemental, not dietary vitamin C >711 mg/day, RR 1. 16 [95% CI: 1. 04, 1. 3] Cui Y et al AJCN 2008; 87: 1009 -1018 • Multivitamin Use and Breast Cancer in Swedish Women 35, 329 mammography negative women followed up for mean 9. 5 yr Multivitamin users RR 1. 19 [95% CI: 1. 04, 1. 37] Larsson SC et al AJCN 2010; 91: 1268 -72

Vitamin C and Cataracts • Women’s Health Initiative study in US Supplement use and Vitamin C and Cataracts • Women’s Health Initiative study in US Supplement use and cataract formation Multivitamins Vitamin C alone + HRT + Corticosteroids RR 1. 09 [95% CI: 0. 94, 1. 25] RR 1. 38 [95% CI: 1. 12, 1. 69] RR 1. 56 [95% CI: 1. 20, 2. 02] RR 1. 97 [95% CI: 1. 35, 2. 88] Rautiainen S et al AJCN 2010; 91: 487 -493 • Male US Physicians 11, 545 >50 yrs: vitamin C 500 mg/day and or vitamin E 400 IU/alt. days Vitamin E Vitamin C RR 0. 99 [95% CI: 0. 88, 1. 11] RR 1. 02 [95% CI: 0. 91, 1. 14] Christen WG et al Arch Ophthalmol 2010; 128: 1397 -405

Selenium: UK position GL 350 ug (2003) • Adult intakes from food average 50 Selenium: UK position GL 350 ug (2003) • Adult intakes from food average 50 - 70 ug/day • Food sources: grains, meat, offal, Brazil and cashew nuts; content of Brazil nuts can vary widely French Ref • Low intake/status associated with increased risk of some cancers and vascular disease • Deficiency can occur in animals – miscarriage; sheep are often supplemented • Plasma selenium was measured as part of NDNS: deficiency uncertain but may occur in frail, anaemic elderly and lower levels in some young people Bates CJ et al J Trace Elem Med Biol. 2002; 16: 1 -8 • Selenium preparations contain 50 to 200 ug per day

Selenium Toxicity • Acute toxicity: supplements mg doses: muscle and joint pains, hair loss, Selenium Toxicity • Acute toxicity: supplements mg doses: muscle and joint pains, hair loss, nail changes, sour taste, garlic breath and neurological problems • Chronic toxicity: diet or long term supplement use hair loss dermatitis, bad breath, neurotoxicity • Excess is excreted via faeces, integument and breath • Diagnosed by: raised plasma/whole blood or hair Se. • Possible association between Se. excess and T 2 D but this may reflect obesity or altered metabolism Stranges S et al. 2010 • Safe supplement dose for long term use is probably <100 ug/day

Selenium Acute Toxicity USA 2008 FDA Notification 04/10/2008 • Total Body Formula/Total Mega Formula Selenium Acute Toxicity USA 2008 FDA Notification 04/10/2008 • Total Body Formula/Total Mega Formula • Most samples contained 200 times the stated amounts • Toxic effects were observed after 5 to 10 days of daily ingestion • Effects included: hair loss, muscle cramps, diarrhoea, joint pains, deformed finger nails and fatigue • In total there have been 43 reports from 9 states • The product has been recalled • See http: //www. thedoctorwillseeyounow. com/content/nutrition/art 2036. html Pictures of selenium excess in humans

UK Food Content of Selenium ug/100 g Mc. Cance and Widdowson’s The Composition of UK Food Content of Selenium ug/100 g Mc. Cance and Widdowson’s The Composition of Foods (Year of Publication)

Estimated UK Adult Intakes of Selenium Total Dietary Intake (ug/kg bw/day) 1997 2000 2006 Estimated UK Adult Intakes of Selenium Total Dietary Intake (ug/kg bw/day) 1997 2000 2006 Mean 0. 77 0. 63 – 0. 67 0. 83 – 0. 95 High Level 1. 43 1. 2 – 1. 3 1. 65 – 1. 79 • Committee on Toxicity 2009. Measurement of the Concentrations of Metals and other Elements from the UK Total Diet Study • www. food. gov. uk/science/surveillance • EVM (2003) Safe Upper Level 5 ug/kg bw/day • Acute/chronic toxicity results in nail and hair changes, garlic breath and neurological problems

Plasma Selenium and Supplementation Stranges S et al Annals of Internal Medicine. 2007; 147: Plasma Selenium and Supplementation Stranges S et al Annals of Internal Medicine. 2007; 147: 217 -223 • RDBPC trial of yeast-derived selenium 200 ug/day in 1312 participants • Reduced rates of lung, prostate and colorectal cancers over 7. 7 years • Self-reported T 2 diabetes HR 1. 55 [95% CI: 1. 03, 2. 23] • T 2 D risk greater if baseline Se >121. 6 ng/ml. HR 2. 7 [CI: 1. 3, 5. 61] Equivalent to 1. 5 umol/l • Trial results initially lead to large Se/Vit E primary prevention trial SELECT

Selenium Supplements and Type 2 Diabetes Stranges S et al Annals of Internal Medicine. Selenium Supplements and Type 2 Diabetes Stranges S et al Annals of Internal Medicine. 2007; 147: 217 -223 • Supplementation with 200 ug per day results in a substantial rise in plasma selenium within 3 to 6 months

Serum Selenium and Mortality among US Adults Bleys J et al. Arch Intern Med Serum Selenium and Mortality among US Adults Bleys J et al. Arch Intern Med 2008; 188(4): 404 -410 • Serum Selenium was measured in 13, 887 US adults • Follow-up mortality data over 12 years • Serum Selenium levels <130 ng/ml (1. 6 umol/l) Associated with an inverse association between serum selenium and all-cause and cancer mortalities • Serum Selenium levels >150 ng/ml (1. 9 umol/l) Associated with a modest increase in all-cause mortality • No association between serum Se and cardiovascular mortality • Normal Range: Serum or Plasma Selenium 80 -150 ng/ml 1. 0 -1. 9 umol/l

Plasma Selenium Upper 2. 5 percentiles umol/l NDNS Young People and Adults Plasma Selenium Upper 2. 5 percentiles umol/l NDNS Young People and Adults

SELECT Primary Prevention Trial Lippman SM et al JAMA 2009; 301: 39 -51 • SELECT Primary Prevention Trial Lippman SM et al JAMA 2009; 301: 39 -51 • Phase III RPCT of: Se-methionine 200 ug/ and/or vit E all-rac-alpha-tocopheryl acetate 400 IU daily 4 groups including placebo, intentionally for >7 yrs • 35, 534 men >50/55 yrs (black/white) • Stopped 2009 after an average of 5. 5 yrs • No reduction in prostate or other cancer risk. • Se group non-statistically significant increase in T 2 D • Statistically significant increases in alopecia and dermatitis. • Group will continue to be followed for several years

Selenium Excess: Case Histories Plasma Selenium Age yrs & Sex Suppl. Intake ug/day Clinical Selenium Excess: Case Histories Plasma Selenium Age yrs & Sex Suppl. Intake ug/day Clinical Problem Cause 3. 18 umol/l M 64 100 -200 for years Hypertension >10 supplements/day Wife 2. 16 umol/l F 54 Nil Ate 30 Brazil nuts/day Self 3. 2 umol/l F 57 450 Anxiety, migraine Self 1. 89 umol/l M 71 800 T 2 diabetes for years. Doctor Improved with weight loss 2. 8 umol/l F 64 200 -300 for Chronic sinusitis, CFS years (1. 0 -1. 8 umol/l) Self + Nut Pract

Vitamin E supplements and Oral Anticoagulants “Evidence suggests that Vitamin E has blood thinning Vitamin E supplements and Oral Anticoagulants “Evidence suggests that Vitamin E has blood thinning effects. Vitamin E intakes above 1, 000 International Units, IU, per day may increase the risk of excess bleeding. Research suggests that doses up to 800 IU may be safe for individuals on Coumadin (warfarin), but the evidence is not conclusive. It is best for those taking Coumadin to ask their physicians about taking Vitamin E supplements ” NIH Drug-Nutrient Task Force 2003

Mortality in Randomized Trials of Antioxidant Supplements for Primary and Secondary Prevention Bjelakovic G Mortality in Randomized Trials of Antioxidant Supplements for Primary and Secondary Prevention Bjelakovic G et al. JAMA 2007; 297: 842 -857 • Review and meta-analysis of primary and secondary randomised, controlled prevention trials • 47 low-bias risk trials (180, 938 participants) • Effect on all-cause mortality compared with placebo: All trials - RR 1. 07; 95% CI 1. 04 -1. 10 vitamin A - RR 1. 16; 95% CI 1. 10 -1. 24 beta-carotene - RR 1. 07; 95% CI 1. 02 -1. 11 vitamin C - RR 1. 06; 95% CI 0. 99 -1. 14 vitamin E - RR 1. 04; 95% CI 1. 01 -1. 07 selenium - RR 0. 998; 95% CI 0. 997 -0. 9995 • The adverse effects of beta-carotene, vitamins A and E were dose related • No apparent benefit for elderly >65 yrs

Trials of Antioxidant Supplements: criticisms Bjelakovic G et al. JAMA 2007; 297: 842 -857 Trials of Antioxidant Supplements: criticisms Bjelakovic G et al. JAMA 2007; 297: 842 -857 • Cause of mortality unknown (mainly vascular disease and cancer) • Variety of doses and combinations of antioxidants used • Levels of nutrients were not usually assessed or monitored • Multivitamin/multimineral preparations were not used • Trials do no reflect the use of supplements in those with proven deficiency or in situations of increased need • But there are very few trials showing any benefit of antioxidants

Magnesium: UK position • Adult intakes: mean 233 – 311 [95% CI 96 -562] Magnesium: UK position • Adult intakes: mean 233 – 311 [95% CI 96 -562] mg/day • Food sources: cereals (27%), drinks, meat: supplements 1% • Deficiency (mild) possible: diarrhoea, diuretics, some women • Preparations contain 50 -300 mg per day • GL 375 mg • High intake – reduced absorption and increased urine excretion • Acute toxicity: diarrhoea especially if has gastrointestinal hurry • Chronic toxicity: if renal impairment – drowsiness, hypotension and death • 5% to 10% of UK elderly have abnormal renal function • Excess diagnosed by: raised serum magnesium

Other Nutrients: Adverse Reactions • Acute Toxicity Minor – gastrointestinal upset – Mg, Fe, Other Nutrients: Adverse Reactions • Acute Toxicity Minor – gastrointestinal upset – Mg, Fe, Zn, Severe – large amounts of vitamins A, D, C • Chronic Toxicity Osteoporosis – vitamin A Nervous system – vitamin B 6, Mn, Cu Liver disease – Fe, Cu, vitamin A, beta-carotene Metabolic Effects – hypercalcaemia, renal stones, induced deficiency • Cancer Induction – antioxidants may act as pro-oxidant Growth Rate – zinc, vitamin B • Adverse Pregnancy Effects Fetal development/growth – Fe, vitamins A, C and E • Minor and Idiosyncratic Adverse Effects Dermatological – beta-carotene, vitamin B 12, n-3 EFAs and others

Zinc: UK Position GL 25 mg; US UL 40 mg • • • Adult Zinc: UK Position GL 25 mg; US UL 40 mg • • • Adult intakes average 7. 9 – 10. 7 [95% CI 3. 0 -23. 0] mg/day Food sources: meat (34%), cereals: supplements 3% Deficiency: vegetarians/vegans, alcohol excess, malabsorption Preparations contain 5 -50 mg per day [150 mg on NHS] High intake: reduced absorption and increased urinary excretion Acute toxicity: gastric irritation, nausea, vomiting, metallic taste GI upset more likely if gastritis, ulcer H. pylori • Chronic toxicity: copper deficiency due to trapping of Cu in enterocyte by induced thionein production (anaemia, neutropenia and neurological problems) poor immune function raised cholesterol levels possibly increased cancer growth- greater risk of more advance prostate cancer if intake >100 mg/day ref… • Diagnosis; Pl. zinc, low Pl. copper and neutropaenia/anaemia

Copper deficiency myeloneuropathy and pancytopenia secondary to overuse of zinc supplementation Rowin J, Lewis, Copper deficiency myeloneuropathy and pancytopenia secondary to overuse of zinc supplementation Rowin J, Lewis, SL. J. Neurol, Neurosurg and Psych 2005; 76: 750 -751 • 53 yr old woman; 4 -8 capsules of Zinc gluconate (50 mg) >1 yr • Spastic and ataxic gait, tingling and numbness in fingers and feet • Evidence of a sensory and motor neuropathy in the lower limbs and decreased vibration and proprioception senses • Haemoglobin 8. 3 g/dl (11. 7 -15. 7) MCV 112. 5 u. M (80 -100) WBC count 2. 6 x 103 (3. 8 - 10. 8) • Normal vitamin B 12, folate, immune function, brain and spine MRI • Serum copper 7 ug/dl (70 -150) serum zinc 2. 28 ug/ml (0. 66 -1. 1) • Treated with oral copper 2 mg per day Full haematological but only partial neurological recovery Parenteral copper might be required in severe cases

Iodine Excess: Case History Mrs HF 48 yr old woman • 2004: heavy periods, Iodine Excess: Case History Mrs HF 48 yr old woman • 2004: heavy periods, anxiety, marked premenstrual syndrome [AS] • Improved with dietary change – low wheat, low sodium, high vegetable, and supplements of vitamin B and magnesium • Nov 2006 wholistic doctor, anxiety, period problems & constipation • Normal TFTs but microsomal antibodies +ve titre 1 in 1600 • Given iron, sulphur, vitamin C iodine ~ 5 -10 mg/day • March 2007 T 3 6. 9 pmol/l (3 -6. 5) and TSH 0. 05 mu/L (0. 35 -5. 5) • May 2007 TSH 27. 48 mu/l and fluctuated (1. 82 to 9. 32 mu/l) • Late 2007 severe menorrhagia, endometrial ablation unsuccessful, hysterectomy • [AS] March 2008 v. anxious, hypertensive, fluid retention on HRT advised to improve diet, referred back to GP and endocrinologist • Endocrinologist, commenced on thyroxine – felt much better

Iron: UK position • • Adult intakes average 11. 6 – 14. 0 [95% Iron: UK position • • Adult intakes average 11. 6 – 14. 0 [95% CI 4. 0 – 29. 1] mg/day Food sources: cereals (44%), meat: supplements F 14%, M 5% Deficiency common: vegetarians, menorrhagia and infants Multi preparations contain ~15 mg /day [OTC 65 -100 mg x 3/day] GL 14. 8 mg High intakes result in reduced absorption. No excretion route Acute toxicity: abdominal pain, nausea, diarrhoea, constipation Chronic toxicity: iron accumulates in the liver, skin, joints, resulting in fatigue, arthritis, diabetes, gonadal failure - Haemochromatosis in 0. 6% of Europeans - iron accumulation - Chronic liver disease can also lead to accumulation - Chronic haematological disorders transfusion haemosiderosis) • Excess diagnosed by: raised iron saturation >55% (fasting sample no supplements) raised serum ferritin (if no inflammation) not by measurement of Haemoglobin

Clinical Picture of Chronic Iron Excess Positive Balance Reason or Clinical Picture Intake High Clinical Picture of Chronic Iron Excess Positive Balance Reason or Clinical Picture Intake High from meat, fortified foods, supplements, blood transfusion Absorption Increased by vitamin C, fruit and alcohol Losses Reduced in women after the menopause Requirement Reduced in men and on ceasing blood donation Metabolism Increased absorption due to haemochromatosis and increased liver content in some liver diseases Stores Increase in serum (raised ferritin or iron saturation) liver and tissue levels Symptoms Fatigue, arthritis, loss of libido Signs Type 2 diabetes and bronzed skin discolouration Organ Failure Liver failure and heart muscle damage

Copper: UK position • • • Adult intakes average 1. 0 – 1. 5 Copper: UK position • • • Adult intakes average 1. 0 – 1. 5 [95% CI 0. 31 -3. 56] mg/day Food sources: grains (31%), meat, liver, water: supplements 3% Deficiency rare: malnourished, bariatric surgery and zinc excess Multivit/mineral preparations contain 1 to 2 mg per day [9 mg] GL 1. 0 mg (TSI: food + water + supplements = 10. 0 mg) Any excess is excreted via the bile if liver function is normal 10% to 30% of UK adults/elderly have abnormal liver function • Acute toxicity: nausea, vomiting • Chronic toxicity: possible due to Wilson’s disease 1: 20, 000 Cu accumulation in the liver, brain due to transport defect; neuropsychiatric/liver problems <50 yrs Mild cognitive impairment in elderly if diet high in saturated fat • Excess diagnosed by: raised plasma Cu in simple excess if no inflammation/oestrogen low plasma, high urine and liver Cu in Wilson’s disease

Folate/Folic acid: UK Position GL 1000 ug • • • Adult intakes average 292 Folate/Folic acid: UK Position GL 1000 ug • • • Adult intakes average 292 – 359 [95% CI 91 -754] ug/day Food sources: grains (33%), vegets, potatoes: suppls M/F 5/13% Deficiency: poor diet, coeliac disease, alcohol excess, elderly Multivit/minerals contain 200 -400 ug per day [5 mg on script] routinely given to prevent NTD pregnancy [400 -5000 ug/day] Added to staple foods in over 52 countries not yet in UK Easily absorbed, excess excreted as unmetabolised folic acid UMFA Acute toxicity: none Chronic toxicity: possible due to Might mask haematological effects of vitamin B 12 deficiency Un-Metabolised Folic Acid may disrupt normal folate metabolism Growth promoting effect on some tumors cf Methotrexate is an anti-folate, anti-cancer drug Supplements are given (5 mg x 1 /week) to 600, 000 adults in the UK receiving methotrexate for RA and IBD

Folate Status of the British Population Red Cell Folate NDNS Data Collected 1990 -2001 Folate Status of the British Population Red Cell Folate NDNS Data Collected 1990 -2001

Folic Acid: Prevention of Colorectal Adenomas Cole BF et al. JAMA 2007; 297: 2351 Folic Acid: Prevention of Colorectal Adenomas Cole BF et al. JAMA 2007; 297: 2351 -2359 • • • DBPC Trial 1021 men and women (av. age 57 yrs) All had a colorectal adenoma Folic acid, FA, 1000 ug/day or placebo for 5 yrs Surveillance colonoscopies at 3 ys and 5 yrs Adenomas: FA vs Placebo: 44. 1% vs 42. 4% (3 yrs) and 41. 9% vs 37. 2% (5 yrs) Adverse Event Placebo (n = 505) Folic Acid (n = 516) P Value Death 19 (3. 8%) 10 (1. 9%) . 09 Noncolorectal cancer 32 (6. 3%) 54 (10. 5%) . 02 Colorectal cancer 4 (0. 8%) 3 (0. 6%) . 72 Myocardial Infarction 8 (1. 6%) 14 (2. 7%) . 28 Coronary revascularization 16 (3. 2%) 16 (3. 1%) >. 99 Stroke 5 (1. 0%) 9 (0. 7%) . 42

Folate/Folic Acid and Cancer Risk Ulrich CM. Editorial Am J Clin Nutr 2007; 86: Folate/Folic Acid and Cancer Risk Ulrich CM. Editorial Am J Clin Nutr 2007; 86: 271 -3 • Low intakes of folate increase the risk of alcohol -associated breast cancer • Moderate intakes have no effect on risk • High intakes of folic acid from supplements may increase the growth of an existing tumor • The effect of folate/folic acid may be influenced by other nutrients and genetic factors

Vitamin B Therapy: Progression of Diabetic Nephropathy House AA et al. JAMA 2010; 303: Vitamin B Therapy: Progression of Diabetic Nephropathy House AA et al. JAMA 2010; 303: 1603 -1609 • • DBPC Trial 238 men and women (av. age 57 yrs) All had Type 1 or 2 diabetes and mild diabetic nephropathy Placebo or daily Folic acid 2. 5 mg, vitamin B 6 25 mg and vitamin B 12 1 mg for a mean of 31. 9 months Assessment by radionuclide measure of Glomerular Filtration Rate Measurement of plasma homocysteine Assessment of MI, stroke, need for vascular procedure or all cause death = composite end point Baseline: 89% male, BMI 32. 0 kg/m 2, very little B 12/folate deficiency Outcome Placebo (n = 505) Vitamin B (n = 516) P Value Change in Homocysteine umol/l + 2. 6 (0. 4) - 2. 2 (0. 4) 0. 04 Decline in GFR ml/min 10. 7 (1. 7) 16. 5 (1. 7) 0. 02 Vascular Event or Death 13% (14. 4) 24% (23. 5) 0. 04

Problems with Folate and Vit. B 12 in UK Elderly • Deficiencies of both Problems with Folate and Vit. B 12 in UK Elderly • Deficiencies of both are common in UK (NDNS 65+) • Supplement use is associated with better folate status but only slightly better vit B 12 status (Dangour 2008) • NHANES III in the US: those with a serum B 12 <148 pmol/l (~35% of UK elderly) increasing serum folate was associated with increased HCys and MMA levels Selhub J et al Am J Clin Nutr 2009; 89(2): 702 S-706 S • EPIC no overall association of prostate cancer risk and the status of these nutrients However in those with a high vitamin B 12 level there was an increased risk of more advanced disease. Johansson M et al Cancer Epidemiol Biomarkers Prev 2008; 17(2): 279 -85 See also Hultdin J et al Int J Cancer 2004; 113: 819 -24 • Ca Prostate patients are more likely to die from renal failure

Thiamin Status of the British Population Red Cell Transketolase AC NDNS Data Collected 1990 Thiamin Status of the British Population Red Cell Transketolase AC NDNS Data Collected 1990 -2001

Thiamin and Cancer • Thiamin is needed for ribose production, transketolase enzyme, TKTL • Thiamin and Cancer • Thiamin is needed for ribose production, transketolase enzyme, TKTL • Ribose is a constituent of RNA and DNA and needed for cell growth • Tumours ferment glucose to produce lactate and ribose in anaerobic conditions - Warburg effect • Some cancers upregulate mutated transketolase transcript (TKTL 1) and this may allow enhanced oxygen-independent growth • Strong expression of TKTL 1 in colon and urothelial cancers is associated with a poorer prognosis • Anti-thiamin agents are being develop for cancer treatment • But malnourished cancer patients may develop thiamin deficiency Ref Langbein et al British Journal of Cancer (2006)94; 578 -58

Calcium: UK position • Adult intakes average 809 – 1016 [95% CI 320 - Calcium: UK position • Adult intakes average 809 – 1016 [95% CI 320 - 1783] mg/day • Food sources: dairy foods (48%), cereals: suppl’nts M 1%, F 5% • Deficiency possible: vegans, malabsorption, vit. D deficiency • Preparations contain 100 - 600 mg per day [600 mg x 2/day] • GL 1500 mg • High intakes reduced absorption, increased urinary excretion • Acute toxicity: diarrhoea from excipients sorbitol or xylitol <5% • Chronic toxicity: hypercalcaemia if gross excess and antacids Milk-Alkalai syndr. renal stones if predisposed former cardiovascular disease if no vitamin D supplements • Excess diagnosed by: raised serum calcium

Calcium and Vitamin D • Regularly used to treat/prevent osteoporotic fractures • Used standardly Calcium and Vitamin D • Regularly used to treat/prevent osteoporotic fractures • Used standardly in conjunction with all bisphonates • Large placebo-controlled trial of daily supplements of: calcium 1000 mg vitamin D 3 400 IU (10 ug) 36, 282 postmenopausal women aged 50 -79 years • Slight improvement in hip bone density • No reduction in fracture risk • Increased risk of kidney stone formation - 17% • NEJM 2006; 354: 669 -682

Calcium Supplements and MI, Cardiovascular Events Bolland MJ et al BMJ 2010; July 29 Calcium Supplements and MI, Cardiovascular Events Bolland MJ et al BMJ 2010; July 29 vol 341 • Meta-analysis of calcium only trials • 15 eligible trials only 5 with adequate data • 8151 participants median follow-up 3. 6 years • Outcomes Myocardial Infarction Stroke Composite end point = 0. 057 HR 1. 31 [95% CI 1. 02, 1. 67] HR 1. 20 [95% CI 0. 96, 1. 5] HR 1. 18 [95% CI 1. 00, 1. 39] p • Analysis of other trials 11, 921 participants; Calcium recipients pooled Myocardial Infarction HR 1. 27 [95% CI 1. 01, 1. 59] p = 0. 038 • However, only 3% of NHS prescribed calcium is without vit D! • Take away message: don’t give calcium by itself

Vitamin D: UK position GL 40 ug • Adult food intakes average 2. 8 Vitamin D: UK position GL 40 ug • Adult food intakes average 2. 8 - 3. 7 [95% CI: 0. 2 – 9. 7] ug/day • Food sources: oily fish (24%), meat: suppl’nts M 12%, F 25% • Deficiency possible: poor sun exposure, vegans, liver disease • Preparations contain 2. 5 – 25 ug per day [10 ug x 1 -2/day] • Acute toxicity: Only with massive amounts [MS patients] • • Chronic toxicity: hypercalcaemia if hyperparathyroidism, sacroidosis, TB, cancer present in 1%-0. 1% of UK adults mainly aged >60 yrs • Excess diagnosed by: raised serum calcium Prudent to check in older patients every 2 -5 years

Vitamin D and Adjusted All-Cause Mortality (US) 13, 331 participants in NHANES III age>20 Vitamin D and Adjusted All-Cause Mortality (US) 13, 331 participants in NHANES III age>20 yrs. 8. 7 yr Follow-up; 1806 deaths Melamed ML et al Arch Intern Med 2008; 168(15): 1629 -37 • • • Vitamin D 1 ng/ml = 2. 497 nmol/l Institute of Medicine norm = >50 nmol/l The reason for slight increase in mortality in high serum vit D is unexplained

Statin + EPA Lipid Intervention Study, JELIS Yokoyama M et al Lancet 2007; 369: Statin + EPA Lipid Intervention Study, JELIS Yokoyama M et al Lancet 2007; 369: 1090 -98 • 18, 645 Japanese (69% F) with a total cholesterol >6. 5 mmol/l • Statin (pravastatin 10 -20 mg or simvastatin 5 – 10 mg/day) or Statin + 3 x 600 mg EPA ethyl ester /day; mean follow up 4. 6 years • Excluded many with serious diseases or haemorrhage • EPA reduced major coronary events in those with a history of CAD Adverse Events Statin + EPA P value n = 9319 n = 9326 Pain: joint, lumbar muscle 2. 0% 1. 6% 0. 04 GI Disturbance: nausea, diarrhoea, epigastric discomfort 1. 7% 3. 8% <0. 0001 Skin: eruption, itching, rash, eczema 0. 7% 1. 7% <0. 0001 Haemorrhage: cerebral, fundal, epistaxis, subcutaneous 0. 6% 1. 1% 0. 0006

Other Trace Elements Guidance Levels set by EVM 2003 • Boron • Nickel 6 Other Trace Elements Guidance Levels set by EVM 2003 • Boron • Nickel 6 mg 260 ug • Tin • Cobalt • Vanadium 13 mg 1400 ug 7. 5 mg Uncertain adverse effects Could aggravate nickelsensitive eczema Uncertain adverse effects

Other Minor Reactions • Chewable supplements (Calcium and Vit C) - diarrhoea due to Other Minor Reactions • Chewable supplements (Calcium and Vit C) - diarrhoea due to intolerance of sweetener sorbitol/xylitol • Multivitamins (Centrum and C 50 +) - skin rashes due to azo dye colouring agent • Vitamin B 3 niacin (not nicotinamide) - flushing due to niacin content especially if >50 mg • Vitamin B 2 - yellow discolouration of the urine due to riboflavin; it is of no consequence • Vitamin B Complex - ? Insomnia if taken with 6 hours before bed-time ? Due to high blood levels - Malaise ? due to vitamin B intolerance or variants in metabolism • Choline - Fishy odour to sweat in those with trimethylaminuria

Risk Methodology and Supplement Safety Adapted from FAO/WHO 1995/1997/1998 www. fao. org/docrep/008/ae 922 e Risk Methodology and Supplement Safety Adapted from FAO/WHO 1995/1997/1998 www. fao. org/docrep/008/ae 922 e 03. htm 2. Risk Communication Patient Professionals Authorities Industry Public - Marketing 1. Risk Assessment 3. Risk Management Possible Adverse Effects Dose-Response Effect Exposure Assessment Modifying Factors Policy Options Accept/ Minimize/Remove Implement Options Monitor and Review

Methodology: 2. Risk Communication • Patient - Consumer Information on pack, point of sale, Methodology: 2. Risk Communication • Patient - Consumer Information on pack, point of sale, websites; limited or misleading • Professionals Nutritionists undergraduate training – uncertain information Doctors – little training, few NHS supplements, no incentive Pharmacists/Nutritionists post-grad training – industry sponsored • Authorities Food Standards Agency & EFSA reports – no simple summary FSA website – only limited information • Industry Health Supplement Information Service – errors/omissions on site HFMA – safety statements but limited and out of date ERNA – Safety Publication and Fact Sheets – out of date/inaccurate • Public – Potential consumers/carers Advertisements, marketing, books, TV; mixed messages & no detail

Industry Pack Warnings - Supplementation Risks Holland Barrett “If you are pregnant, breastfeeding or Industry Pack Warnings - Supplementation Risks Holland Barrett “If you are pregnant, breastfeeding or taking any medication consult a doctor before use” Solgar “If you are pregnant, nursing, taking any medication or have a medical condition, please consult your healthcare practitioner before taking any dietary supplement. ” Whitehall Laboratories Centrum Silver 50+ “As with any supplement, if you are pregnant, nursing, or taking medication, consult your doctor before use. Long-term intake of high levels of vitamin A may increase the risk of osteoporosis in adults” Simply Supplements “Caution: If under medical supervision please consult a doctor before use. ”

Risk Communication: Labelling of Food Supplements - Advisory Statements www. food. gov. uk/safereating/chemsafe/supplements • Risk Communication: Labelling of Food Supplements - Advisory Statements www. food. gov. uk/safereating/chemsafe/supplements • Advisory statements written in May 2004 after the EVM Report (May 2003) • Input from Food Standards Agency and Health Food Manufacturer’s Association Council for Responsible Nutrition Proprietary Association of Great Britain • Statements apply to some high dose products • Purpose - protect consumer and allow them to make an informed choice • Statements will be adopted by HFMA/CRN members • Statements are based on current evidence and are subject to change in the light of new evidence.

Risk Communication: Advisory Statements 2004 www. food. gov. uk/safereating/chemsafe/supplements Nutrient Trigger Threshold Label Statement Risk Communication: Advisory Statements 2004 www. food. gov. uk/safereating/chemsafe/supplements Nutrient Trigger Threshold Label Statement or Reformulation Vitamin A 800 ug of preformed retinol Do not take if you are pregnant or likely to become pregnant except on the advice of a doctor or antenatal clinic FSA Any Avoid supplements of retinol during pregnancy Betacarotene >7 mg Encourage reformulation to <7 mg/day FSA any Should not be taken by heavy smokers Vitamin C >1000 mg May cause mild stomach upset in sensitive individuals Zinc >25 mg Long term intake may lead to anaemia Manganese >4. 0 mg Long term intake may lead to muscle pain and FSA >0. 5 mg fatigue

Risk Communication: Advisory Statements 2004 www. food. gov. uk/safereating/chemsafe/supplements Nutrient Trigger Label Statement or Risk Communication: Advisory Statements 2004 www. food. gov. uk/safereating/chemsafe/supplements Nutrient Trigger Label Statement or Reformulation Threshold Iron >20 mg May cause mild stomach upset in sensitive individuals Calcium >1500 mg May cause mild stomach upset in sensitive individuals Magnesium >400 mg May cause mild stomach upset in sensitive individuals Nickel All products May cause a skin rash in sensitive individuals Nicotinic Acid >20 mg Encourage reformulation to nicotinamide May cause mild stomach upset in sensitive individuals Phosphorus >250 mg May cause mild stomach upset in sensitive individuals Vitamin B 6 >10 mg Long tem intakes may lead to mild tingling and numbness >100 mg Encourage reformulation to lower daily amount

Risk Communication: Additional Statements for HFMA members www. hfma. co. uk Nutrient Trigger Threshold Risk Communication: Additional Statements for HFMA members www. hfma. co. uk Nutrient Trigger Threshold Label Statement Vitamin A >800 ug This product contains vitamin A. Do not take if you are pregnant or likely to become pregnant except on the advice of a doctor or antenatal clinic Vitamin K >100 ug If you are taking anticoagulants (blood thinners) do not take this product except on the advice of a doctor of preformed retinol Iron >200 mg This product contains iron, which, if taken in excess, may be harmful to very young children. Keep out of sight and reach.

Risk Communication: Industry • Health Supplement Information Service www. hsis. co. uk accessed 19/1/2011 Risk Communication: Industry • Health Supplement Information Service www. hsis. co. uk accessed 19/1/2011 Information for public and media by PR company • Health Food Manufacturer’s Association www. hfma. co. uk accessed 19/1/2011 Mission statement 4 “ To promote high standards of product manufacture and presentation to ensure consumer safety. . ” Produced several Safety Advisory Statements • Council for Responsible Nutrition UK www. crn. org. uk accessed 19/1/2011 • “members all agree to abide by voluntary quality standards to ensure consumer safety and confidence. ” Expert advisory board. No reference to Safe Upper Levels but members products are usually low strength European Responsible Nutrition Alliance www. erna. org “ERNA is striving to ensure a future European market with a range of safe, quality products that reflect the latest in supplementation research”

Health Supplement Information Service: Errors Information on Safe Upper Levels • Retinol “Safe supplemental Health Supplement Information Service: Errors Information on Safe Upper Levels • Retinol “Safe supplemental daily dose is 1500 ug” However this is the Total Safe Intake and the figure for supplements should be 800 ug/day • Manganese “Safe supplement daily dose is 4. 0 mg” However no mention that for those aged >50 years the safe dose is 0. 5 mg/day

Marketing and Promotion: 7 “deadly” sins • Cod Liver Oil and Multivitamins 3 for Marketing and Promotion: 7 “deadly” sins • Cod Liver Oil and Multivitamins 3 for 2 offers and linked sales can lead to excess retinol intake • Unnecessary Repeat Sales vitamin A, selenium and manganese, which can easily accumulate • Controlling Information Holland Barrett no books for sale. Healthnotes on Line US not UK data • Marketing via non-Experts (Opticians) of very high dose product ICAPS Supplement for AMD [Alcon] Mn 10 mg, Zn 60 mg, Cu 4 mg per day Formula now amended with greatly reduced content (2010? ) • Medical Endorsement Healthspan - articles by seven doctors with scant mention of safety • Nutritional Practitioner Education Minimal/no safety data provided to practitioner who profits from sales Results in “Incentivised Risk” similar to UK banking crisis • “Good Manufacturing Practice = Safe” GMP = Quality Manufacture. It does not mean safe for every consumer

Ethical Marketing: Good Example - PAGB The Proprietary Association of Great Britain www. pagb. Ethical Marketing: Good Example - PAGB The Proprietary Association of Great Britain www. pagb. co. uk Trade association for OTC medicine/supplement industry • Codes for advertising, point-of-sale, website, pack information • Products have authorised Indications and Warnings • PAGB Consumer Code: 3. 5. 1 (16) “Care should be taken not to encourage, either directly or indirectly, the indiscriminate, unnecessary or excessive use of any medicine” 3. 5. 3 (30) “ All such advertisements must encourage a cautious approach to the use of medicines in pregnancy” 3. 5. 4 (33) “Advertising shall not suggest that the safety or efficacy of a product is due the fact that it is natural” 3. 5. 8 (45) “Advertising shall not state or imply that a product is recommended or used by a health professional or scientist”

Ethical Marketing – Modern Standards “Marketing is also in the front line of an Ethical Marketing – Modern Standards “Marketing is also in the front line of an organisation’s attitude to social responsibility and corporate citizenship. Society now expects organisations to ensure that their products are safe and to communicate any risks or problems clearly to the consumer” Preface from Principles of Marketing nd 2 Edition Drs. F Brassington & F Pettitt. Prentice Hall 2000

Risk Methodology and Supplement Safety Adapted from FAO/WHO 1995/1997/1998 www. fao. org/docrep/008/ae 922 e Risk Methodology and Supplement Safety Adapted from FAO/WHO 1995/1997/1998 www. fao. org/docrep/008/ae 922 e 03. htm 2. Risk Communication Patient Professionals Authorities Industry Public 1. Risk Assessment 3. Risk Management Possible Adverse Effects Dose-Response Effect Exposure Assessment Modifying Factors Policy Options Accept/ Minimize/Remove Implement Options Monitor and Review

Risk Management: Policy Options - Industry • Wait for changes to SULs/GLs from EFSA Risk Management: Policy Options - Industry • Wait for changes to SULs/GLs from EFSA 2011/2? • HFMA/CRN initiate changes: Do all members apply label safety statements? Adverse Reaction reporting “system under development” Database of major reports on adverse events • Individual Companies initiate changes – possible • Do nothing – quite likely for many • So, how real is industry’s commitment to safety?

Risk Management: Policy Options - Practitioners • Safety is an unaddressed issue for some Risk Management: Policy Options - Practitioners • Safety is an unaddressed issue for some current patients • Insurer Balens (Summer 2010) – will wait for individual cases, no desire to issue guidance • Practitioner liability means doing nothing is not an option • EFSA changes to SULs/GLs will make little difference • Advice from companies is unlikely to be adequate • BANT plays a key role in maintaining standards CPD Criteria - companies should address safety issues: dose >SUL/GL, duration of use, major contraindications and warnings Formal Guidance on supplement safety would be helpful

Risk Management: Cancer Warning Royal College of Radiologists/CR-UK [2006] www. rcr. ac. uk/docs/oncology/pdf/Herbal. Supplements. Risk Management: Cancer Warning Royal College of Radiologists/CR-UK [2006] www. rcr. ac. uk/docs/oncology/pdf/Herbal. Supplements. FINALVERSION. pdf Cancer Treatment, Herbal and Nutritional Supplements • Ask patients what they are taking before commencing treatment • Urge patients to seek professional advice on diet and supplements • If patients are keen take a good quality one-a-day multivitamin and mineral; do not exceed the dose • Antioxidants may reduce the effectiveness of chemotherapy; avoid their use especially high doses • Monitor and report any adverse interaction through the Yellow Card Scheme (www. mhra. gov. uk)

Risk Management: Supplement Warnings US NIH National Center for Complementary and Alternative Medicine http: Risk Management: Supplement Warnings US NIH National Center for Complementary and Alternative Medicine http: //nccam. nih. gov/health/vitamins Alerts, Advisories and Guidelines: • Coral Calcium – false claims of cure 2004 • Vitamin E and Selenium 2008 no benefit in trials HOPE-TOO, SELECT 13% more heart failure with vit E 400 iu/day • Anticoagulants and vitamin K interactions 2003 • Infants, possible overdose with vitamin D 2010 • Parkinson’s disease and alternative treatments 2006 • Guidelines on supplements and nutraceuticals 2003 www. aace. com/pub/pdf/guidelines/Nutraceuticals 2003. pdf

Nutritional Supplements: Major Contraindications Nutrients that may be or are often contraindicated Condition Nutrients Nutritional Supplements: Major Contraindications Nutrients that may be or are often contraindicated Condition Nutrients Cancer: on treatment Folic acid, thiamin anti-oxidants Cancer: in remission Beta-carotene, retinol and others Smoking Beta-carotene Asbestos exposure Beta-carotene Alcohol excess Retinol, iron and beta-carotene Liver disease Retinol, copper, manganese and iron Diabetes and Prediabetes Retinol and possibly selenium and fish oils Peripheral neuropathy Vit. B 6 >100 mg/day, Zinc >25 mg/day Osteoporosis Retinol Liver consumers Retinol Pregnancy Retinol, high dose vitamins C and E Hypercalcaemia Calcium, vitamin D and retinol Heart Attack Beta-carotene Kidney stones Calcium and vitamin C if hyperoxaluria Drugs: Warfarin Vitamin K Folic acid Vitamin C? Renal disease Retinol, potassium Magnesium High dose B vits Copper if high saturated fat diet Haemochromatosis Iron and vitamin C > 500 mg/day Methotrexate Steroids/HRT/OC Cognitive Decline

Nutritional Supplements: Major Contraindications Approximate prevalences in millions of UK population Condition Number Condition Nutritional Supplements: Major Contraindications Approximate prevalences in millions of UK population Condition Number Condition Cancer: on treatment 0. 27 Cancer: in remission 2. 0 Smoking 12. 5 Asbestos exposure 0. 22 Alcohol excess 10 Liver disease 5. 0 Diabetes and Prediabetes 2. 0/6. 0 Peripheral neuropathy 1. 0 Osteoporosis 7 Liver consumers 0. 5 Pregnancy 0. 7 Hypercalcaemia 0. 02 Heart Attack 0. 25 Kidney stones 1. 0 Drugs: Warfarin 1. 0 0. 6 0. 5/3. 0 Renal disease 0. 25 0. 7 Haemochromatosis 0. 2 Methotrexate Steroid. S/HRT/OC Cognitive Decline Number

Risk Management: Options – The Big Picture • Information Published cases, review articles, adverse Risk Management: Options – The Big Picture • Information Published cases, review articles, adverse events reported to MHRA • Education Professionals, Public, Industry and Media “ Without a grounding in nutrition it is impossible for anyone to know whether diets are satisfactory, whether an unfamiliar recipe is nutritious or not, whether advice in an advertisement or an article in a newspaper is good advice. ” Magnus Pyke. Preface to Manual of Nutrition 1945 • Regulation “Regulation is effective, risk-based and proportionate, is clear about the responsibilities of food business operators, and protects consumers and their interests from fraud and other risks. “ Food Standards Agency Targets 2010 -2015 • Legislation “Nestle believes that, as a general rule, legislation is the most effective safeguard of responsible conduct. ” www. nestle. com/All. About/All/About. Nestle. htm [26/1/10]

Risk Methodology and Supplement Safety – Done! Adapted from FAO/WHO 1995/1997/1998 www. fao. org/docrep/008/ae Risk Methodology and Supplement Safety – Done! Adapted from FAO/WHO 1995/1997/1998 www. fao. org/docrep/008/ae 922 e 03. htm 2. Risk Communication Patient Professionals Authorities Industry Public 1. Risk Assessment 3. Risk Management Possible Adverse Effects Dose-Response Effect Exposure Assessment Modifying Factors Policy Options Accept/ Minimize/Remove Implement Options Monitor and Review

The End Small workshops on Nutritional Assessment and Safety of Supplements will be available The End Small workshops on Nutritional Assessment and Safety of Supplements will be available in UK from late 2011/12 Thank you for your participation. If you would like a two sides of A 4 sheet summarizing the main contraindications to nutritional supplements please email me dr. [email protected] co. uk