Download Safety of Nutritional Supplements

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
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 & DoH 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
CNH8. 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 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 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
• “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
50%
45%
Total
Multi Vit+Mins
40%
Multivitamins
35%
Vits A,C+D
30%
Multivits+Iron
25%
Vitamin C
20%
Iron only
15%
Minerals
10%
CLO +Fish Oil
EPO
5%
0%
•
•
•
Infants
Children
Adults
F-L Elderly
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
Intakes from Food, and Food + Supplements < LRNI
Food Sources
30%
Food + Supplements
27%
24%
21%
18%
15%
12%
9%
6%
3%
0%
Vit A
B1
B2
B3
B6
B12 Folate Vit C
Fe
Ca
P
Mg
K
Zn
I
Proportion of Adult Females with low Intakes
Intakes from Food, and Food + Supplements < LRNI
Food Sources
30%
Food + Supplements
27%
24%
21%
18%
15%
12%
9%
6%
3%
0%
Vit A
B1
B2
B3
B6
B12 Folate Vit C
Fe
Ca
P
Mg
K
Zn
I
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
• State of Adequacy
• State of Negative Balance:
• State of Positive Balance:
1. Poor Intake
2. Reduced absorption
3. Increased losses
4. Increased requirement
5. Altered metabolism
illness, alcohol, drugs, genetics
1. Increased Intake
2. Increased absorption
3. Reduced losses
4. Reduced requirement
5. Altered metabolism
illness, alcohol, drugs, genetics
increased sensitivity to nutrient
• Decline in Tissue Stores
• Increase in Tissue Stores
• Loss of Function:
• Loss of Function:
1. Symptoms
2. Physical Signs
3. Organ Failure
• Death
1. Symptoms
2. Physical Signs
3. Organ Failure
• Death
Risk Methodology and Supplement Safety
Adapted from FAO/WHO Environmental Health Criteria 240 (2009) and 1995/1997/1998
www.fao.org/docrep/008/ae922e/ae922e03.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 1995/1997/1998
www.fao.org/docrep/008/ae922e/ae922e03.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 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
May 2003
Expert Group on Vitamins and Minerals, FSA
Safe Upper Levels and Guidance Levels
www.food.gov.uk/multimedia/pdfs/vitmin2003.pdf
•
Review of Dietary Advice on Vitamin A
Sept 2005
Scientific Advisory Committee on Nutrition
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
Feb 2006
Scientific Committee on Food, European Food Safety Authority
http://europa.eu.int/comm/food/fc/sc/scf/index_en.html
•
Mortality in Randomized Trials of Antioxidant
Supplements for Primary and Secondary Prevention
Mar 2007
Bjelakovic G et al JAMA.2007;297:842-857
www.cochrane.org/reviews/en/ab007176.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 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 Level
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; 138:1992S-1995S
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 B6 = 2
• Folic acid = 5
• Vitamin E = 36
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, Zn,
Severe – large amounts of vitamins A, D, C
• Chronic Toxicity
Osteoporosis – vitamin A
Nervous system – vitamin B6, 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 B12, n-3 EFAs and others
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 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 data
50%
Males 18-64 yrs
45%
Females 18-64 yrs
40%
35%
30%
25%
20%
15%
10%
5%
0%
Vit. A
B-Ct
Vit. C
Mn
Cu
Zn
Fe
Vit B6
Folate
Thiam
• 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
EFSA EU
US IoM
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)
25
Vitamin B6 mg (TSI)
10
No
conclusion
[Avoid]
(2000)
40
100?
(100)
Folic Acid ug
400
1000
?
1000
(1000)
Thiamin mg
100
100
120
No limit
None set
Use of Nutritional Supplements in UK
National Diet and Nutrition Surveys
50%
45%
Total
Multi Vit+Mins
40%
Multivitamins
35%
Vits A,C+D
30%
Multivits+Iron
25%
Vitamin C
20%
Iron only
15%
Minerals
10%
CLO +Fish Oil
EPO
5%
0%
•
•
•
Infants
Children
Adults
F-L Elderly
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
• 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 (19-64yrs) M 9%, F 4%
- elderly (65+ yrs) M 11%, F10%
• 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
>50,000ug/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, CoF Composition of Foods HMSO/RSC
25000
20000
MoN 1947
CoF 3rd 1960
CoF 4th 1978
CoF 5th 1991
CoF 6th 2002
15000
10000
5000
0
Ox Liver
Lamb Liver
Retinol Content of Supplements
Safe Upper Level 800 ug/day
•
•
•
•
•
•
Cod Liver Oil 10 mls
1,800ug
Holford Multivitamin
1,200ug
HealthSpan 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
CLO in Norway reduced by
None
None
None
70%
Retinol Status of the British Population (estimates)
Plasma Retinol Levels NDNS Data Collected 1990-2001
Deficient <0.7/0.75 umol/l
Borderline 0.75-1.0 umol/l
Adequate 1.0-2.8 umol/l
Mild Excess 2.8-3.5 umol/l
Significant excess >3.5 umol/l
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
1.5 - 4.5 yrs
4 - 18 yrs
19 - 64 yrs
F-L 65+ yrs
Inst 65 + yrs
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
• 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 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
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 bisphosphonate 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 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 65-84yrs
65.5
43.0-91.0
Cases
1.95
1.88-2.02
Controls
2.00
1.96-2.05
NDNS 65-84yrs
2.20
1.2-3.5
Cases
40.0
38.3-42.0
Controls
41.9
40.8-43.0
NDNS 65-84yrs
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 retinol
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
50%
40%
30%
20%
10%
0%
50%
40%
30%
20%
10%
0%
AP Men
AP Women
65-74 yrs 75-84 yrs
85+yrs 65-84 yrs 85+ yrs
Inst
Inst
GGT Men
GGT Women
65-74 yrs 75-84 yrs
85+yrs
65-84 yrs 85+ yrs
Inst
Inst
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
Vitamin A: Liver Disease and Alcohol
DNSBA 1989 alcohol consumption and plasma retinol in British Adults
Men
3.5
Women
3
2.5
2
1.5
1
0.5
0
Nil
<168g/wk
168-400g/wk
>400g/wk
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 6mg, Vitamin C 120mg, Vitamin E 30mg, Zinc 20 mg, Selenium 100ug
Placebo - Before
3
Placebo - After
2.5
Active - Before
Active- After
2
1.5
1
0.5
0
Retinol
Beta-carotene
Zeaxanthin/Lutein
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
• RBP4 is produced by adipocytes and is the main carrier
protein for retinol in serum
• Elevated RBP4 is associated with abdominal obesity,
raised TG levels, decreased HDL levels and systolic
hypertension
• Serum RBP4 correlates with insulin resistance in obese
and pre-diabetic subjects
• Serum RBP4 and serum retinol levels are moderately
correlated
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 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/m2 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 B3 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 umol/l
Sex
Supplements
Presenting Problem
Cause
4.45 umol/l
83 F
800 ug
More in past
Headaches, severe
osteoporosis, alcohol 2u/day
Self
3.74 umol/l
M 58
~ 800 ug
None for 4 months
Renal impairment, obese,
hypertension, alcohol 4u/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, T2D, liver
eater, alcohol+, Na valproate
Multiple
3.81 umol/l
F26
~400 ug
Cornelia De Lange, 40kg
epilepsy, Na valproate
Multiple
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
1800
DNSBA (1990)
NDNS (2002)
•
•
1800
1500
1500
1200
1200
900
900
600
600
300
300
0
0
16/19-24 yrs
•
•
All Sources - Retinol Equiv.
25-34 yrs
35-49 yrs
DNSBA (1990)
NDNS (2002)
16/19-24 yrs
25-34 yrs
35-49 yrs
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 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 RBP4 if obese, T2D 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, 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 T2D 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
• 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 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% current smokers
• 2x2 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 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 [RR1.46]
cardiovascular disease [RR1.26]
• 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
• 2x2 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 (>11g 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
•
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 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/CG48FullGuideline.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 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
• 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 – 3.42 [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, DMT1, 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 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
whether there are risks associated with dietary
exposure to manganese”.
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 ~ 15mg/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 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)
•
•
•
Data derived from 323 subjects; controls(106), low-exposure (122) and high
exposure (95) workers in a smelting plant in China
pMIR 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 blood Mn and MRI changes
Fotron DM et al. Gut 2004;53:587-592
•
Neurological problems related to drinking water Mn conc. (1.8-2.3 mg/l)*
Kondakis XG et al Arch Environ Health 1989;44:175-8
•
High total intakes of iron and manganese increased risk of PD
Powers KM et al Neurology 2003;60:1761-1766
•
Impairment of postural balance and high hair Mn (mean 4.4ug/g)*
Standridge JS et al J Occup Environ Med 2008;50:1421-9
Reproduction
•
Reduced sperm motility and concentration with high blood Mn
Wirth JJ et al Epidemiology 2007;18:270
•
Lower Infant Birth Wt assoc. with high (>4.0 ug/dl) or low maternal blood Mn
Zota AR et al Epidemiology 2009;20:367-73
Child Development
•
Reduced child intelligence and high hair Mn (Mean 471.5 ppb)*
Wright RO et al Neurotoxicity 2006;27:210-6
•
Reduced child intelligence and high blood Mn (1.4 ug/l) and high blood Pb
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 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 yrs
• Enzyme cofactor in cartilage
• Two US trials Glucosamine plus
Manganese 34 - 45mg/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 1-5mg
• High Dose Supplements
Nutri many products <60mg/day
Health Plus Zinman 9mg/day
ZMC 15mg/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
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
• 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 10mg 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 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 1gm 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,
RR1.16 [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 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 - 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, 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 T2D 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
• 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/art2036.html
Pictures of selenium excess in humans
UK Food Content of Selenium ug/100g
McCance and Widdowson’s The Composition of Foods (Year of Publication)
250
225
200
175
150
125
100
75
50
25
0
5th (1991)
6th (2002)
White
Brd
Whole
Brd
Whole
Milk
Beef
Pork Chicken
Stew St. Chops Roast
Grilled
Lamb
Leg
Roast
Lambs' Lambs'
Kidneys Liver
Fried
Fried
Pigs'
Liver
Stewed
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;147:217-223
• RDBPC trial of yeast-derived selenium 200ug/day in
1312 participants
• Reduced rates of lung, prostate and colorectal cancers
over 7.7 years
• Self-reported T2 diabetes HR 1.55 [95% CI:1.03, 2.23]
• T2D risk greater if baseline Se >121.6ng/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. 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 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
Male
2
Female
1.8
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
0
4-6yr
7-10yr 11-14yr 15-18yr 19-24yr 25-34yr 35-49yr 50-64yr
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 T2D
• 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 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
T2 diabetes for years.
Doctor
Improved with weight loss
2.8 umol/l
F 64
200-300 for Chronic sinusitis, CFS
years
(1.0-1.8umol/l)
Self +
Nut Pract
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 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
• 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] 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, Zn,
Severe – large amounts of vitamins A, D, C
• Chronic Toxicity
Osteoporosis – vitamin A
Nervous system – vitamin B6, 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 B12, n-3 EFAs and others
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, SL. J. Neurol, Neurosurg and Psych 2005;76:750-751
• 53 yr old woman; 4-8 capsules of Zinc gluconate (50mg) >1yr
• 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 8.3g/dl (11.7-15.7)
MCV 112.5 uM (80-100)
WBC count 2.6 x103 (3.8 - 10.8)
• Normal vitamin B12, 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 2mg 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, 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 T3 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% 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 ~15mg /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 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 [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 <50yrs
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 – 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 B12 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
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
<350 nmol/l
350-1463 nmol/l
>1460 nmol/l
1.5 4.5 yrs
4 - 18
yrs
19 - 64 F-L 65+ Inst 65
yrs
yrs
+ yrs
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 had a colorectal adenoma
Folic acid, FA, 1000 ug/day or placebo for 5 yrs
Surveillance colonoscopies at 3ys and 5 yrs
Adenomas: FA vs Placebo: 44.1% vs 42.4% (3yrs) and 41.9% vs 37.2% (5yrs)
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;86:271-3
• 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;303:1603-1609
•
•
•
•
•
•
•
DBPC Trial 238 men and women (av. age 57 yrs)
All had had Type 1 or 2 diabetes and mild diabetic nephropathy
Placebo or daily Folic acid 2.5 mg, vitamin B6 25 mg and vitamin
B12 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/m2, very little B12/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. B12 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 B12 status (Dangour 2008)
• NHANES III in the US: those with a serum B12 <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):702S-706S
• EPIC no overall association of prostate cancer risk and
the status of these nutrients
However in those with a high vitamin B12 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 1990-2001
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
>1.25
<1.25
1.5 - 4.5 4 - 18 yrs 19 - 64
yrs
yrs
F-L 65+ Inst 65 +
yrs
yrs
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 (TKTL1)
and this may allow enhanced oxygen-independent growth
• Strong expression of TKTL1 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 - 1783] mg/day
• Food sources: dairy foods (48%), cereals: suppl’nts M1%, F5%
• 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 in conjunction with all bisphosphonates
• Large placebo-controlled trial of daily supplements of:
calcium 1000mg
vitamin D3 400 IU (10ug)
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 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
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 = 0.057
• 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 - 3.7 [95% CI: 0.2 – 9.7] ug/day
• Food sources: oily fish (24%), meat: suppl’nts M12%, F25%
• 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)
13,331participants 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;369:1090-98
• 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
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 mg
260 ug
• Tin
• Cobalt
• Vanadium
13 mg
1400 ug
7.5mg
Uncertain adverse effects
Could aggravate nickelsensitive eczema
Uncertain adverse effects
Uncertain adverse effects
Uncertain adverse effects
Other Minor Reactions
• Chewable supplements
(Calcium and Vit C)
- diarrhoea due to intolerance of
sweetener sorbitol/xylitol
• Multivitamins
(Centrum and C50 +)
- skin rashes due to azo dye colouring
agent
• Vitamin B3 niacin
(not nicotinamide)
- flushing due to niacin content
especially if >50 mg
• Vitamin B2
- 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/ae922e/ae922e03.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, 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 and 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
• 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 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 <7mg/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 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 B6
>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
Vitamin A >800 ug
of preformed
retinol
Label Statement
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
>200 mg
This product contains iron, which, if taken in
excess, may be harmful to very young
children. Keep out of sight and reach.
Iron
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 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 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 and 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] Mn10 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.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 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
2nd 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/ae922e/ae922e03.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 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 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/HerbalSupplementsFINALVERSION.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://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/Nutraceuticals2003.pdf
Nutritional Supplements: Major Contraindications
Nutrients that may be or are often contraindicated
Condition
Nutrients
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. B6 >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 >
500mg/day
Methotrexate
Steroids/HRT/OC
Cognitive Decline
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
0.5/0.5/3.0
Renal disease
0.25
0.7
Haemochromatosis 0.2
Methotrexate
SteroidS/HRT/OC
Cognitive Decline
Number
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/AllAbout/All/AboutNestle.htm [26/1/10]
Risk Methodology and Supplement Safety – Done!
Adapted from FAO/WHO 1995/1997/1998
www.fao.org/docrep/008/ae922e/ae922e03.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 in UK from
late 2011/12
Thank you for your participation.
If you would like a two sides of A4 sheet
summarizing the main contraindications to
nutritional supplements please email me
[email protected]