CAUTION:
MULTIVITAMINS MAY BE
TOXIC
Kristal Benally
Megan Gleason
Heather Kho
Emma Pindra
Click and Enjoy
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Multivitamins
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OK, lets be honest. When was the last time you took
multivitamins?
What did they actually contain?
According to Standford.edu the content list is long. → → →
Observe the Maximum Safety Intake
Aren’t vitamins good for us?
Why are there safety limits for what’s good for us?
As Toolson said on the first day of class;
“Everything is toxic, its the dose that
determines whether it is beneficial
or not. There is no free lunch.”
http://www.ksl.stanford.edu/people/kpfleger/multivitamins/cached/
www.mothernature.com_cg_multi_vitamins.asp.html
Vitamin Safety Margins
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We blazed through the long list of vitamins available and found that Vitamins A, C, E, and D had
multiple reports of toxicity. We chose these vitamins keeping in mind their prevalence in
multivitamins.
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Vitamin A toxicity can cause skin discoloration, bone abnormalities, vomiting, diarrhea, and
teratogenic effects.
• Caused by increased concentrations of retinyl esters within the liver.
Vitamin C toxicity causes diarrhea, vomiting, and stomach cramps.
• Due to overloading of iron molecules in the small intestine.
Vitamin E toxicity produces increased risk of hemorrhaging.
• Mechanism is not yet known.
Vitamin D toxicity can cause anorexia, weight loss, polyuria, heart arrhythmias, increased calcium
concentrations in the blood, and kidney stones.
• Primarily caused by increase calcium absorption in the GI tract.
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Mechanisms of vitamin toxicity are not fully understood, however, there have been several
hypothesized mechanisms. The most supported mechanisms are discussed here.
Vitamin A (Retinol)
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Fat-soluble vitamin
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Two Forms found in daily diet
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Preformed- Found in animal products
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Eggs, meats/fish, and dairy products
Pro-vitamin- Found in plant-based foods, most
common form is beta-carotene.
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Sweet potatoes, carrots, dark leafy greens,
winter squashes, lettuce
http://cdn.theatlantic.com/static/mt/assets/food/Supplements-SS-Post.jpg
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Dried apricots, cantaloupe, bell peppers,
tropical fruits
Dietary supplement forms
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Retinyl acetate or retinyl palmitate (preformed)
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Beta-carotene (pro-vitamin)
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Combination of preformed and pro-vitamin A
http://www.medindia.net/patients/lifestyleandwellness/images/vitamin-a-rich-
Recommended Dietary Allowance
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Dosage Units: Recommended daily allowance for vitamin A are given as mcg of retinol activity
equivalents (RAE) to account for the different forms of vitamin A.
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1 IU retinol = 0.3 mcg RAE
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1 IU β-carotene from dietary supplements = 0.15 mcg RAE
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1 IU β-carotene from food = 0.05 mcg RAE
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1 IU ɑ-carotene or β-carotene = 0.025 mcg RAE
http://ods.od.nih.gov/factsheets/VitaminA-HealthProfessional/
Vitamin A- Biochemical Functions
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Metabolic Pathways
Retinyl ester ↔ Retinol/Vitamin A ↔ Retinal → Retinoic Acid
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Retinyl Ester: Stored in the liver until further notice.
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Retinol: Transported from liver to tissues through the plasma. Retinol binds to Retinol Binding
Protein (RBP) then once in the plasma RBP binds to transthyretin (TTR) to form a Holo-RBPTTR complex.
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Retinal: Aldehyde group, 11-cis retinal, binds with Opsin to form Rhodopsin.
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Retinoic Acid: Acid binds and activates two nuclear protein receptors, retinoic acid receptor
(RAR) and retinoid X receptor (RXR), which induce gene transcription.
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Improves vision by providing retinal in the synthesis of rhodopsin.
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Stimulation to the function of the immune system and increases resistance to infections.
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Maintains healthy skin by increasing cell proliferation of epithelial cells.
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Vitamin A supports cell growth and differentiation which is important in development of a fetus.
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Influencing the development of bone growth by actively regulating osteoblasts and osteoclasts.
Interactions
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Vitamin A Toxicity
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Excessive amounts of storage form of Vitamin A in the liver causing it to become saturated.
Retinyl esters begin to diffuse into the bloodstream causing random reactions with cell
membranes rather than with Holo-RBP-TTR complex.
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Can be caused by Accutane
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Carotenemia- increased pro-vitamin A intake causes skin to turn yellow-orange
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Hypervitaminosis A- increased intake of preformed vitamin A causing retinyl esters to
circulate with plasma lipoproteins.
Symptoms
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Acute: Nausea, vomiting, diarrhea, weakness, increased intracranial pressure.
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Chronic: Skin desquamation, chronic fatigue, double vision, liver damage, bone abnormalities,
joint pain, alopecia, coma, renal dysfunction.
Metabolism- Normal Dosage
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http://www.mdpi.com/nutrients/nutrients-05-02646/article_deploy/html/images/nutrients-05-02646-g001-1024.png
Active retinol form must be
deactivated by transformation into
retinyl esters.
Retinyl esters are a form of storage
which could later be transformed
back into retinol for either gene
transcription or rhodopsin
synthesis.
Retinyl esters are stored in the
stellate cells within the liver.
• Hence, fat-soluble vitamin.
Metabolism- Over consumption
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http://www.mdpi.com/nutrients/nutrients-05-02646/article_deploy/html/images/nutrients-05-02646-g0011024.png
Increased intake of Vitamin A causes large
concentrations of retinyl esters after transformation.
Over loading of retinyl esters in the stellate cells causes
saturation of the liver.
Retinyl esters begin to leak out of the liver and invade
the bloodstream causing liver and renal damage.
Increased levels of Vitamin A have been reported to
interact with the metabolism of Vitamin D, E, and K.
Hypervitaminosis A disrupts cell proliferation and
differentiation in fetal development which can lead to
teratogenic effects.
Treatment
• Immediately ceasing vitamin A intake
• Intravenous fluids and diuretics to counteract effects of
diarrhea and vomiting.
• Immediate lumbar puncture as treatment for intracranial
pressure
http://paleo.com.au/wp-content/uploads/2013/05/Paleo-Diet-Primal-Vitamin-A-Beta-CaroteneToxicity.png
Vitamin C (Ascorbic Acid)
Fruits with the highest sources of vitamin C
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Citrus fruits and juices, such as orange and grapefruit
Cantaloupe
Kiwi
Mango
Papaya
Pineapple
Strawberries, raspberries, blueberries, cranberries
Watermelon
Vegetables which contain a high source of Vitamin C
• Broccoli, Brussels sprouts, cauliflower
• Green and red peppers
• Spinach, cabbage, turnip greens, and other leafy
greens
• Sweet and white potatoes
• Tomatoes and tomato juice
• Winter squash
• Vitamin C is currently being added to some cereals and beverages, such as milk. For the best intake of vitamin C
is to eat the vitamin containing fruits and vegetables raw, instead of cooked
• Deficiency of Vitamin C could lead to various tissue in the body to break down, general health and repair of the
body also become affected, and with persistent deficiency can lead to scurvy.
Recommended Dietary Allowance
Infants and children
• 0-6 months
• 7-12 months
• 1-3 years
• 4-8 years
• 9-13 years
40 mg/day
50 mg/day
15 mg/day
25 mg/day
45 mg/day
Adolescents
• Girls 14-18 years
• Pregnant teens
• Lactating teens
• Boys 14-18 years
65 mg/day
80 mg/day
115 mg/day
75 mg/day
Adults
• Men 19+
• Women 19+
• Pregnant women
• Lactating women
90 mg/day
75 mg/day
85 mg/day
120 mg/day
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It is suggested to not exceed 2 grams/day
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Overconsumption of vitamin C is rare due as it is readily soluble, with excess removal by kidneys
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Vitamin C is used in the body to reduce copper and iron
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Vitamin C is also used as a protective antioxidant
Vitamin C - Biochemical Function
• Amino acid and protein
metabolism
• Collagen synthesis
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Connective tissue essential for
wound healing
• Thyroxine Synthesis
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Thyroid hormone vital to
digestion, heart + muscle function,
brain development
• Neurotransmitter synthesis:
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Epinephrine + norepinephrine
(utilizing tyrosine derived
cofactor)
• Key facilitator in absorption of
nonheme iron
• Highly effective antioxidant
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Protects against DNA mutations
Regenerates and recycles other
antioxidants (vitamin E alphatocopherol)
• Promotes and maintains
immunocompetence
Mechanism of Absorption
• Vitamin C is absorbed in the lumen of small intestine via
active transport processes
• Tissue saturation increases proportionally with vitamin c
uptake
• Vitamin C retained via renal-tubular reabsorption
mechanism; excess vitamin c excreted via urine
• Oxidation of Vitamin C from
JAMA. 1999;281(15):1415-1423. doi:10.1001/jama.281.15.1415
Copyright © 2015 American Medical Association. All rights reserved.
L-ascorbic acid to Dehydro-Lascorbic acid releases two
donor electrons which
become available for other
biochemical reactions.
Ascorbic acid enhances the absorption of nonheme iron
• Non-heme iron enters the GI tracts in Ferric form Fe³⁺
• Fe³⁺ is not bioavailable and has to be converted into
ferrous iron Fe²⁺
• This reduction is assisted by Ascorbic acid and its release
of electrons
• Ascorbic acid reduces Fe³⁺ in the lumen of the small
intestine
Vitamin C Toxicity
Though very rare if vitamin C is over consumed it can cause
• Diarrhea
• Nausea
• Stomach cramps
Usually treated by stopping further supplement intake
Increased dosage of vitamin C increases iron uptake conferring a therapeutic
benefit to anemic individuals
However, individuals with hemochromatosis are susceptible to iron overload and
consequently must monitor their vitamin C intake
Vitamin E
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Potent fat soluble antioxidant
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Only vitamin actively maintained in
human body
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Food sources: nuts, seeds, green leafy
vegetables, vegetable oils, fish, tofu
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Alpha-tocopherol is the most abundant
and metabolically active component of
vitamin E (only component maintained
in plasma) in both whole foods and
supplements
90% Americans are deficient
(reported average 6.9mg/day in
contrast to RDA of 15 mg/day)
Recommended Daily Allowance (RDA)
http://ods.od.nih.gov/factsheets/VitaminE-HealthProfessional/#en6
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1 mg alpha-tocopherol equates to 1.49
IU natural and 2.22 IU synthetic form
of vitamin E
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People need 50% more IU of synthetic
alpha tocopherol (from supplements)
to obtain same amount from whole
foods
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Supplements have >100 IU
(significantly more than RDA)
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1999-2000 National Health and
Nutrition Examination Survey found
that 11.3% adults took vitamin E
supplements containing at least 400
IU
Function
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Antioxidant (neutralizes free radicals)
• Prevents cell damage
• Prevents lipo peroxidation
• maintains cell membrane integrity
• protects against cardiovascular
diseases
• Immunity
• supports cellular mediated response
(promotes immature T cell
differentiation)
• Blood
• Formation of erythrocytes
• Prevents clot formation (via vasodilation)
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Brain health
• Maintains normal levels of DHA
(omega 3 fatty acid required for
structural formation and
maintenance of brain matter)
• Disease prevention
• Prevents LDL oxidation which upon
aggregation in vessels results in
atherosclerosis
• Decreased risk of dementia
• Slower progression of Alzheimers
Exists in 8 forms, as tocopherols + tocotrienols
Chemical Properties | (alpha,
beta, gamma, and delta)
▪ Alpha–tocopherol is most metabolically active form of Vitamin E
•Predominant form in supplements
•Primary antioxidant for LDL’s (maintains plasma membrane
integrity) and protects against chronic diseases
•Upon neutralizing a free radical, antioxidant property of alphatocopherol restored by Vitamin C
▪ Gamma-tocopherol while less metabolically pronounced lower levels
within humans, is most common form in American diets
▪ Potent scavenger of lipoprotein electrophiles
▪ Possesses anti inflammatory properties (unlike the alpha form)
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Mechanism of Absorption
Vitamin E requires de-esterification in stomach
Aggregation of vitamins by micelles
Bile salts emulsify the vitamin into water soluble form
Small intestine enterocytes absorb alpha-tocopherol
Transportation from GI to liver via chylomicrons (lipoproteins) and erythrocytes in the blood and lymph
Liver incorporates alpha tocopherol into LDL’s and HDL’s for subsequent distribution to respective organs
Vitamin E toxicity
▪ Overconsumption of vitamin E from whole food sources is rare
▪ Toxicity primarily from excessive vitamin E supplementation
▪ Recommended daily dose of 1000 mg/day (1500 IU)
▪ Primary toxic effect : Increased bleeding
▪ Reduced platelet aggregation and blood coagulation(clotting)
▪ Especially critical during trauma or injury
▪ increased risk of hemorrhaging (internal + external)
▪ Increased risk of hemorrhagic stroke (22%)
▪ However, research shows decreased risk of ischemic stroke (10%)
▪ Drug interactions must be carefully considered
▪ Anticoagulants (ex. Warfarin, Plavix) and non steroid anti inflammatory drugs
(ex. Aspirin, ibuprofen) may result in increased hemorrhaging
Ultimately, while vitamin E supplementation does demonstrate various
benefits, natural forms of vitamin E (from whole foods) provide much
greater therapeutic benefits with significantly reduced risk for toxicity.
Vitamin D
• Vitamin D is a fat-soluble vitamin.
• Two dietary forms: D2 (ergocalciferol, from yeast and plant sterol) and D3
(cholecalciferol, from a precursor for cholesterol when generated in the skin)
• Whole food sources:
• Flesh of some fish: salmon, tuna, mackerel
• Fish liver oils (best source)
• Beef liver, egg yolks, cheese (small amounts)
• Some mushrooms (grown under controlled exposure of UV light)
• Another source of Vitamin D is the sun-- exposure to ultraviolet rays triggers endogenous
Vitamin D production
• The main source of Vitamin D comes from food fortified with Vitamin D:
• Milk, some yogurts, most breakfast cereals, some brands of orange juice, and infant
formulas
Recommended Daily Allowances
• Vitamin D intake should not reach excess
of 250-1000 mcg/day over a prolonged
period of time
• Excess intake due to over
supplementation rather than from food
sources or sun exposure
• However, too much sun exposure can
result in the photogdegradation of D3
(formed previtamin) prior to it being able
to be utilized
Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academy Press, 2010.
Vitamin D: Biochemical Functions
The body uses Vitamin D for a number of functions:
• Calcium absorption in the gut
• Maintains calcium and phosphate serum concentration for normal
mineralization of bones
• Used in bone growth and remodeling
• Modulation of cell growth
• Modulation of protein coding genes
•proteins involved in cell proliferation, differentiation, and
apoptosis
• Neuromuscular and immune function
• Reduction of inflammation
Vitamin D: Biochemical Functions
• Vitamin D is measured in the body by serum 25(OH)D
concentrations in the blood.
• This serum level is the indicator for Adequate Intake (AI) of
Vitamin D.
Vitamin D: Mechanism of Absorption
Metabolic Pathway
• From skin/digestive tract D3
enters the circulatory system
• Accumulates in the liver and
undergoes the first
hydroxylation: 25(OH)D
• Then moves to the kidneys
and undergoes another
hydroxylation into the
biologically active form of
Vitamin D: 1, 25(OH)2 D
http://www.nature.com/nrc/journal/v7/n9/fig_tab/nrc2196_F1.html
Vitamin D: Interactions
• Vitamin D deficiencies are the more common interaction or lack of,
however rare, it is possible to intake too much, Hypervitaminosis D, and
have it reach upper intake levels.
• Symptoms (non-specific) include:
• Anorexia
• Weight loss
• Polyuria
• Heart arrhythmias
• Increased calcium levels in the blood (that can lead to):
• Vascular and tissue calcification, that damages the heart,
kidneys, and blood vessels
• Kidney stones (in postmenopausal women)
Vitamin D: Interactions
• Vitamin D intoxication (VDI) is another possible diagnosis when serum
25(OH)D levels are above the upper intake levels.
• This is primarily caused in pediatrics who are being treated for Rickets
without having serum 25(OH)D levels checked before treatment.
• VDI is indicated by hypercalcemia, depending on the severity of
hypercalcemia symptoms can be observed in:
• GI, renal, central nervous, cardiovascular, and musculoskeletal
systems
• Eyes and skin
Vitamin D: Toxicity Treatment
Hypervitaminosis D and Vitamin D Intoxication
• Correct hypercalcemia
• Discontinue intake of Vitamin D
• Switch to low Calcium/Phosphorus diet
• IV fluids
• Loop diuretics
• Glucocorticoids or Prednisolone (steroids)
• Calcitonin (hormone reducing blood calcium levels)
• Possible hospitalization for treatment and observation (if VDI is severe)
Conclusion
• Overall Vitamin toxicity can be either very rare or highly
dangerous.
• Hypervitaminosis A, C, E, or D can lead to serious
problems as previously stated.
• Vomiting, diarrhea, stomach cramps, skin
discoloration, intracranial pressure, teratogenic
effects, heart arrhythmias, kidney stones, and
increased hemorrhaging (just to name a few).
• Take home message: Take vitamin supplements when
needed and as directed. AND…
There is no such thing as
free lunch
Thanks for reading.
Vitamin A Sources
http://www.nlm.nih.gov/medlineplus/ency/article/002400.htm
http://ods.od.nih.gov/factsheets/VitaminA-HealthProfessional/#h2
https://www.ebi.ac.uk/interpro/potm/2005_6/Page2.htm
http://www.healthaliciousness.com/articles/food-sources-of-vitamin-A.php
http://www.fao.org/docrep/004/y2809e/y2809e0d.htm#bm13.8
http://www.merckmanuals.com/professional/nutritional-disorders/vitamin-deficiencydependency-and-toxicity/vitamin-a
• http://flipper.diff.org/app./items/info/6430
• http://emedicine.medscape.com/article/819426-clinical
• Gropper, Sareen S., and Jack L. Smith, 2013, Advanced Nutrition and Human Metabolism, Wadsworth,
Belmont, CA, 371 p.
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Vitamin C Sources
• Maiken Lindblad , Pernille Tveden-Nyborg and Jens Lykkesfeldt. Regulation of Vitamin C
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Homeostasis during Deficiency. Nutrients 2013, 5(8), 2860-2879; doi:10.3390/nu5082860
http://www.drugbank.ca/drugs/DB00126
http://jama.jamanetwork.com.libproxy.unm.edu/article.aspx?articleid=189543
http://eds.b.ebscohost.com.libproxy.unm.edu/eds/detail/detail?sid=dac8655b-9212-4093-83c3807c56f908ee%40sessionmgr198&vid=0&hid=111&bdata=JnNpdGU9ZWRzLWxpdmUmc2NvcGU9
c2l0ZQ%3d%3d#db=e000xna&AN=398814
http://www.annualreviews.org.libproxy.unm.edu/doi/abs/10.1146/annurev.nu.14.070194.00210
3
http://www.mdpi.com/2072-6643/5/8/2860/htm
http://ajcn.nutrition.org/content/73/1/93.full
http://www.wjgnet.com/1007-9327/13/4716.pdf
http://www.ncbi.nlm.nih.gov/pubmed/6940487
Vitamin E Sources
• http://www.hsph.harvard.edu/nutritionsource/vitamin-e/
• https://www.uic.edu/classes/phar/phar332/Clinical_Cases/vitamin%20cases/vitamin%20E/Vit%
20E%20Physiology.htmhttp://healthyeating.sfgate.com/can-happen-someone-taking-excessiveamounts-vitamin-supplements-7485.html
• http://www.livestrong.com/article/417483-what-does-vitamin-e-do-for-the-body/
• http://www.vivo.colostate.edu/hbooks/pathphys/misc_topics/vitamine.html
• http://www.ncbi.nlm.nih.gov/pubmed/11722951
• http://ajcn.nutrition.org/content/74/6/714.long
Vitamin D Sources
• http://www.merckmanuals.com/professional/nutritional-disorders/vitamin-deficiencydependency-and-toxicity/vitamin-d
• http://www.nal.usda.gov/fnic/DRI/Essential_Guide/DRIEssentialGuideNutReq.pdf Vitamin D, p.
225-234
• http://www.nature.com/nrc/journal/v7/n9/fig_tab/nrc2196_F1.html
• http://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/#en2
• http://www.turkishjournalpediatrics.org/?fullTextId=1031&lang=eng, Ozkan, B., Hatun, S., and
Bereket, A. Vitamin D Intoxication. Turkish Journal of Pediatrics. 2012, 54:93-98.