Vitamin A and Toxicity    
toxicity of vitamin A Saskia van der Kam 15.04.98
toxicity of vitamin A -Reply Penny Nestel 15.04.98
Vitamin A and toxicity Annoek van den Wijngaart 11.08.98
vitamin A dose in severely malnourished < 6 month old infants Michael Golden 07.08.98
Vitamin A and toxicity -Reply -Reply Janak Upadhyay 12.08.98
Vitamin A & Toxicity Joan Hildebrand 16.08.98
Re: Vitamin A & Toxicity Laurie Aomari 20.08.98


Date: Wed, 15 Apr 1998 11:51:34 +0100

From: sakatamsterdam.msf.org (Saskia VD KAM)

Subject: toxicity of vitamin A

 

What is the toxicity of Vitamin A?

In the discussion of standard administration of vitamin A during the

treatment of malnourished children, Andrew Seal PhD (Centre for

International Child Health, Institute of Child Health) writes while

citing

the book: Refugee health, published by MSF in 1997:" ... vitamin A

should not be administered if therapeutic milk (e.g. Nutriset) is

given (p.103). It also recommends that preventative doses should be

withheld if red palm oil is given in the ration. Any comments?......"

Currently MSF thinks that the recommendation given in the book

Refugee Health is outdated. MSF is fully aware of new insights, fully

supports the recommendations advocated in the new, soon to be

published WHO manual on treatment of severe malnutrition.

The recommendation in the book Refugee Health (actually written in

1994) was based on discussions held with an esteemed nutrition

specialist. The basis of the modest recommendation of the use of

vitamin A in refugee situations was lead by the fear of overdoses of

vitamin A. In 1994 MSF encountered several situations where refugees

went from one camp to an other, and some of them received several

preventative doses of vitamin A

At that time the product F100 or the vitamin/mineral supplement to

make F100 from DSM was new and experience on its use was limited.

Although MSF tries to comply with the latest recommendations of the

WHO, we still have our reservations concerning chronic and acute

toxicity of vitamin A given to malnourished. I will illustrate this

with calculations of the vitamin A actually consumed during the

treatment of severe malnutrition.

The F100 currently on the market supplies 1720 ug vitamin A per litre

milk.

The mineral mix supplies a similar amount. As we faithfully follow the

international recommendations, the home-made F-100 is made from DSM

fortified with vitamin A. This means a supply of 1200 ug per litre of

milk through the DSM. The total of vitamin A in the home-made F100

with the vitamin mineral mix results in about 3000 ug vitamin A per

litre.

A 5 years old child gets throughout the treatment about ½ litre of

milk per day, what means a consumption of 1500 ug/ day or 5000 IU

/day, if the fortified home-made F-100 is used.

A 3 year old child gets with the home made F-100 3000 IU per day.

The 5 year old child seems save, but the intake of the 3 year old

comes closer to the allowed daily vitamin A doses as expressed by the

FAO expert consultation of 1988: Requirements of vitamin A, Iron,

Folate and B12.

Daily dose to pregnant women should not exceed 10.000 IU

Daily dose infants should not exceed 3000 IU

Chronic toxicity in adults after daily dose of 25.000 IU

More specific limits can be found in: Present knowledge in nutrition

(ed. Ziegler et al. 1996),:

... Chronic toxicity, which is much more common than acute toxicity,

is induced by the recurrent ingestion over a period of weeks to years

of excessive doses of vitamin A that are usually <= 10 times the

recommended intake (RDI or RDA)........

When 400 ug is taken as recommended intake, expressed in IU and

multiplied with 10 the outcome is 13200 IU / day as a maximum.

The actual daily consumption of the five years old malnourished case

treated with home-made F-100 had an intake of 5000 IU, still less then

half of the maximum indicated in relation to chronic toxicity.

The above calculation shows that the use of double fortified milk

doesn't increase the risk for chronic vitamin A toxicity.

But what happens if, on top of that, three times an oral supplement is

given?

The three doses totals 600.000 IU in 30 days, on average this means

20.000 IU daily. Added the 5000 IU of the milk the calculated average

daily intake is 25.000 IU/ day during the treatment. This is twice

the allowed maximum for chronic vitamin A toxicity.

It can be argued that the majority of the vitamin A intake is not a

daily intake. The accent is on 3 large doses in a short interval.

Therefor acute toxicity might be a risk.

According to the work: Present knowledge in nutrition (ed. Ziegler et

al. 1996),:...

Acute toxicity is produced by one or several closely spaced very large

doses of vitamin A, usually > 100 times the recommended intake (RDI or

RDA) in adults and > 20 times the RDI in Children.......

This indicates a limit of 26.000 IU for the 5 year old child for acute

toxicity.

The daily intake of the 5 year old malnourished case is on average

25.000 IU very close to the suggested maximum related to acute

toxicity.

In the treatment daily vitamin A is consumed through the F-100, and

three supplements are given, two in the beginning and one at the end.

For the 5 year old a treatment of about 30 days means 150.000 IU in

total through the double fortified F-100.

The recommended dosage of WHO of is 3 doses in one month: 600.000 IU.

The total consumption of the double fortified milk and the vitamin a

treatment is 750.000 IU vitamin A per month. This amount is close to

4 single doses of 200.000 IU, what is suggested to be the maximum

tolerated yearly vitamin A supplement.

Tomkins, A. ; Poux, MP. Personal communication 1995.

...........

toxic effects of multiple vitamin A doses on the long term is not

known

Theoretical not more than 3-4 doses (capsules) per year, because

negative effect on immune system........

Although theoretical, these calculations learn that we should be

careful with vitamin A supplementation and we should be aware of any

hazard possible.

The situations of excess does not necessary happen within the

treatment period. The combination of the treatment for malnutrition

and possible other vitamin A supplements makes MSF alert on the

possible toxicity of vitamin A.

For example:

If the malnourished had been exposed to the vitamin A campaign,

before or just after the treatment of malnutrition, the doses

received comes close to the total of five doses. In total 950.000 IU

vitamin A in about a month time.

Although there are no toxic effects reported regarding preventive and

curative measures as proposed, little is known (by MSF) about the long

term toxic effects of an increase of that dose by situations faced by

refugees and displaced.

The calculations above are rather artificial, in the sense that we

speak about the treatment of severe malnutrition and that in the

treatment of malnutrition vitamin A status should be restored. Still

the above calculations justify the following question:

What are the toxic levels of vitamin A supplementation in malnourished

children.

 

Saskia van der Kam

Médecins Sans Frontières Holland


Date: Wed, 15 Apr 1998 09:43:30 -0400

From: Penny Nestel <penny_nestelatjsi.com>

Subject: Ngonut: toxicity of vitamin A -Reply

 

Below is a summary of issues related to vitamin A safety that Prof James Olson and I recently put together that answers some of the issues raised.

In addition, the WHO/UNICEF/IVACG Task Force (1997. Vitamin A supplements: a guide to their use in the treatment and prevention of vitamin A deficiency and xerophthalmia. 2nd edition. Geneva) recommendations are:

High dose universal-distribution schedule for prevention of vitamin A deficiency

1. non breastfed infants < 6 mo: 50,000 IU orally 2. breastfed infants whose mothers have not received supplemental vit A: 50,000 IU orally

3. infants 6-12 mo: 100,000 IU orally, every 6 mo 4. children >12 mo: 200,000 IU orally, every 4-6 mo 5. Mothers: 200,000 IU orally within 6 weeks post partum

 

High dose prevention schedule for children at high risk of vitamin A deficiency (measles, diarrhoea, resp disease, chicken pox, other severe infections, or severe PEM, or who live in the vicinity of children with clinical vitamin A def)

1. Infants < 6 mo: 50,000 IU orally

2. infants 6-12 mo: 100,000 IU orally

3. children >12 mo: 200,000 IU orally

Note: for any of the above 3 groups, those known to have received a routine high-dose vit A supplement within the last 30 days should NOT receive an additional dose.

 

Treatment schedule for xerophthalmia for all age groups except women of reproductive age

Immediately on diagnosis

1. < 6 mo: 50,000 IU

2. 6-12 mo: 100,000 IU

3. > 12 mo: 200,000 IU

Next day - same age specific dose

At least 2 weeks later - same age specific dose.

 

The therapeutic feeding experts will have to comment on both the use of vit A fortified food and supplements for this special group. For non-therapeutically fed children, consumption of vit A fortified foods concurrent with preventive and or therapeutic vit A supplements should be safe.

 

The following, written by Prof. Jim Olson and me, may help answer your concerns.

 

VITAMIN A SAFETY

by Prof. Jim Olson

 

PHYSIOLOGICAL ROLE

Vitamin A functions in vision, cell differentiation, embryonic development, spermatogenesis, the immune response, taste, hearing, appetite, and growth. Except for vision, these processes largely depend directly or indirectly on cell differentiation.

 

CONSEQUENCE OF DEFICIENCY

Vitamin A deficiency can cause eye signs, blindness, reduced resistance to infection, and an increased risk of mortality.

 

DIETARY SOURCES

Vitamin A is naturally found in the diet in two forms: 1) as preformed vitamin A (mostly as retinyl esters or retinol) from foods of animal origin such as liver, milk and milk products, fish and meat and 2) as provitamin A carotenoids, generally from plant foods, which can be biologically transformed to vitamin A. Globally, about 60% of dietary vitamin A comes from provitamins A. The conversion of provitamin A to vitamin A is increased when the vitamin A status is poor. Many factors influence the absorption and utilization of provitamin A such as the amount, type, and physical form of the carotenoids in the diet; intake of fat, vitamin A, and fibre; protein and zinc status; existence of certain diseases; and parasitic infections.

 

RECOMMENDED DIETARY INTAKES

The WHO safe recommended dietary intake (RDI) of vitamin A is 350 *g/day for infants, 400 *g/day for children 1 to 6 years, 600 *g/day for pregnant women, and 850 *g/day for lactating women. These values are expressed in total *g retinol equivalents, in which 6 *g of the most common provitamin A (beta-carotene) in food is equivalent nutritionally to 1 *g retinol. One IU of preformed vitamin A is equivalent to 0.3 *g all-trans retinol.

 

TOXICITY

Vitamin A toxicity can be classified into three categories: acute, chronic, and teratogenic. Acute toxicity results from one or several closely spaced very large doses of vitamin A, usually more than 100 times the safe RDI. The signs are usually transient and disappear after a few days. Chronic toxicity occurs with recurrent intakes over a period of months to years of excessive doses of vitamin A that are usually at least 10 times the safe RDI. Most people recover fully from chronic toxicity.

Teratogenic toxicity, in pregnant women, is known to result from substantial doses (more than 7,500 *g or 25,000 IU) of vitamin A injected daily, from larger doses (more than 30,000 *g or 100,000 IU) taken for several days or weeks, or from a single large dose (150,000 *g or 500,000 IU). Daily doses of 4,500 *g or 15,000 IU, however, have been taken by pregnant women for significant periods without apparent harm to their offspring. Safe levels of intake for periodic low doses and for single large doses have not been defined. The most sensitive period for toxic effects at all doses is the first trimester of pregnancy. Beyond the first trimester, the risk to the fetus is much less. Teratogenic toxicity results in fetal resorption, abortion, birth defects, and permanent learning disabilities in the offspring as well as toxic effects on the mother.

 

AVAILABLE SUPPLEMENTS

Most oral vitamin A supplements contain retinyl palmitate in oil together with a small amount of vitamin E. The upper safe level of vitamin A from supplements for pregnant women in regions of the world where vitamin A deficiency is common is accepted as being 3,000 *g or 10,000 IU/day.

 

POST-PARTUM SUPPLEMENTATION

Following the birth of a child, women are highly unlikely to become pregnant for a period of 6 to 8 weeks: thus, current IVACG guideline of administering a single oral dose of up to 60,000 *g (20,000 IU) within 6 to 8 weeks postpartum is considered to be safe. Furthermore, there is no evidence that the fetus of a woman who becomes pregnant 2 to 3 months after taking a post-partum mega dose is adversely affected. The reason is that retinyl ester concentrations rise rapidly in the plasma in response to an oral mega dose but they are quickly cleared, usually returning to low normal values within 24 hours. Much of a dose of vitamin A is stored in the stellate cells of the liver and, to a much lesser degree, in other tissues. Stored vitamin A is innocuous. Thus, the teratogenic toxic period for a single mega dose is limited to the first 6 to 48 hours after oral administration. No disastrous short-term outcomes have been reported in mothers of young infants where the dose and timing of post-partum vitamin A have been controlled. In summary, for healthy nonpregnant women, whether lactating or not, there is essentially no risk in taking a mega dose of vitamin A.

 

SUPPLEMENTATION DURING PREGNANCY

In pregnant women, whose estimated daily dietary intake of retinol equivalents is below 400 *g/day or in geographic areas where vitamin A deficiency is common, daily supplements of 3,000 *g preformed vitamin A (10,000 IU) or 7,500 *g (25,000 IU) at weekly intervals is recommended. Care must be taken to avoid giving supplements of vitamin A to pregnant women who frequently ingest liver and other foods rich in preformed vitamin A. Dietary carotenoids are not teratogenic.

Supplementation at the recommended levels of preformed vitamin A during one pregnancy should not adversely affect, and might well benefit, the outcome of subsequent pregnancies.

 

FORTIFIED FOODS

Fortified sugar generally contains 15 *g/g (50 IU) retinol. A preschool child eating 20 g sugar/day (about 3 teaspoons) would get 300 *g (1,000 IU) retinol/day from sugar. An adult eating 150 g sugar/day would get 2,250 *g (7,500 IU) retinol/day. Given that the upper safe level of intake from supplemental vitamin A for pregnant women is 3,000 *g (10,000 IU)/day, the safety margin would be 750 *g (2,500 IU), which is more than the equivalent of a RDI.

 

There have been no reports of toxicity in countries that fortify sugar. A daily intake of 200 to 300 *g (670 to 1,000 IU) retinol along with periodic mega dosing should not predispose children to toxicity. Furthermore, once a sugar fortification program is in place and the level of vitamin A in the sugar meets the required norms, there should be no need for mega dosing if the high-risk groups eat fortified sugar.


From: annoekatzamnet.zm (Annoek van den Wijngaart)

Subject: Ngonut: Vitamin A and toxicity

Date: Tue, 11 Aug 1998 17:52:58 +0200

 

Could anyone please send me some information on Vitamin A and toxicity?

I am interested in toxicity risk in countries where vitamin A deficiency is highly prevalent and where different interventions are in place: supplementation, fortification and dietary diversification.

Thanks,

Annoek van den Wijngaart, Associate Professional Officer, Nutrition World Health Organisation

P.O. Box 32346, Lusaka, Zambia

Tel 260-1-227803, Fax 260-1-223209, E-mail: annoekatzamnet.zm


Date: Fri, 07 Aug 1998 15:08:47 +0100

From: Michael Golden <m.goldenatabdn.ac.uk>

Subject: Ngonut: vitamin A dose in severely malnourished < 6 month old infants

 

The current recommendations are for severely malnourished children over 12

months to get 200,000 iu of vitamin A orally immediately they are admitted

and for those less than 12 months to get half this dose - 100,000 iu.

It would make more sense to me to make this recommendation only on a per kg

basis, as even at this age some mums do not know the age of their children

- and more importantly - there are many children over 12 months who have

the weight of a 3 or 6 month old child!

As we discussed before there do not seem to be any studies of comparative

doses - and it is difficult to find the rationale for the choice of these

doses in severe malnutrition.

In some centres about 10% of the children who present with severe

malnutrition are much younger - less than 6 months, often with weights of

2-4 kg. Would the vitamin A gurus please advise on whether the dose should

be 100,000 iu in this young infant group or whether it should be halved

again - say to 50,000 iu? Does anyone have figures for the incidence of

bulging fontanelle, or other sign of vitamin A toxicity, in severely

malnourished children treated with the recommended doses on an age basis.

Thank you

 

Prof. Michael H.N.Golden


Date: Wed, 12 Aug 1998 08:59:07 +0200

From: Janak Upadhyay <UPADHYAYatunhcr.ch>

Subject: Ngonut: Vitamin A and toxicity -Reply -Reply

 

Let us all use one Unit!

Dear NGOnuts:

The unit used for determining vit A requirement is

microgram or I.U. But at times it is very

confusing whether to divide or multiply by 3 or

3.33 etc. My suggestion is can we not use only one

unit not to confuse our field worker who are the

one responsible for implementing.


Date: Sun, 16 Aug 1998 11:41:20 +0100

From: joan_hildebrandatWorldvision.CA (by way of Michael Golden <refugeesatabdn.ac.uk>)

Subject: Ngonut: Vitamin A & Toxicity

 

Thanks for the excellent overview on this topic. Just a question -

under the section "Post-partum supplementation", should the value

20,000 be replaced with 200,000 in the sentence "...thus, current

IVACG guideline of administering a single oral dose of up to 60,000 *g

(20,000 IU) within 6 to 8 weeks postpartum..."?

Thanks again...

 

Joan Hildebrand, MSc, R.D., Nutrition Officer

World Vision Canada, joan_hildebrandatworldvision.ca


Date: Thu, 20 Aug 1998 12:56:10 -0400

From: Laurie Aomari <LAomariatilsi.org>

Subject: Re: Ngonut: Vitamin A & Toxicity

 

Dear colleagues:

Joan Hildebrand graciously forwarded the earlier communications to me.

Joan had a question about Penny's response. You can read Joan's question again at the very end of this email.

To clarify, the IVACG Statement Safe Doses of Vitamin A During Pregnancy and Lactation, includes the following information:

"The review of both published and available unpublished data reconfirmed earlier recommendations of IVACG (1986) that:

"--It is safe to give fertile women, independent of their vitamin A status, as much as 10,000 IU (3000 micro-grams RE) daily at any time during pregnancy.

"The recommendation was extended by noting that:

"--No benefits have been demonstrated from taking a supplement during gestation where habitual vitamin A intakes exceed about three times the RDA (about 8000 IU or 2400 micro-grams RE) from sources rich in provitamin A.

"The earlier recommendations of IVACG for supplementation of women residing in endemically deficient areas also were extended to include the following timing and doses:

"--A weekly supplement of up to 25,000 IU (8500 micro-grams RE) is a safe alternative to daily supplementation during pregnancy.

"--A single high-dose supplement of up to 200,000 IU to breast-feeding women is safe up to 8 weeks postdelivery.

"--For non-breast-feeding women, a single high-dose supplement of up to 200,000 IU is safe up to 6 weeks postdelivery."

I encourage you to read the new statement from IVACG. If you do not yet have a copy, let me know.

 

Best personal regards,

Laurie

Laurie Aomari, RD

IVACG Secretariat

 

>>> Laurie Aomari <LAomariatilsi.org> 08/20 11:08 AM >>> Dear Joan and colleagues:

Your email dated 16 August just arrived in my email. As I'm new to this listserve, I missed the earlier communications. I am naturally intrigued and would be interested in knowing more about the original discussion and questions. If anyone saved that can you forward it directly to my email address? (LAomariatilsi.org)

It would be helpful for me to know what questions are coming up in the field related to information that is contained in IVACG publications.

This could help us to add to the value of the IVACG statements. One was just recently issued on Safe Doses of Vitamin A During Pregnancy and Lactation. It will be up on our website (www.ilsi.org) very soon if you wish to read it there.

Best personal regards,

Laurie

Laurie Aomari, RD

IVACG Secretariat

 

>>> by way of Michael Golden <refugeesatabdn.ac.uk> <joan_hildebrandatWorldvision.CA> 08/16 6:41 AM >>>

Thanks for the excellent overview on this topic. Just a question - under the section "Post-partum supplementation", should the value 20,000 be replaced with 200,000 in the sentence "...thus, current IVACG guideline of administering a single oral dose of up to 60,000 *g (20,000 IU) within 6 to 8 weeks postpartum..."?

Thanks again...

Joan Hildebrand, MSc, R.D.

Nutrition Officer

World Vision Canada

joan_hildebrandatworldvision.ca