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Retinol

1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Brand names, Trade names
   1.6 Manufacturers, Importers
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Properties of the substance
      3.3.2 Properties of the locally available formulation
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Shelf-life of the locally available formulation
      3.4.3 Storage conditions
      3.4.4 Bioavailability
      3.4.5 Specific properties and composition
4. USES
   4.1 Indications
   4.2 Therapeutic dosage
      4.2.1 Adults
      4.2.2 Children
   4.3 Contraindications
5. ROUTES OF ENTRY
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Other
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination by route of exposure
7. PHARMACOLOGY AND TOXICOLOGY
   7.1 Mode of action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
   7.7 Main adverse effects
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection
         8.1.1.1 Toxicological analyses
         8.1.1.2 Biomedical analyses
         8.1.1.3 Arterial blood gas analysis
         8.1.1.4 Haematological analyses
         8.1.1.5 Other (unspecified) analyses
      8.1.2 Storage of laboratory samples and specimens
         8.1.2.1 Toxicological analyses
         8.1.2.2 Biomedical analyses
         8.1.2.3 Arterial blood gas analysis
         8.1.2.4 Haematological analyses
         8.1.2.5 Other (unspecified) analyses
      8.1.3 Transport of laboratory samples and specimens
         8.1.3.1 Toxicological analyses
         8.1.3.2 Biomedical analyses
         8.1.3.3 Arterial blood gas analysis
         8.1.3.4 Haematological analyses
         8.1.3.5 Other (unspecified) analyses
   8.2 Toxicological Analyses and Their Interpretation
      8.2.1 Tests on toxic ingredient(s) of material
         8.2.1.1 Simple Qualitative Test(s)
         8.2.1.2 Advanced Qualitative Confirmation Test(s)
         8.2.1.3 Simple Quantitative Method(s)
         8.2.1.4 Advanced Quantitative Method(s)
      8.2.2 Tests for biological specimens
         8.2.2.1 Simple Qualitative Test(s)
         8.2.2.2 Advanced Qualitative Confirmation Test(s)
         8.2.2.3 Simple Quantitative Method(s)
         8.2.2.4 Advanced Quantitative Method(s)
         8.2.2.5 Other Dedicated Method(s)
      8.2.3 Interpretation of toxicological analyses
   8.3 Biomedical investigations and their interpretation
      8.3.1 Biochemical analysis
         8.3.1.1 Blood, plasma or serum
         8.3.1.2 Urine
         8.3.1.3 Other fluids
      8.3.2 Arterial blood gas analyses
      8.3.3 Haematological analyses
      8.3.4 Interpretation of biomedical investigations
   8.4 Other biomedical (diagnostic) investigations and their interpretation
   8.5 Overall Interpretation of all toxicological analyses and toxicological investigations
   8.6 References
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 CNS
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Other
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ear, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-base disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Other
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Relevant laboratory analyses
      10.2.1 Sample collection
      10.2.2 Biomedical analysis
      10.2.3 Toxicological analysis
      10.2.4 Other investigations
   10.3 Life supportive procedures and symptomatic/specific treatment
   10.4 Decontamination
   10.5 Elimination
   10.6 Antidote treatment
      10.6.1 Adults
      10.6.2 Children
   10.7 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
   11.2 Internally extracted data on cases
   11.3 Internal cases
12. Additional information
   12.1 Availability of antidotes
   12.2 Specific preventive measures
   12.3 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)
    PHARMACEUTICALS
    1. NAME
     1.1 Substance
       Retinol
     1.2 Group
       Vitamin A
     1.3 Synonyms
       15- apo-B-caroten-15-ol (3,7-dimethyl-9-(2,6,
       6-trimethylcyclohex-1-enyl) nona- 2
       anti-infective vitamin
       Anti-xerophthalmic vitamin
       Axerophtholum
       Biosterol
       Oleovitamin A
       Retinal (vitamin A aldehyde)
       vitamin A1
     1.4 Identification numbers
       1.4.1 CAS number
             68-26-8
       1.4.2 Other numbers
             Martindale online monograph link no. 7823-k
     1.5 Brand names, Trade names
       To be completed by each centre.
     1.6 Manufacturers, Importers
       A 313                    (Chabre, France)
       Acaren                   (Belgium)
       Afaxin                   (Canada)
       AFI-A diagnostikum       (Nyco, Norway)
       Alfa Monovit             (Italy)
       Alfatar                  (Arnaldi, Italy)
       Alphalin                 (Lilly, USA)
       Amirale                  (IDI, Italy)
       Amplex-A                 (Spain)
       A-Muslin                 (Mucos, Germany)
       Anol Standard            (Belgium)
       A-OM                     (Spain)
       Aquasol A                (Argentina, Rover Canada, Armour USA)
       Ariovit                  (Roche, Denmark)
       Arovit                   (Belgium; Roche in France, Germany, 
                                 Italy, Netherland, South Africa, Spain,
                                 Sweden, Switzerland)
       Astrapin, oily form      (Germany)
       Atunol                   (Argentina)
       Auxina A Masiva          (Gayoso Wellcome, Spain)
       Avibon                   (Theraplix, France)
       A-Vicotrat               (Heyl, Germany)
       Avimin                   (Ferrosan, Denmark)
       Avita                    (South Africa)
       Avitam Masivo            (Spain)
       A-vitamin                (DAK, Denmark)
       Avitina                  (CT, Italy)
       Axerol                   (Wander, Switzerland).
       Isotretinoil             (CAPS, South Africa).
       Medox, Vitamin A tablet  (CAPS, Zimbabwe)
       
       To be completed by the centre.

    2. SUMMARY
     2.1 Main risks and target organs
       The main risk is hypervitaminosis A which occurs both in young 
       children and adults receiving more than 100,000 units/daily 
       over several months or in acute poisoning.
       
       Target organs are the skin, CNS, bone and liver.
     2.2 Summary of clinical effects
       Chronic vitamin A intoxication produces musculo-skeletal and 
       skin disorders, dry hair, alopesia, anemia, headache, 
       hepatomegaly, fever and gastrointestinal disturbanaces in the 
       adult.  Headache, nausea, vomiting and irritability have been 
       observed after excessive consumption of animal liver 
       containing vitamin A or one dose of 1,500,000 IU.  Toxicity is 
       reversible on withdrawal of vitamin A, but in children, 
       premature closure of epipyses of long bones may arrest bone 
       growth.
       
       Infants aged 3-7 months who ingested 350,000 IU developed 
       vomiting, irritability, bulging fontanelles and elevated 
       cerebrospinal fluid pressure (Ellenhorn & Barceloux, 1988).
       
       Toxicity usually occurs about 6 h after ingestion in acute 
       poisoning with vitamin A.  Acute overdose also results in 
       hydrocephalus in infants and increased intracranial pressure 
       (pseudotumor cerebri) in older children and adults.  Symptoms 
       of acute overdose include bleeding from gums or sore mouth and 
       a bulging soft spot on head.  In babies, confusion or unusual 
       excitement, diarrhoea, dizziness, or drowsiness, double vision,
        severe headache, severe irritability, peeling of skin, 
       especially on lips and palms, seizures, and severe vomiting 
       have been reported.
     2.3 Diagnosis
       The diagnosis is made by history of exposure to vitamin A and 
       the presence of nausea, vomiting, anorexia, headache, 
       irritability, engthema, prurities, fever, features of acute 
       vitamin A poisoning. There may be fatigue hepatosplenomegaly, 
       visual disturbances, skin lesions, dry hair, bleeding and 
       haematological abnormalities in chronic exposure.
       
       In children raised intracranial pressure with bulging 
       fontanelles, papilloedema and diplopia may be symptoms of 
       chronic toxicity.     
       
       Laboratory analyses may show raised serum aspartate 
       transaminase (SGOT), alanine transaminase (SGPT), erythrocyte 
       sedimentation rate, serum calcium and alkaline phosphatase in 
       blood.  Complete blood count may reveal haematological 
       abnormalities such as anaemia, leucopenia or leucocytosis, and 
       thrombocytopenia. 
     2.4 First aid measures and management principles
       In acute poisoning by ingestion, induce emesis or perform 
       gastric lavage and administer activated charcoal.
       
       In cases of eye contact, immediately irrigate with copious 
       amounts of water.

       
       In severe overdoses, maintain clear airway, establish and 
       monitor breathing and circulatory functions.  Reduce 
       intracranial pressure with mannitol or corticosteroids.  Monitor
       blood pressure, fluids, electrolytes, papilledema and CNS status.
    3. PHYSICO-CHEMICAL PROPERTIES
     3.1 Origin of the substance
       Vitamin A ester concentrate (natural) consists of a natural 
       ester, or mixture of natural esters of retinol, or of a 
       solution of ester, or mixture of esters in arachis oil or 
       other suitable vegetable oil.  It contains in 1 g not less 
       than 485,000 units of vitamin A and not less than 97.0% of the 
       number of units of vitamin A stated on the label.  It may 
       contain a suitable antioxidant or mixture of antioxidants (BP 
       1988).
       
       Synthetic vitamin A concentrate (oily form) consists of an 
       ester or mixture of esters of retinol (the acetate, propionate 
       or palmitate) prepared by synthesis.  It may be diluted with a 
       suitable vegetable oil.  It contains in 1 g not less than 500,
       000 units of vitamin A and not less than 95.0% and not more 
       than 110.0% of the number of units of vitamin A stated on the 
       label.  It may contain suitable stabilizing agents such as 
       antioxidants (BP 1988).
       
       Synthetic vitamin A concentrate (powder form) consists of an 
       ester or mixture of esters of retinol (the acetate, propionate 
       or palmitate) prepared by synthesis and dispersed in a matrix 
       of gelatin, acacia or other suitable material.  It contains in 
       1 g not less than 250,000 units of vitamin A and not less than 
       95.0% and not more than 115.0% of the number of units of 
       vitamin A stated on the label. It may contain suitable 
       stabilizing agents such as antioxidants (BP 1988).
       
       Synthetic vitamin A concentrate (water-dispersible form) 
       consists of an ester or mixture of esters of retinol (the 
       acetate, propionate or palmitate) prepared by synthesis to 
       which suitable solubilizers have been added.  It contains in 1 
       g not less than 100,000 units of vitamin A and not less than 
       95.0% and not more than 115.0% of the number of units of 
       vitamin A stated on the label.  It may contain suitable 
       stabilizing agents such as antimicrobial preservatives and 
       antioxidants (BP 1988).
     3.2 Chemical structure
       Structural formula:  C20H3O
       
       Molecular weight:  286.5 
     3.3 Physical properties
       3.3.1 Properties of the substance
             - Vitamin A Ester Concentrate (Natural)
             
             Characteristics: A yellow oil or mixture of oil 
             and crystalline material which yields an 
             homogenous yellow oil on warming with a faint 
             odour.
             

             Solubility: Practically insoluble in water; 
             soluble or partly soluble in ethanol (96%); 
             miscible with chloroform, with ether and 
             petroleum spirit.
             
             - Synthetic Vitamin A Concentrate (Oily Form)
             
             Characteristics: A yellow to brownish-yellow 
             oily liquid with a faint and characteristic 
             odour.
             
             Solubility: Practically insoluble in water; 
             soluble or partly soluble in absolute ethanol; 
             miscible with organic solvents.  Partial 
             crystallization may occur in highly concentrated 
             solutions.
             
             - Synthetic Vitamin A Concentrate (Water-dispersible Form)
             
             Characteristics: a yellow or yellowish liquid of 
             variable opalescence and viscosity and a 
             characteristic odour.  Highly concentrated 
             solutions may become cloudy at low temperatures 
             or take the form of a gel at room temperature.
             
             Solubility: Soluble in water.
             
             Melting points:
                  Vitamin A acetate   about 57 C 
                  Vitamin A palmitate 28-30 C.
       3.3.2 Properties of the locally available formulation
             To be completed by each centre.
     3.4 Other characteristics
       3.4.1 Shelf-life of the substance
             Up to 2 years depending on the preparation.
       3.4.2 Shelf-life of the locally available formulation
             To be completed by each centre.
       3.4.3 Storage conditions
             Vitamin A ester concentrate (natural), synthetic Vitamin 
             A concentrates (oily, powder and water-miscible forms) 
             should be kept in an airtight container, protected from 
             light and stored at a temperature of 8C to 15C.  Once 
             the container has been opened its contents should be 
             used as soon as possible; any part of the contents not 
             used at once should be protected by an atmosphere of an 
             inert gas.
       3.4.4 Bioavailability
             To be completed by each centre.
       3.4.5 Specific properties and composition
             To be completed by each centre.
    4. USES
     4.1 Indications
       - Vitamin A deficiency (prophylaxis and treatment).  
       
       Vitamin A is indicated only for prevention or treatment 
       of Vitamin A deficiency states, which may occur as a 

       result of inadequate nutrition or intestinal 
       malabsorption in patients receiving an adequate balanced 
       diet.  Dietary improvement is preferred over 
       supplementation whenever possible.  Deficiency of 
       vitamin A may lead to keratomalacia, xerophthalmia, and 
       nyctalopia (night blindness).  Requirements of vitamin A 
       may be increased and/or supplementation may be necessary 
       in the following persons or conditions (although 
       clinical deficiencies are usually rare) (Reynolds, 1989; 
       USP DI, 1989; McEvoy, 1988; Speight, 1987; Vanderveen, 
       1980).
       
       - During prolonged stress or infection or chronic fever
       
       In malabsorption syndromes associated with pancreatic 
       insufficiency (pancreatic disease, cystic fibrosis); 
       hepatic biliary tract disease (hepatic function 
       impairment, cirrhosis, obstructive jaundice);  diseases 
       of the small intestine (coeliac disease, tropical sprue, 
       regional enteritis, persistent diarrhoea); or 
       postgastrectomy in patients with diabetes mellitus, 
       hyperthyroidism, or severe protein deficiency.
       
       In general, Vitamin A absorption will be impaired in any 
       condition in which fat malabsorption (steatorrhoea) occurs.  
       In addition, conversion of dietary beta-carotene to vitamin A 
       may be impaired in diabetes mellitus and hyperthyroidism.
       
       Supplementation with vitamin A is necessary in patients 
       receiving total parenteral nutrition (TPN); undergoing 
       rapid weight loss regimes; or in those with malnutrition,
       because of inadequate dietary intake.
       
       Requirements of all vitamins are increased during 
       pregnancy and breast-feeding. However, high doses of 
       vitamin A are teratogenic and there are few indications 
       for supplementation during pregnancy.
       
       Requirements may be increased by the following 
       medications: cholestyramine, colestipol, mineral oil, 
       neomycin and sucralfate.
       
       Vitamin A is not appropriate for the treatment of dry or 
       wrinkled skin, eye problems, or prevention or treatment 
       of infections not related to vitamin A deficiency.
       
       Vitamin A dietary intake has been reported in a 
       population-based case-control study to have reduced the 
       risk of cervical cancer (Verreault et al, 1989).
       
       - Dermatological disorders

       The oral retinoids, or synthetic derivatives of vitamin 
       A, are used in the treatment of various dermatoses.  The 
       most useful drugs are isotretinoin (13-cis-retinoic 
       acid) for nodulocystic acne and etretinate for 

       refractory psoriasis vulgaris.  Retinoids are also 
       effective in the treatment of papulomatous dermatoses 
       other than psoriasis (e.g., inherited disorders of 
       keratinization), cutaneous T-cell lymphoma and in the 
       chemotherapy of cancer (Pasterino et al, 1988, Caffery & 
       Josephson, 1988).  However, systemic administration of 
       these compounds is frequently associated with liver 
       toxicity, abnormalities of serum lipid profiles, 
       teratogenic effects and adverse mucocutaneous effects 
       (David et al, 1988).  A potential role of vitamin A in 
       prevention of treatment of cancer has been suggested but 
       efficacy has not been proven.
     4.2 Therapeutic dosage
       4.2.1 Adults
             A daily dietary intake of about 750 g of vitamin A is 
             recommended for healthy adults.  Dietary vitamin A is 
             derived from 2 sources: retinol is provided by dairy 
             products, eggs and fish liver oils (the most 
             concentrated natural source); pro-vitamin carotenoids 
             can be obtained from many plants.

             In the treatment of xerophthalmia: Vitamin A palmitate 
             110 mg or vitamin A acetate 66 mg (200,000 units of 
             vitamin A) administered orally.  The dose should be 
             repeated the next day followed by an additional dose 
             administered 1 to 2 weeks later.
             
             When there is repeated vomiting or severe diarrhoea. a 
             water-miscible vitamin A palmitate 55 mg (100,000 units) 
             should be given by intramuscular injection instead of 
             the first oral dose.
             
             In the prophylaxis of blinding xerophthalmia vitamin A 
             palmitate 110 mg of vitamin A acetate 66 mg (100,000 
             units) may be given by mouth every 4 to 6 months.
                            
             Note: Vitamin A injection should not be administered 
             intravenously because of the risk of anaphylactic shock 
             and death.
       4.2.2 Children
             The recommended daily intake in children aged 6 - 12 
             months is 300 g.
             
             Treatment of xerophthalmia: as adults, except in 
             children younger than 12 months for whom the dose is 
             halved. 
             
             In the prophylaxis of blinding xerophthalmia in children 
             less than 12 months old, vitamin A palmitate 55 mg or 
             vitamin A acetate 33 mg (100,000 units of vitamin A) 
             should be given by mouth.  The dose should be repeated 
             every 4 to 6 months. 
             
             In children under 12 months, water miscible vitamin A 
             palmitate 27.5 mg (50,000 units) should be given by 
             intramuscular injection instead of the first oral dose 

             when this latter is not acceptable - for example in 
             nausea, diarrhoea, pre-operative and post-operative 
             conditions, in malabsorption syndromes or when ocular 
             damage is severe.
                            
             Note: Vitamin A injection should not be administered 
             intravenously because of the risk of anaphylactic shock 
             and death.
     4.3 Contraindications
       Caution is recommended in young children, who are usually more 
       sensitive to the effects of high doses of vitamin A.  Normal 
       daily requirements vary according to age.  Adequate and well-
       controlled studies have not been done.
       
       Excessive doses of vitamin A should be avoided in pregnancy 
       beccause of potential teratogenic effects (Reynolds, 1993).
    5. ROUTES OF ENTRY
     5.1 Oral
       This is the most important route of entry.
     5.2 Inhalation
       No data available.
     5.3 Dermal
       Absorption of the retinoid tretinoin is minimal after 
       application of commercial
       formulations to the skin. 
     5.4 Eye
       No data available.
     5.5 Parenteral
       This route is used for patients with absorption problems, e.g: 
       coeliac disease and sprue.
     5.6 Other
       No data available.
    6. KINETICS
     6.1 Absorption by route of exposure
       In oral doses that do not greatly exceed the physiological 
       requirements, vitamin A is readily and easily absorbed 
       provided fat absorption is normal.  Absorption is incomplete 
       on administration of larger doses and in patients with fat 
       malabsorption, low protein intake or hepatic or pancreatic 
       disease.  Water-miscible preparations of retinol or its esters 
       are absorbed more rapidly from the GI tract than oil 
       solutions. Retinol esters are hydrolysed in the GI lumen by 
       pancreatic enzymes.  Retinol is absorbed and re-esterified 
       mainly to retinal palmitate.  Fatty acid esters of retinol 
       enter the circulation by transport in chylomicrons of lymph.  
       Peak plasma concentrations of retinol esters occur about 4 - 5 
       hours after oral administration of retinol in an oil solution 
       and 3 - 4 hours after administration of a water miscible 
       retinol; higher plasma concentrations are obtained after 
       administration of a water miscible preparation of vitamin A 
       than after an oily solution.  Normal serum concentrations of 
       retinol range from 300 to 700 ng/l adults and from 200 to 500 
       ng/l in infants (McEvoy, 1988).
     6.2 Distribution by route of exposure
       Retinal palmitate and small amounts of retinol and retinal are 
       stored in the liver.  Small amounts of retinal palmitate are 

       stored in the kidney, lung, adrenal glands, retina and 
       intraperitoneal fat.  Normal body stores of vitamin A are 
       sufficient to meet the body's requirements for several months. 
        Vitamin A passes into milk. Retinol in circulation is bound 
       to a specific globulin, retinol binding protein (RPB).  
       Release of retinol from the liver depends on several factors 
       including protein and zinc.  RPB circulates as a complex with 
       a prealbumin protein and concentrations of RPB may be 
       decreased in patients with protein malnutrition.  However, the 
       serum concentration of retinol is not a good index of hepatic 
       stores as these may be depleted.  After taking a meal 
       deficient in vitamin A, normal serum concentrations are 
       maintained until the liver stores are depleted.  On 
       administration to a patient deficient in vitamin A, vitamin A 
       correction occurs in the retina followed by accumulation in 
       the liver; serum concentrations remain normal until the liver 
       stores are saturated.  Patients with glomerulonephritis or 
       lipoid nephrosis may have increased serum concentrations of 
       vitamin A because of RBP or storage abnormalities.  If large 
       doses of vitamin A are administered after saturation of 
       storage sites, the binding capacity of RBP may be exceeded and 
       unbound retinol carried by lipoproteins may enter the 
       circulation.  This unbound retinol may bring about many of the 
       toxic effects on cellular membranes from hypervitaminosis A 
       (McEvoy, 1988).
     6.3 Biological half-life by route of exposure
       By ingestion, 1.9 hours.
     6.4 Metabolism
       Retinol is conjugated with glucuronic acid; the B-glucuronide 
       undergoes enterohepatic circulation and oxidation to retinol 
       and retinoic acid.  Retinoic acid undergoes decarboxylation 
       and conjugation with glucuronic acid.
     6.5 Elimination by route of exposure
       Retinol, retinoic acid and water-soluble metabolites are 
       excreted in faeces and urine.  Normally no unchanged retinol 
       is excreted in urine.  However, in patients with pneumonia or 
       chronic nephritis, unchanged vitamin A may be excreted (McEvoy,
       1988).
       
       20% to 50% of the absorbed retinol is eliminated in faeces and 
       urine as conjugation or oxidation products. Approximately 20% 
       is not absorbed and is eliminated in faeces (Hathcock et al, 
       1990).
    7. PHARMACOLOGY AND TOXICOLOGY
     7.1 Mode of action
       7.1.1 Toxicodynamics
             Toxicity from a large dose of vitamin A is more common 
             in young children than in adults.  A few hours after 
             administration of vitamin A at a dose of about 75,000 
             units/kg, irritability, drowsiness, vertigo, delirium, 
             coma, vomiting and diarrhoea may occur.  Increased 
             intracranial pressure with bulging fontanelles in 
             infants, headache, papilloedema, exophthalmos and visual 
             disturbances have been reported.  Erythema and general 
             peeling of the skin may occur a few days later and may 
             persist for several weeks.  However, symptoms usually 

             disappear within a few days after the drug has been 
             discontinued.
       7.1.2 Pharmacodynamics
             Vitamin A is required for growth and bone development, 
             vision, reproduction and the integrity of mucosal and 
             epithelial surfaces.  In the retina, retinol is 
             converted to the aldehyde, cis-retinal, which combines 
             with opsin to form rhodopsin, the visual pigment.  
             Vitamin A has been reported to act as a co-factor in 
             various reactions including mucopolysaccharide synthesis,
             cholesterol synthesis and hydroxysteroid metabolism.  
             The retinoid tretinoin increases cell turnover.  Vitamin 
             A deficiency leads to xerophthalmia, Bitot's spots, 
             keratomalacia, night blindness (nyctalopia), 
             hyperkeratosis of the skin, epithelial metaplasia of 
             mucous membranes and decreased resistance to infections. 
             Administration of vitamin A completely reverses signs of 
             vitamin A deficiency unless keratomalacia has resulted 
             in irreversible ocular damage.
             
             Retinol esters are hydrolysed in the gastrointestinal 
             tract, absorbed as  retinol and re-esterified mainly to 
             retinal palmitate.  This is transported by chylomicrons 
             to the relevant tissues, including the retina, liver, 
             mucosa and epithelia.  Retinol is metabolized by 
             conjugation pathways and excreted.
     7.2 Toxicity
       7.2.1 Human data
             7.2.1.1 Adults
                     There have been reports of papilloedema 
                     associated with vitamin A.  Nodular liver 
                     cirrhosis and portal hypertension occurred in a 
                     36-year-old man 3.5 years after receiving 
                     vitamin A 70 million units by mouth over 7 weeks 
                     for psoriasis.  Peripheral neuritis and pain 
                     developed in 2 leprotic patients treated with 
                     thiambutosine when vitamin A 15,000 and 120,000 
                     units daily  respectively were taken; nerve pain 
                     stopped when the excess vitamin A was withdrawn. 
                     Hypercalcaemia and skeletal changes occurred in 
                     5 patients who had taken excess amounts of 
                     vitamin A (David et al, 1986).
                     
                     Congenital malformations associated with 
                     maternal over-use of high doses of vitamin A 
                     have also recently been reported (Bendich and 
                     Langseth, 1989).  However, no cause and effect 
                     relationship has been established.  Deficiency 
                     of the vitamin during pregnancy has also been 
                     associated with congenital abnormalities.
                     
                     Reported cases of vitamin A toxicity are rare.
             7.2.1.2 Children
                     Administration of more than 50,000 to 500,000 UI 
                     daily for months has produced hepatosplenomegaly 
                     (Babb & Kieraldo, 1978) and other effects.

                     
                     Allergy to vitamin A especially in children, has 
                     been reported and confirmed.
       7.2.2 Relevant animal data
             There is no evidence that vitamin A at any dose is 
             lethal to animals.  However, both deficiency and excess 
             of vitamin A in pregnant animals are teratogenic.
       7.2.3 Relevant in vitro data
             No data available.
     7.3 Carcinogenicity
       - Animal data
       
       In rats (and probably in man), vitamin A appears to play a 
       role in testosterone synthesis.  If vitamin A increases 
       endogenous levels of this hormone, which may mediate the 
       development of prostatic cancer, this effect may be more 
       significant in older animals (and man) whose natural levels of 
       testosterone are declining (Dukes & Beeley, 1989).
       
       - Human data
       
       Although epidemiological studies have demonstrated a reduced 
       risk of certain cancers with increasing consumption of vitamin 
       A, there is strong evidence that vitamin A has the opposite 
       effect with regard to prostatic cancer.  The risk
       increases directly with the intake of vitamin A in men at all 
       ages, but the trend was strong in those of 70 years and older. 
       Vitamin A seems to influence tumour progression rather than 
       the early stages of carcinogenesis.  The mechanism by which 
       vitamin A may enhance carcinogenesis is not yet established 
       (Dukes & Beeley, 1989).
     7.4 Teratogenicity
       The teratogenicity of vitamin A in both high and low doses is 
       well established in animals. However, it is uncertain whether 
       vitamin A is teratogenic in man. A 1983 case report suggested 
       that a multivitamin product containing vitamin A may have 
       caused a cleft palate in one infant; there may be an 
       association between the birth of two malformed children to 
       mothers who had taken excess vitamin A and the birth of 120 
       malformed children with deficiency of vitamin A; there has 
       been a case of a baby born with congenital xerophthalmia and 
       bilateral cleft because of deficiency of vitamin A in the 
       mother; excess intake in some mothers resulted in defects of 
       the urinary tract, urogenital system and microcephaly in the 
       infants (Briggs et al, 1986). There are few documented reports 
       in humans which link teratogenic consequences to high intakes 
       of supplemental retinol taken either acutely or chronically.  
       Until more is known about the mechanisms of placental transfer 
       and control as well as about the dose-related teratogenicity 
       of vitamin A at different stages of gestation, there are few 
       justifications for routine ingestion by fertile women of 
       supplemental vitamin A in excess of 8,000 to 10,000 IU.  
       Exceptions occur when clinical signs are evident and hospital 
       diets are unusually deficient (Underwood, 1989).
       
       By contrast, the retinoids isotretinoin and etretinate are 

       highly teratogenic in man. Their use is contraindicated during 
       pregnancy and conception must be prevented for at least 4 
       weeks after use of isotretinoin and for at least 2 years after 
       use of etretinate.
     7.5 Mutagenicity
     7.6 Interactions
     7.7 Main adverse effects
    8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
     8.1 Material sampling plan
       8.1.1 Sampling and specimen collection
             8.1.1.1 Toxicological analyses
             8.1.1.2 Biomedical analyses
             8.1.1.3 Arterial blood gas analysis
             8.1.1.4 Haematological analyses
             8.1.1.5 Other (unspecified) analyses
       8.1.2 Storage of laboratory samples and specimens
             8.1.2.1 Toxicological analyses
             8.1.2.2 Biomedical analyses
             8.1.2.3 Arterial blood gas analysis
             8.1.2.4 Haematological analyses
             8.1.2.5 Other (unspecified) analyses
       8.1.3 Transport of laboratory samples and specimens
             8.1.3.1 Toxicological analyses
             8.1.3.2 Biomedical analyses
             8.1.3.3 Arterial blood gas analysis
             8.1.3.4 Haematological analyses
             8.1.3.5 Other (unspecified) analyses
     8.2 Toxicological Analyses and Their Interpretation
       8.2.1 Tests on toxic ingredient(s) of material
             8.2.1.1 Simple Qualitative Test(s)
             8.2.1.2 Advanced Qualitative Confirmation Test(s)
             8.2.1.3 Simple Quantitative Method(s)
             8.2.1.4 Advanced Quantitative Method(s)
       8.2.2 Tests for biological specimens
             8.2.2.1 Simple Qualitative Test(s)
             8.2.2.2 Advanced Qualitative Confirmation Test(s)
             8.2.2.3 Simple Quantitative Method(s)
             8.2.2.4 Advanced Quantitative Method(s)
             8.2.2.5 Other Dedicated Method(s)
       8.2.3 Interpretation of toxicological analyses
     8.3 Biomedical investigations and their interpretation
       8.3.1 Biochemical analysis
             8.3.1.1 Blood, plasma or serum
             8.3.1.2 Urine
             8.3.1.3 Other fluids
       8.3.2 Arterial blood gas analyses
       8.3.3 Haematological analyses
       8.3.4 Interpretation of biomedical investigations
     8.4 Other biomedical (diagnostic) investigations and their 
       interpretation
     8.5 Overall Interpretation of all toxicological analyses and 
       toxicological investigations
     8.6 References
    9. CLINICAL EFFECTS
     9.1 Acute poisoning
       9.1.1 Ingestion

             Doses of vitamin A that do not exceed the physiologic 
             requirements are not usually toxic (McEvoy, 1988).  
             However, acute intoxication has generally been observed 
             following ingestion of vitamin A-rich liver from the 
             polar bear, halibut or shark.  The doses have been in 
             the range of one million units of vitamin A, but as low 
             as 30,000 IU in children.  The symptoms occur 6 to24 h 
             after ingestion and are characterized by acute onset of 
             drowsiness, irritability, vertigo, headache, delirium 
             and convulsions, diarrhoea and intolerance to food. Long-
             term administration of as little as 10,000 IU daily may 
             be sufficient to cause chronic hypervitaminosis A. The 
             main symptoms of chronic intoxication include malaise, 
             gastrointestinal complaints, changes in the skin and 
             mucous membranes, headache, tenderness and pain in the 
             bone and joints, and fever (Helsing, 1988).  
             Hypersensitivity reactions do not seem to occur.
             
             Toxicity from large doses of vitamin A is more common in 
             young children than in adults.  A few hours after 
             administration of 25,000 units/kg, severe irritability, 
             drowsiness, or vertigo, delirium, coma, vomiting and 
             diarrhoea may occur.  Increased intracranial pressure 
             with bulging fontanelles in infants, headache, 
             papilloedema, exophthalmos, and visual disturbances have 
             been reported.  Erythema and generalized peeling of the 
             skin occur a few days later and may persist for several 
             weeks.  However, symptoms usually disappear within a few 
             days after the drug is discontinued (McEvoy, 1988; 
             Speight, 1987).
       9.1.2 Inhalation
             No data available.
       9.1.3 Skin exposure
             Skin reactions are more common after topical application 
             of the retinoids
             etretinate, isotretinoin and tretinoin.  The most common 
             cutaneous side effects are xerosis of the skin 
             associated with pruritus and sometimes with erythema, 
             skin hyperfragility and desquamation of the skin, 
             particularly of the palms and soles (David et al, 1988); 
             hair loss from scalp, eyebrows and/or eyelashes.
       9.1.4 Eye contact
             No data available.
       9.1.5 Parenteral exposure
             The same as for oral exposure.
       9.1.6 Other
             No data available.
     9.2 Chronic poisoning
       9.2.1 Ingestion
             Chronic overdose results in hepatotoxicity, papilloedema,
             intracranial hypertension, hypomenorrhoea, portal 
             hypertension, haemolysis and anaemia, radiographic bone 
             changes and, in children, premature closure of the 
             epiphyses.  Toxicity is slowly reversible on withdrawal 
             of vitamin A, but may persist for several weeks.  Bone 
             or joint pain fever, general feeling of bodily 

             discomfort or weakness, headache, increase in the volume 
             and frequency of urination, especially at night, 
             irritability, loss of appetite, stomach pain, unusual 
             tiredness and vomiting are also reported (David et al, 
             1988; USP DI 1989; McEvoy, 1988).
       9.2.2 Inhalation
             No data available.
       9.2.3 Skin exposure
             After repeated administration to the skin, the retinoid 
             tretinoin may cause drying or cracking of skin or lips, 
             increased sensitivity of skin to sunlight, loss of hair, 
             yellow-orange patches on soles of feet, palms of hands 
             or skin around nose and lips.
       9.2.4 Eye contact
             No data available.
       9.2.5 Parenteral exposure
             As for oral exposure.
       9.2.6 Other
             No data available.
     9.3 Course, prognosis, cause of death
       Toxicity in both acute and chronic vitamin A is reversible on 
       withdrawal of vitamin A.  In chronic overdose, toxicity may 
       persist for several weeks.  In children, the premature closure 
       of ephphyses of the long bones may result in arrested bone 
       growth (Reynolds, 1993).
       
       In general, most signs and symptoms of overdoes rsolve within 
       one week after withdrawal of vitamin A and appropriate 
       symptomatic treatment.  Benign intracranial hypertension 
       resolves usually after symptomatic treatment.  However, 
       papilloedema and skeletal abnormalities may persist for 
       several months and visual impairement (blindness) due to optic 
       atcoply may remain as a permanent sequela (Goldfrank, 1986).
     9.4 Systematic description of clinical effects
       9.4.1 Cardiovascular
             Tachycardia, possibly secondary to fever (Helsing, 
             1988).
       9.4.2 Respiratory
             No information available.
       9.4.3 Neurological
             9.4.3.1 CNS
                     Acute symptoms of vitamin A poisoning include 
                     drowsiness, sluggishness, irritability and 
                     somnolence, severe headache and papilloedema.  
                     In young children, raised intracranial pressure 
                     with bulging of the fontanelles, papilloedema 
                     and diplopia have been observed.  Intracranial 
                     hypertension may sometimes occur together with 
                     skin and hair changes, pain in musculoskeletal 
                     system and fatigue.  Chronic daily doses of 3,
                     000,000 IU of vitamin A have induced central 
                     nervous symptoms such as psychosis, with 
                     pathological changes in the cerebrospinal fluid 
                     (Helsing, 1988; USP DI 1989).  Pseudotumour 
                     cerebri (benign intracranial hypertension), 
                     vertigo and papilloedema have occurred following 

                     the daily intake of 10,000 - 20,000 IU for 2 
                     years in adults; in children even few months of 
                     treatment may suffice (Helsing, 1988; USP DI, 
                     1989).  Similar effects have been reported for 
                     retinoids for both acute and chronic 
                     intoxication (David et al, 1988; Reynolds, 
                     1989).
             9.4.3.2 Peripheral nervous system
                     No data available.
             9.4.3.3 Autonomic nervous system
                     No data available.
             9.4.3.4 Skeletal and smooth muscle
                     No data available.
       9.4.4 Gastrointestinal
             Nausea, vomiting and anorexia are common symptoms of 
             acute vitamin A intoxication, as are dryness and scaling 
             of the lips, gingivitis and bleeding from the gums (USP 
             DI, 1989, Helsing, 1988).  
       9.4.5 Hepatic
             Enlargement of the liver, spleen and lymph nodes have 
             been reported in adults (Helsing, 1988).  Liver damage 
             due to vitamin A and its derivatives occurs after acute 
             poisoning; whether liver toxicity occurs after chronic 
             poisoning is still uncertain (David et al, 1988).  
             Excessive administration of vitamin A and its 
             derivatives can lead to fibrosis in the Disse space and 
             obstruction of sinusoidal blood flow, causing non-
             cirrhotic portal hypertension and hepatocellular 
             dysfunction (Reynolds, 1989).  Elevated serum 
             concentrations of aspartate transaminase (AST, SGOT), 
             alanine transaminase (ALT, SGPT) and occasionally lactic 
             dehydrogenase (GGT) and alkaline phosphatase have been 
             reported (David et al, 1988; McEvoy, 1988; Krishnaswany, 
             1987).
       9.4.6 Urinary
             9.4.6.1 Renal
                     In chronic intoxication, polyuria, increased 
                     frequency of micturition, urinary incontinence, 
                     enuresis and acute renal failure due to tubular 
                     necrosis may occur (Dukes, 1984; USP DI, 1989).  
                     Patients with renal dysfunction, in chronic 
                     dialysis and haemodialyzed patients appear to 
                     have increased circulating vitamin A levels.
             9.4.6.2 Other
                     No data available.
       9.4.7 Endocrine and reproductive systems
             Hypomenorrhoea may be an early symptom of chronic 
             intoxication.
       9.4.8 Dermatological
             In acute intoxication, peeling of the entire skin can 
             occur as a delayed symptom.  Among the early and most 
             commonly reported symptoms of chronic poisoning with 
             vitamin A and its derivatives are pruritus; erythema; 
             hyperkeratosis; dryness, haemorrhage and fissures of the 
             lips (Krishnaswany, 1987; McEvoy, 1988; USP DI, 1989; 
             Reynolds, 1989).  A yellow to yellow-orange 

             discoloration of the skin, decreased tolerance to 
             sunlight, changes in pigmentation, hair loss and brittle 
             nails can occur (USP DI, 1989; Reynolds, 1989; Helsing, 
             1988).  Spider angiomas and palmar erythema in patients 
             with serious hepatic damage due to chronic use of 
             vitamin A have also been reported.
       9.4.9 Eye, ear, nose, throat: local effects
             Eye: ocular toxicities involve the conjunctival membrane,
             cornea and retina manifested by photophobia, palsy of 
             the ocular muscle, retinal haemorrhage and protrusio 
             bulbi, nystagmus, diplopia, dryness, irritation and 
             pain.  These are due to raised intracranial pressure.  
             Intoxication can also lead to papilloedema, which in 
             some cases may be the only symptom (Helsing, 1988; David 
             et al, 1988).  Anterior segment inflammation, contact 
             lens intolerance and altered refraction have also been 
             reported with the retinoid isotretinoin (Caffery & 
             Josephson, 1988).
             
             Ear, nose, and throat: no data available.
       9.4.10 Haematological
              High doses of vitamin A reduce the stability of the 
              hypoprotein boundary layer of erythrocytes, which can 
              lead to haemolysis and anaemia.  Neutropenia or 
              leucocytosis, thrombocytopenia, aplastic anaemia and 
              increased sedimentation rate have been reported after 
              high doses of vitamin A (McEvoy, 1988; USP DI, 1989; 
              Dukes, 1984).
       9.4.11 Immunological
              No data available.
       9.4.12 Metabolic
              9.4.12.1 Acid-base disturbances
                       No data available.
              9.4.12.2 Fluid and electrolyte disturbances
                       Oedema and ascites are sometimes seen in 
                       patients with chronic intoxication (Helsing, 
                       1988). Polydipsia may also occur.
              9.4.12.3 Others
                       Chronic intoxication with vitamin A has been 
                       reported to cause hyperglycaemia, increased 
                       alkaline phosphatase, hypoproteinuria, 
                       hypoprothrombinaemia, increased 
                       sulphobromphthalein retention, elevated serum 
                       transaminases, low serum ascorbic acid, 
                       decreased protein content of cerebrospinal 
                       fluid, elevated urinary hydroxyproline, and 
                       hypercalciuria.  Continued vitamin A 
                       administration or accumulation is associated 
                       with an increase in serum cholesterol and 
                       consequently might be linked with 
                       atherosclerosis (Helsing, 1988).

                       Hyperlipidaemia: As a result of liver damage, 
                       vitamin A and its derivatives produce a rise 
                       in serum triglycerides and, in particular, in 
                       very low density lipoproteins.  The changes 

                       are reversible on stopping treatment 
                       (Krishnaswamy, 1987; David et al, 1988). 
       9.4.13 Allergic reactions
              Hypersensitivity reactions do not seem to occur 
              (Hellriegel, 1984).
       9.4.14 Other clinical effects
              Excessive intake of vitamin A leads to accelerated 
              resorption of trabecular and cortical bone due to 
              increased osteoclast activity.  Pain in bones and 
              joints is a common symptom.  Bone tenderness with 
              complications such as periosteum, hyperostosis and, in 
              children, premature closure of the epiphyses of the 
              long bones causing growth arrest (Reynolds, 1989, USP 
              DI, 1989; Helsing, 1988).  Similar effects have been 
              reported for vitamin A derivatives (David et al, 1988). 
               Skeletal deformities involving the lower limbs and the 
              spine were seen in a 15-month old girl who had received 
              during the previous few months a total dose of 10.5 
              million IU of vitamin A (Helsing, 1988).
       9.4.15 Special risks
              Pregnancy: Vitamin A in high doses induces congenital 
              abnormalities in the offspring of rats and has been 
              reported to impair learning ability in rat offspring.  
              In man, epidemiological data on teratogenicity is 
              lacking.  However, human teratogenicity of synthetic 
              vitamin A derivatives such as isotretinoin is now well 
              accepted.  Results from an epidemiological case-control 
              study on prenatal exposure to vitamin A alone or in 
              combination with other vitamins have indicated that a 
              teratogenic effect could exist for exposures to high 
              doses of vitamin A.  Urinary tract malformations, 
              growth retardations, and early epiphyseal closure have 
              been reported in children whose mothers took excessive 
              amounts during pregnancy (Krishnaswany, 1987; USP DI, 
              1989; Rosa et al, 1986).
              
              Breast-feeding: Problems in humans have not been 
              documented with intake of normal daily requirements; 
              however, vitamin A is excreted in breast milk (USP DI, 
              1989).
              
              Enzyme deficiencies: No data available.
     9.5 Other
       No data available.
     9.6 Summary
    10. MANAGEMENT
      10.1 General principles
         Treatment is mainly supportive.  Make a proper assessment of 
         the airway, breathing and neurological status of the 
         patient.  Reduce intracranial pressure with mannitol or 
         corticosteroids.
         
         After oral exposure, gastric lavage is indicated if more 
         than the therapeutic doses is ingested.  Alternatively, 
         emesis is indicated unless the victim is comatose.  A 
         cathartic may be administered.

         
         Wash contaminated skin thoroughly with soap and water. If 
         the eyes are affected, irrigate with copious amounts of 
         water for 10 to 15 minutes and consult ophthalmologist if 
         pain persists.
         
         Monitor patient for dark adaptation tests, 
         electronystagmogram, electroretinogram and plasma vitamin A 
         determinations.  Hepatic and renal status should be 
         evaluated, especially in chronic exposure.
      10.2 Relevant laboratory analyses
         10.2.1 Sample collection
                Blood sample and 24 h urine collection.
         10.2.2 Biomedical analysis
                Routine blood and urine analysis of retinol and 
                metabolites may confirm the severity of poisoning.
                
                Monitor for haematologic effects, including 
                haemolysis, anaemia, thrombocytopenia and leucopenia. 
                 Monitor serum AST (SGOT) and ALT (SGPT) 
                concentrations (McEvoy, 1988).
         10.2.3 Toxicological analysis
                Analysis of vitamin A in blood and urine may be done 
                by colorimetric or gas chromatography.
         10.2.4 Other investigations
      10.3 Life supportive procedures and symptomatic/specific 
         treatment
         Maintain clear airway, establish and monitor breathing and 
         circulation.
         
         Control seizures with IV diazepam or phenobarbital.
         
         Reduce intracranial pressure with mannitol or corticostreoids.
         
         Support other CNS functions. Neuroleptics may be required to 
         control psychotic reactions.
         
         Monitor hepatic function.
         
         Correct anaemia and other haematological abnormalities, if 
         necessary.
      10.4 Decontamination
         Ingestion: Gastric lavage and emesis are indicated if large 
         amounts are ingested.
         
         Activated charcoal should be administered in usual doses of 
         30 to 100 g in adults and 15-30 g in children.
         
         A saline cathartic (e.g. sodium sulphate) may be given in 
         doses of 20 to 30 g in adults and 150 mg/kg in children over 
         2 years.  However, saline cathartics are contraindicated in 
         patients with impaired renal function.
         
         Skin: wash exposed areas thoroughly with soap and water.
         
         Eyes: irrigate eyes copious amounts of water for at least 15 

         min.  Consult an ophthalmologist, if pain persists.  
      10.5 Elimination
         Since the volume or frequency of urination may be increased, 
         especially at night, osmotic diuresis or haemodialysis has 
         been  suggested.
      10.6 Antidote treatment
         10.6.1 Adults
                There is no specific antidote available.
         10.6.2 Children
                There is no specific antidote available.
      10.7 Management discussion
         Vitamin E may increase the absorption, utilization and 
         storage of vitamin A and may protect against 
         hypervitaminosis A; however,   these effects are 
         controversial (McEvoy, 1988).
    11. ILLUSTRATIVE CASES
      11.1 Case reports from literature
         -    Hypercalcaemia caused by vitamin A toxicity was 
         observed in a 16-year-old patient.  Diagnosis was difficult 
         because she denied recent ingestion of vitamin A and was 
         thought to be bulimic.  Symptoms included vomiting,
         diarrhoea, thirst and polyuria.  She also developed a 
         dry scaly skin rash on her back, face and extremities. The 
         findings on physical examination were normal except for 
         multiple excoriations on her extremities, a dry scaly rash over 
         her upper arms, fissures at the corners of her mouth and
         dry mucous membranes.  Intravenous fluids and loop diuretics 
         lowered the serum calcium and ameliorated the symptoms of nausea 
         and vomiting temporarily.  During the 10 days of this therapy, 
         the serum calcium never fell below 11.5 mg/dl.  Oral prednisone 
         was then started and produced a prompt and lasting reduction of 
         the serum calcium to normal (Bergman et al, 1988).
         
         -    Plasma retinol levels and toxicity were evaluated in 
         thirteen metastatic breast cancer patients treated orally with
         high dose (300,000 IU/day) retinal acetate in combination with 
         tamoxifen.  During the first 2 months of treatment, a cumulative 
         increase of plasma retinol occurred; long-term systemic toxicity 
         was acceptable and included gastrointestinal symptoms, skin 
         toxicity and headache.  These symptoms could be related to the 
         long-term increase of retinol systemic concentrations (Ressasco 
         et al, 1988).

         -    The teratogenicity of vitamin A has been repeatedly 
         reported in the literature and confirmed on the basis of several
         cases of adverse pregnancy outcome associated with maternal 
         isotretinoin exposure.  Teratogenic effects have been reported 
         after normal supplementation with vitamin A during pregnancy 
         (Lungarotti et al, 1987).
         
         -    A 7-year-old girl, a 13-year-old boy and a 26-year-old 
         woman, all with renal failure, developed biochemical and clinical 
         findings of vitamin A toxicity (hypervitaminosis A) while 
         receiving a total parenteral nutrition regime containing 
         vitamin A; the symptoms improved after withdrawal of vitamin A 
         from the regime. These cases demonstrate that patients with

         renal failure may be at risk for symptomatic vitamin A toxicity,
         if given standard supplementation (Gleghorn et al, 1986).
         
         -    A 29-year-old man developed hepatic cirrhosis as a 
         manifestation of vitamin A toxicity induced by the ingestion of 
         6 to 8 ounces of beef liver per week for 8 to 9 years.  However,
         a history of infectious mononucleosis was probably a contributing 
         factor.  A 41-year-old woman developed chronichypervitaminosis A due to long-term use of special 
         regimen utilizing an emulsified vitamin A product containing 
         15,000 IU per drop (Inkeles et al, 1986).
         
         -    Vitamin A intake was assessed from dietary histories of 
         452 men with prostate cancer and 899 population controls in 
         Hawaii during the period 1977-1983.  In the group of men less 
         than 70 years of age, there was no significant association 
         between vitamin A and the risk of prostate cancer.  In the men 
         aged 70 or older, the risk correlated directly with the amount
         of vitamin A consumed. The findings were consistent across the 
         5 ethnic groups and similar for the various components of 
         vitamin A and its metabolites but were somewhat stronger for 
         total carotenes than for total retinol. These data suggest 
         possible mechanisms for this risk enhancement by vitamin A in 
         the elderly men (Kolonel et al, 1987).
      11.2 Internally extracted data on cases
         To be completed by each centre.
      11.3 Internal cases
         To be completed by each centre.
    12. Additional information
      12.1 Availability of antidotes
         No antidotes are available.
      12.2 Specific preventive measures
         No data available.
      12.3 Other
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    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE 
    ADDRESS(ES)
    Dr O.J. Kasilo 
    Drug and Toxicology Information Service
    Department of Pharmacy
    University of Zimbabwe Medical School
    P.O.Box A178
    Avondale
    Harare,
    Zimbabwe
    
    Dr C.F.B. Nhachi
    Department of Clinical Pharmacology and Toxicology
    University of Zimbabwe Medical School
    (address as above).
    
    Tel:      263-4-790233 or 791631, Ext. 117/172
    Telex:    2526801 UNIVZ ZW
    Fax:      263-4-303 292
    
    Date:     December 1989.



    See Also:
       Toxicological Abbreviations