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Alkalis

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 Main brand names, main trade names
   1.6 Main manufacturers, main 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 Colour
      3.3.2 State/Form
      3.3.3 Description
   3.4 Hazardous characteristics
4. USES
   4.1 Uses
      4.1.1 Uses
      4.1.2 Description
   4.2 High risk circumstance of poisoning
   4.3 Occupationally exposed populations
5. ROUTES OF EXPOSURE
   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 and excretion
7. TOXICOLOGY
   7.1 Mode of action
   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
      7.2.4 Workplace standards
      7.2.5 Acceptable daily intake (ADI)
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
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 Central nervous system (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 Life supportive procedures and symptomatic/specific treatment
   10.3 Decontamination
   10.4 Enhanced elimination
   10.5 Antidote treatment
      10.5.1 Adults
      10.5.2 Children
   10.6 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
12. Additional information
   12.1 Specific preventive measures
   12.2 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)




     Alkalis

    International Programme on Chemical Safety
    Poisons Information Monograph G012 (Group PIM)
    Chemical


    1.  NAME

        1.1  Substance

             Alkalis

        1.2  Group

             Substances included:

             Sodium hydroxide
             Potassium hydroxide
             Calcium hydroxide

        1.3  Synonyms

             Sodium hydroxide:
             Caustic flake; Caustic soda;
             Hydroxyde de sodium (French);
             Hydroxyde de sodium, solide (French);
             Hydroxyde de sodium, solutions (French);
             Lewis-red devil lye; 
             Liquid caustic
             (solutions of 45-75% sodium hydroxide in  water);
             Lye; Natriumhydroxid (German);
             Natriumhydroxyde (Dutch); Soda lye;
             Soda, caustic; Soda, hydrate;
             Sodio(idrossido di); Sodium hydrate;
             White caustic;

             Potassium hydroxide
             Caustic potash;
             Caustic potash solutions; 
             Hydroxyde de potassium (French); 
             Hydroxyde de potassium, solide (French);
             Hydroxyde de potassium, solutions (French);
             Kaliumhydroxid (German); 
             Kaliumhydroxyde (Dutch); KOH;
             Lye; Potassa; 
             Potasse caustique; 
             Potassio (idrossido di); 
             Potassium (hydroxyde de); 
             Potassium hydrate; 
             Potassium hydrate solutions;

             Calcium hydroxide:
             Agricultural lime; Bell mine;
             Biocalc; Calcium dihydroxide;
             Calcium Hydrate; Calvit;
             Calvital; Carboxide; 

             Caustic lime; Caustic lime water;
             Hydrated lime; Hydroxyde de calcium;
             Kalkhydrate; Kemikal;
             Limbux; Lime hydrate; 
             Lime milk; Lime water; 
             Milk of lime; Slaked lime

        1.4  Identification numbers

             1.4.1  CAS number

                    Sodium hydroxide:       1310-73-2
                    Potassium hydroxide:    1310-58-3
                    Calcium hydroxide:      1305-62-0

             1.4.2  Other numbers

                    Sodium hydroxide, solid:  UN1823 (DOT)
                    Sodium hydroxide, solution: UN1824 (DOT)
                    Sodium hydroxide NIOSH/RTECS: WB4900000

                    Potassium hydroxide, solid: UN1813 (DOT)
                    Potassium hydroxide, solution: UN1814 (DOT)
                    Potassium hydroxide NIOSH/RTECS: TT2100000

                    Calcium hydroxide NIOSH/RTECS: EW2800000

        1.5  Main brand names, main trade names

        1.6  Main manufacturers, main importers

    2.  SUMMARY

        2.1  Main risks and target organs

             Alaklis are one of the most common causes of chemical
             burn.  On ingestion alkalis are capable of causing severe
             damage and even a very small quantity may cause significant
             morbidity requiring prolonged and repeated
             hospitalisation.
    
             Ingestion: Alkalis cause the most severe corrosive effects
             on the oesophagus, rather than the stomach as is the case
             with acids. However, following deliberate ingestion of a
             large quantity of an alkali both the stomach and small
             intestine may be involved.  The severity of injury depends on
             a number of factors including the concentration of the agent,
             the duration of contact and the volume ingested and the
             presence of food in stomach.  It is greatest where the pH is
             above 12. However, pH is not the only factor which determines
             the extent to which a substance can cause corrosive injury. 
             Solid preparations and viscous liquids are also more likely
             to produce severe injury due to prolonged contact.  Following

             ingestion of a small amount the injury is usually limited to
             the oropharyngeal region and the oesophagus.  The greater the
             volume the greater the risk of duodenal and gastric
             damage.
    
             Oesophageal changes can be divided into 3 stages:
    
             1) acute necrotic phase in which cell death occurs due to
             coagulation of intracellular protein,
             2) intense inflammatory reaction in viable tissues
             surrounding the necrotic area, thrombosis of vessels occurs,
             and
             3) sloughing of superficial necrotic layer 2 to 4 days later.
    
             Classification or grading of Oesophageal Burns:
    
             First Degree:   mucosa only, hyperemic odematous mucosa, may
                             be superficial sloughing;
    
             Second degree:  destruction of mucosa ans submucosa,
                             penetration into muscle layers, exudate is
                             present, erosions and shallow ulcers;
    
             Third degree:   full thickness injury, possible perforation,
                             deep ulcerations, black coagulation.
    
             Skin burns: Alkali injuries differ from those of other
             burns for a number of reasons. The injury may be painless and
             not be immediately evident.  This initial lack of pain may
             lead to a delay in treatment.  The injury can progress over
             several hours and the skin may be discoloured brown or black
             within a short period of time, these factors make initial
             assessment of the burn depth difficult.  Also, there may be
             recurring skin breakdown over a long period after the initial
             injury which can complicate and delay recovery.
    
             Ocular burns: Alkali burns of the eye are very serious
             because they cause disruption of the protective permeability
             barriers and rapidly penetrate the cornea and anterior
             chamber resulting in blindness.

        2.2  Summary of clinical effects

             Ingestion
             This may cause an immediate burning pain in the mouth,
             oesophagus and stomach (retrosternal and epigastric pain),
             with swelling of the lips.  This is followed by vomiting,
             haematemesis, increased salivation, ulcerative mucosal burns,
             dyspnoea, paralytic ileus, stridor, dysphagia and shock. 
             Oesophageal and pharyngeal oedema may occur.
    

             Acute complications: These include gastrointestinal
             haemorrhage and perforation of the gut (mediatinitis and
             peritonitis as suggested by increasing abdominal pain,
             persistent vomiting, direct and indirect tenderness and a
             rigid abdominal wall).  Dyspnoea and stridor may occur and in
             severe cases there may be upper airway obstruction. 
             Aspiration can be a serious complication.
    
             Late complications: Oesophageal stricture and pyloric
             stenosis may occur as late complications.  Stricture
             formation usually begins to develop 14 to 21 days after
             ingestion.  Most strictures become manifest within the first
             two months.  Strictures may prevent an adequate nutritional
             intake and in severe cases patients may be unable to swallow
             their own saliva.  Gastric necrosis and stricture may occur,
             usually in patients who have oesophageal injury as well. 
             Gastric injury is more likely to occur following ingestion of
             liquid alkali rather than a solid.  The small intestine may
             also be involved.  Oesophago-aortic fistulae and rupture of
             the aorta are rare complications of corrosive ingestion.
             Tracheo-oesophageal fistulae and less commonly,
             broncho-oesophageal fistulae, have been reported following
             ingestion of alkalis.  Perforation and fistula may develop as 
             a consequence of invasive diagnostic procedure and treatment
             (ie. oesophageal dilatation).
    
             Severe corrosive injury to the stomach may result in small
             scarred immobile stomach and in such cases small, frequent
             intakes of food may be necessary to prevent dumping syndrome. 
             Achlorhydria with reduced or absent intrinsic factor may also
             occur.
    
             Long-term risks: Patients with oesophageal strictures are
             at significant risk for developing squamous cell carcinoma,
             which can occur years after the initial injury.  The vast
             majority of data is on sodium hydroxide about which there
             have been more reports of ingestion.  The incidence of
             carcinoma following oesophageal injury from sodium hydroxide
             is 0.8 to 4%.
    
             Skin exposure
             Alkalis can cause deep penetrating burns and necrosis.  There
             is also a risk of secondary infection of the damaged skin.
    
             Eye contact
             Alkalis are responsible for some of the most severe, blinding
             injuries to the eye.  Urgent ophthalmological referral is
             required.  Even if the initial manifestations are mild, the
             injuries may develop into opacification, vascularization,
             ulcerations and perforations.


        2.3  Diagnosis

             The history of exposure to alkali vapors, solutions or
             solids and the evidence of corrosive lesions on the
             gastrointestinal tract (GI) tract, skin or eyes are essential
             for the diagnosis. pH indicator shows alkaline reaction in
             contact with affected tissues or stomach content. Chemical
             identification of the toxic agent will help to fulfil the
             diagnosis.

        2.4  First aid measures and management principles

             Ingestion:
             Asymptomatic/mildly symptomatic patients: It should be
             noted that oesophageal damage may occur in the absence of
             oral burns.  Gastric lavage and emesis are contraindicated
             because of the risks of further injury on re-exposure of the
             oesophagus.  Nasogastric aspiration of the stomach contents
             is probably less effective for ingestion of alkali than for
             acids, since alkalis tend to damage the oesophagus rather
             than the stomach. Neutralising chemicals should never be
             given because heat is produced during neutralisation and this
             could exacerbate any injury.
    
             Gastro-oesophagoscopy should be undertaken within 12 to 24
             hours of the event to assess the extent and severity  of the
             injury. Endoscopy is contraindicated in patients with third
             degree burns of the hypopharynx, burns involving the larynx
             or those with respiratory distress.  Traditionally the
             endoscopist terminates the procedure at the first deep,
             penetrating and/or circumferential burn because of the risk
             of perforation.  However some physicians now recommend the
             use of flexible endoscopy to include the stomach and small
             intestine (panendoscopy) regardless of the presence of second
             or non-perforating third degree burns to the oesophagus.  If
             perforation is suspected or severe hypopharyngeal burns are
             present, radiographic studies with water-soluble contrast
             media may be used instead.
    
             Patients with grade 1 oesophageal burns may be discharged
             after 2 to 3 days, if they are able to take oral fluids and
             semi-solids. Those with grade 2 burns should be admitted and
             given parenteral nutrition.  Intensive care is usually
             required for patients with grade 3 burns. For discussion on
             the use of steroids and antibiotics - see below.
    
             Severely affected patients: Treatment is supportive. In
             severely affected patients aggressive intervention is
             essential.  Urgent assessment of the airway and endoscopic
             evaluation is required. A supraglottic-epiglottic burn with
             erythema and oedema is usually a sign that further oedema
             will occur which will lead to airway obstruction and is an
             indication to evaluate for early intubation or tracheostomy.
    

             Give plasma expanders/intravenous fluids for shock and check
             and correct the acid/base balance. Abdominal and chest X-rays
             need to be taken to check for perforation.  Analgesia will
             almost certainly be needed. Intubation and ventilation may be
             necessary for patients with respiratory distress.  Parenteral
             feeding will be necessary. Surgical intervention may also be
             required for gastrointestinal perforation or haemorrhage.
    
             Late complications: strictures that prevent adequate
             nutritional intake and do not respond to dilatation require
             oesophagectomy and colonic interposition.  Surgical
             intervention may also be required for gastrointestinal
             perforation or haemorrhage.  There may be loss of speech and
             inability to swallow as a result of severe corrosive injury.
    
             Severe cases of alkali ingestion may result in long-term
             problems and require prolonged hospitalisation and several
             surgical procedures and psychological treatment is
             recommended.  On discharge all patients must be advised on
             the possibility of late onset sequelae and advised to return
             if necessary.  In patients who have developed oesophageal
             stricture monitoring for life is recommended because of the
             risk of malignant disease.
    
             Dermal injury: The most important therapy for dermal alkali
             injuries is removal of contaminated clothes and irrigate with
             copious running water. This effectively cleanses the wound of
             unreacted chemical, dilutes the chemical already in contact
             with tissue and restores tissue water lost to the hygroscopic
             effect of alkalis.  The earlier the irrigation is begun the
             greater the benefit.  Irrigation should, therefore, be
             started as soon as possible, until the slippery and soapy
             sensation is no longer felt in the affected area.  The
             testing the pH of the skin immediately after irrigation may
             be misleading.  It is recommended that 15 minutes elapse
             before this is undertaken to allow residual alkali to diffuse
             up from the deeper regions of the dermis. Referral to a burns
             unit is recommended.
    
             Ocular injury: Copious and immediate irrigation of exposed
             eyes is essential.  Contact lenses should be removed prior to
             irrigation.  Tepid water (preferably sterile) or normal
             saline may be used, although other solutions have been
             employed in an emergency including tap water.  Particulate
             matter should be removed with cotton wool buds or forceps. 
             The pH of the cornea and irrigating fluid from the eye should
             be monitored with universal indicator paper.  Irrigation
             should be continued until the pH of the eye is normal and
             remains so for 2 hours. Pain and blepharospasm may make
             irrigation difficult and the use of anaesthetic drops (e.g.
             amethocaine, lignocaine) may be needed to facilitate thorough
             irrigation.  A lid speculum may be used if required. It is

             essential that the whole eye is irrigated including under the
             upper and lower lids.  After irrigation further treatment is
             aimed at preventing optic nerve damage from raised
             intraocular pressure and to protect the cornea from
             ulceration, perforation and infection.  Urgent referral to an
             ophthamologist is recommended.
    
             The use of steroids in corrosive injury
             Steroids have an anti-inflammatory effect and decrease
             fibroblastic activity and scar tissue formation.  Animal data
             has demonstrated that strictures formed in subjects given
             steroids have been less well structured with fewer
             inflammatory changes and less fibrin deposition.  The use of
             steroids for corrosive injury in man is a controversial
             subject which has generated a huge amount of literature (see
             section 10).
    
             Steroids are valuable in the management of laryngeal oedema,
             a complication of alkali ingestion.
    
             The main aim of steroids is to reduce stricture formation. 
             The role of steroids in alkali injury is still the subject of
             much debate, however most authors agree that patients with
             first degree burns do not require steroids since these burns
             usually heal without stricture formation.  The difficulty
             here is determining the severity of the injury from
             oesophagoscopy since it is difficult to determine the depth
             of the burn and the endoscope is sometimes not passed beyond
             the first identified burn due to the risk of perforation. 
             Some burns are so severe and extensive that strictures may
             develop despite steroid therapy  and may be delayed .
    
             However, there is no clinical evidence that steroid therapy
             is more effective than non-steroid therapy in reducing
             oesophageal stricture in any patient, even those with second
             degree burns.  Some authors believe there is no place for
             steroid therapy in the management of corrosive injury.
    
             Contraindications and problems in steroid therapy: It
             should be noted that there are definite contraindications to
             the use of steroids, these are as follows:
             a) infections
             b) perforation of the gastrointestinal tract or secondary
             mediastinitis
             c) gastrointestinal bleeding
             d) active ulcer
    
             Steroids depress the immune system and as a result the
             patient is more susceptible to infection.  Also steroids may
             mask the signs and symptoms of infection as well as those of
             perforation and peritonitis.  Steroid therapy may also result
             in a thin-walled oesophagus vulnerable to perforation due to
             reduced wound healing and scar formation.
    

             When to begin therapy: Once the decision has been made to
             use steroids, therapy should be started within 24 to 48 hours
             of the injury because the major inflammatory insult occurs
             within the first 48 hours and after this time steroids have
             little antifibroblastic activity.  Therapy started later may
             reduce scar formation but all evidence indicates that the
             best results are obtained with early institution of therapy. 
             The short duration of steroid therapy should not produce a
             significant reduction in intrinsic steroid production or
             alter the metabolic balance.
    
             The use of antibiotics in corrosive injury
             Antibiotics should be used in all patients with evidence of
             infection.  Some authors suggest that prophylactic
             antibiotics should be given in patients on steroid therapy,
             but others considered this unnecessary  since the risk of
             infection is low.
    
             Adjuntive treatment
    
             The use of H2-blockers and metoclopramide may help to prevent
             secondary acid injury to the esophagus.

    3.  PHYSICO-CHEMICAL PROPERTIES

        3.1  Origin of the substance

        3.2  Chemical structure

             Calcium hydroxide
             Molecular mass: 74.1
             Chemical formula: Ca(OH)2
    
             Potassium hydroxide
             Molecular mass:  56.1
             Chemical formula: KOH
    
             Sodium hydroxide
             Molecular mass: 40.0
             Chemical formula: NaOH

        3.3  Physical properties

             3.3.1  Colour

                    Calcium hydroxide: white/greyish-white
                    Potassium hydroxide: white

             3.3.2  State/Form

                    Calcium hydroxide: solid-powder
                    Potassium hydroxide: deliquescent solid


             3.3.3  Description

                    Calcium hydroxide
                    Melting point (decomposes):             580°C
                    Relative density (water = 1):           2.
                    Solubility in water:                    None
    
                    Potassium hydroxide
                    Boiling point:                          1324°C
                    Melting point:                          380°C
                    Relative density (water = 1):           2.04
                    Solubility in water, g/100 mL at 25°C:  110
                    Vapour pressure, kPa at 714°C:          0.13
    
                    Sodium hydroxide
                    Boiling point:                          1390°C
                    Melting point:                          318°C
                    Relative density (water = 1):           2.1
                    Solubility in water, g/100 mL at 20°C:  109

        3.4  Hazardous characteristics

             Calcium hydroxide
             The substance decomposes on heating producing calcium oxide.
             The substance is a medium strong base.
    
             Potassium hydroxide
             The substance is a strong base, it reacts violently with acid
             and is corrosive in moist air toward metals such as zinc,
             aluminum, tin and lead forming a combustible/explosive gas.
             Rapidly absorbs carbon dioxide and water from air. Contact
             with moisture or water will generate heat .
    
             Sodium hydroxide
             The substance is a strong base, it reacts violently with acid
             and is corrosive in moist air to metals like zinc, aluminum,
             tin and lead forming a combustible gas. Attacks some forms of
             plastics, rubber and coatings.Contact with moisture or water
             may generate heat.

    4.  USES

        4.1  Uses

             4.1.1  Uses

             4.1.2  Description

                    Alkalis are present in a number of household
                    products (e.g. drain cleaners, oven cleaners,
                    dishwasher products, some paint strippers) and are
                    also used in industry.


        4.2  High risk circumstance of poisoning

        4.3  Occupationally exposed populations

    5.  ROUTES OF EXPOSURE

        5.1  Oral

             Alkalis cause the most severe corrosive effects on the
             oesophagus, rather than the stomach as is the case with
             acids. However, following deliberate ingestion of a large
             quantity of an alkali both the stomach and small intestine
             may be involved. The severity of injury depends on a number
             of factors including the concentration of the agent, the
             duration of contact and the volume ingested and the presence
             of food in stomach.  It is greatest where the pH is above 12.
             However, pH is not the only factor which determines the
             extent to which a substance can cause corrosive injury. 
             Solid preparations and viscous liquids are also more likely
             to produce severe injury due to prolonged contact.  Following
             ingestion of a small amount the injury is usually limited to
             the oropharyngeal region and the oesophagus.  The greater the
             volume the greater the risk of duodenal and gastric damage.

        5.2  Inhalation

             Not relevant.

        5.3  Dermal

             Alkali injuries differ from those of other burns for a
             number of reasons. The injury may be painless and not be
             immediately evident.  This initial lack of pain may lead to a
             delay in treatment.  The injury can progress over several
             hours and the skin may be discoloured brown or black within a
             short period of time, these factors make initial assessment
             of the burn depth difficult.  Also, there may be recurring
             skin breakdown over a long period after the initial injury
             which can complicate and delay recovery (OœDonoghue et al.,
             1996).

        5.4  Eye

             Alkali burns of the eye are very serious because they
             cause disruption of the protective permeability barriers and
             rapidly penetrate the cornea and anterior chamber resulting
             in blindness.

        5.5  Parenteral

             Not relevant.


        5.6  Other

             Not relevant.

    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 and excretion

    7.  TOXICOLOGY

        7.1  Mode of action

             Alkalis cause liquifactive necrosis with saponification
             of fats and solubilisation of proteins, they are also
             hygroscopic and will absorb water from the tissues.  These
             effects result in adherence and deep penetration into the
             tissues.

        7.2  Toxicity

             7.2.1  Human data

                    7.2.1.1  Adults

                    7.2.1.2  Children

                             Children are commonly reported to
                             ingest corrosive substances but severe
                             effects are relatively rare.  Several studies
                             have been carried out in children in an
                             effort to correlate clinical effects and
                             injury.  Gaudreault et al. (1983) found that
                             signs and/or symptoms do not adequately
                             predict the presence or severity of an
                             oesophageal lesion.  Crain et al. (1984)
                             found that the presence of two or more signs
                             or symptoms (vomiting, drooling, stridor) may
                             be a reliable predictor of oesophageal
                             injury. In another study, prolonged drooling
                             and dysphagia (12 to 24 hours) were observed
                             to predicted oesophageal scar formation with
                             100% sensitivity (Nuutinen et al., 1994).  In
                             a study of 224 children (aged 0 to 14 years)
                             serious complications were due to ingestion
                             of sodium hydroxide or a dishwasher product.

                             Children without any signs or symptoms at the
                             first examination did not develop stricture
                             or epiglottal oedema (Clausen et al., 1994).

             7.2.2  Relevant animal data

             7.2.3  Relevant in vitro data

             7.2.4  Workplace standards

             7.2.5  Acceptable daily intake (ADI)

        7.3  Carcinogenicity

        7.4  Teratogenicity

        7.5  Mutagenicity

        7.6  Interactions

    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
                             "Basic analyses"
                             "Dedicated analyses"
                             "Optional analyses"

                    8.3.1.2  Urine
                             "Basic analyses"
                             "Dedicated analyses"
                             "Optional analyses"


                    8.3.1.3  Other fluids

             8.3.2  Arterial blood gas analyses

             8.3.3  Haematological analyses
                    "Basic analyses"
                    "Dedicated analyses"
                    "Optional 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

                    This may cause an immediate burning pain in the
                    mouth, oesophagus and stomach (retrosternal and
                    epigastric pain), with swelling of the lips.  This is
                    followed by vomiting, haematemesis, increased
                    salivation, ulcerative mucosal burns, dyspnoea,
                    paralytic ileus, stridor, dysphagia and shock. 
                    Oesophageal and pharyngeal oedema may occur.
    
                    Acute complications: these include gastrointestinal
                    haemorrhage and perforation of the gut leading to
                    mediastinitis nad peritonitis (suggested by increasing
                    abdominal pain, persistent vomiting, direct and
                    indirect tenderness and a rigid abdominal wall). 
                    Dyspnoea and stridor may occur and in severe cases
                    there may be upper airway obstruction.  Aspiration can
                    be a serious complications.
    
                    Late complications: oesophageal stricture and
                    pyloric stenosis may occur as late complications. 
                    Stricture formation usually begins to develop 14 to 21
                    days after ingestion.  Most strictures become manifest
                    within the first two months.  Strictures may prevent
                    an adequate nutritional intake and in severe cases
                    patients may be unable to swallow their own saliva. 
                    Gastric necrosis and stricture may occur, usually in
                    patients who have oesophageal injury as well.  Gastric
                    injury is more likely to occur following ingestion of
                    liquid alkali rather than a solid.  The small

                    intestine may also be involved.  Oesophago-aortic
                    fistulae and rupture of the aorta are rare
                    complications of corrosive ingestion.
                    Tracheo-oesophageal fistulae and less commonly,
                    broncho-oesophageal fistulae, have been reported
                    following ingestion of alkalis. Perforation and
                    fistula may develop as  a consequence of invasive
                    diagnostic procedure and treatment (ie. oesophageal
                    dilatation).
    
                    Severe corrosive injury to the stomach may result in
                    small scarred immobile stomach and in such cases
                    small, frequent intakes of food may be necessary to
                    prevent dumping syndrome.  Achlorhydria with reduced
                    or absent intrinsic factor may also occur.
    
                    Long-term risks: alkalis are known to increase the
                    risk of oesophageal cancer, which can occur years
                    after the initial injury (Appelqvist and Salmo, 1980;
                    Benirscke, 1981; Isolauri  and Markkula, 1989; Kinnman
                    et al., 1968).  The vast majority of data is on sodium
                    hydroxide about which there have been more reports of
                    ingestion.  The incidence of carcinoma following
                    oesophageal injury from sodium hydroxide is 0.8 to 4%.

             9.1.2  Inhalation

                    Not relevant

             9.1.3  Skin exposure

                    Alkalis can cause deep penetrating burns and
                    necrosis.  There is also a risk of secondary infection
                    of the damaged skin.

             9.1.4  Eye contact

                    Alkalis are responsible for some of the most
                    severe, blinding injuries to the eye.  Urgent
                    ophthalmological referral is required.

             9.1.5  Parenteral exposure

                    Not relevant

             9.1.6  Other

                    Not relevant


        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

             See Section 9.1

        9.4  Systematic description of clinical effects

             9.4.1  Cardiovascular

             9.4.2  Respiratory

             9.4.3  Neurological

                    9.4.3.1  Central nervous system (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

             Ingestion:
             Asymptomatic/mildly symptomatic patients: It should be
             noted that oesophageal damage may occur in the absence of
             oral burns.  Gastric lavage and emesis are contraindicated
             because of the risks of further injury on re-exposure of the
             oesophagus.  Nasogastric aspiration of the stomach contents
             is probably less effective for ingestion of alkali than for
             acids, since alkalis tend to damage the oesophagus rather
             than the stomach.  Oral fluids may be given unless there is
             evidence of severe injury.  Neutralising chemicals should
             never be given because heat is produced during neutralisation
             and this could exacerbate any injury.
    
             Gastro-oesophagoscopy should be undertaken within 12 to 24
             hours of the event to assess the extent and severity  of the
             injury. Endoscopy is contraindicated in patients with third
             degree burns of the hypopharynx, burns involving the larynx
             or those with respiratory distress.  Traditionally the
             endoscopist terminates the procedure at the first deep,
             penetrating and/or circumferential burn because of the risk
             of perforation.  However some physicians now recommend the
             use of flexible endoscopy to include the stomach and small
             intestine (panendoscopy) regardless of the presence of second
             or non-perforating third degree burns to the oesophagus
             (Ford, 1991; Meredith, 1996).  If perforation is suspected or
             severe hypopharyngeal burns are present, radiographic studies
             with water-soluble contrast media may be used instead.
    

             Patients with grade 1 oesophageal burns may be discharged if
             they are able to take oral fluids.  Those with grade 2 burns
             should be admitted and given parenteral nutrition.  Intensive
             care is usually required for patients with grade 3 burns.  A
             laparotomy may be required if there is evidence of gastric
             injury or the gastric pH is persistently alkaline (Meredith,
             1996).  For discussion on the use of steroids and antibiotics
             - see below.
    
             Severely affected patients: Treatment is supportive. In
             severely affected patients aggressive intervention is
             essential.  Urgent assessment of the airway and endoscopic
             evaluation is required. A supraglottic-epiglottic burn with
             erythema and oedema is usually a sign that further oedema
             will occur which will lead to airway obstruction and is an
             indication for early intubation or tracheostomy.
    
             Give plasma expanders/intravenous fluids for shock and check
             and correct the acid/base balance. Abdominal and chest X-rays
             need to be taken to check for perforation.  Analgesia will
             almost certainly be needed. Intubation and ventilation may be
             necessary for patients with respiratory distress.  Parenteral
             feeding will be necessary.
    
             Late complications: strictures that prevent adequate
             nutritional intake and do not respond to dilatation require
             oesophagectomy and colonic interposition.  In the case of
             oesophageal strictures a lumen >10mm does not impede normal
             life and should not require intervention.  Surgical
             intervention may also be required for gastrointestinal
             perforation or haemorrhage.  There may be loss of speech and
             inability to swallow as a result of severe corrosive injury. 
             Speech and swallowing rehabilitation is a complex subject and
             is discussed by Shikowitz et al. (1996) with description of
             the surgical techniques used and the tools used to determine
             the success of the reconstruction.
    
             Severe cases of alkali ingestion may result in long-term
             problems and require prolonged hospitalisation and several
             surgical procedures and psychological treatment is
             recommended.  On discharge all patients must be advised on
             the possibility of late onset sequelae and advised to return
             if necessary.  In patients who have developed oesophageal
             stricture monitoring for life is recommended because of the
             risk of malignant disease.
    
             Dermal injury: The most important therapy for dermal alkali
             injuries is removal of contaminated clothes and irrigate with
             copious running water. This effectively cleanses the wound of
             unreacted chemical, dilutes the chemical already in contact
             with tissue and restores tissue water lost to the hygroscopic
             effect of alkalis.  The earlier the irrigation is begun the
             greater the benefit.  Irrigation should, therefore, be

             started as soon as possible.  Testing the pH of the skin
             immediately after irrigation may be misleading.  It is
             recommended that 15 minutes elapse before this is undertaken
             to allow residual alkali to diffuse up from the deeper
             regions of the dermis (Herbert and Lawrence, 1989; OœDonoghue
             et al., 1996).  Referral to a burns unit is recommended.
    
             Ocular injury: Copious and immediate irrigation of exposed
             eyes is essential.  Water (preferably sterile) or normal
             saline may be used, although other solutions have been
             employed in an emergency including tap water.  Particulate
             matter should be removed with cotton wool buds or forceps. 
             The pH of the cornea and irrigating fluid from the eye should
             be monitored with universal indicator paper.  Irrigation
             should be continued until the pH of the eye is normal and
             remains so for 2 hours. Pain and blepharospasm may make
             irrigation difficult and the use of anaesthetic drops (e.g.
             amethocaine, lignocaine) may be needed to facilitate thorough
             irrigation.  A lid speculum may be used if required. It is
             essential that the whole eye is irrigated including under the
             upper and lower lids.  After irrigation further treatment is
             aimed at preventing optic nerve damage from raised
             intraocular pressure and to protect the cornea from
             ulceration, perforation and infection.  Urgent referral to an
             ophthamologist is recommended.
    
             The use of steroids in corrosive injury
             Steroids have an anti-inflammatory effect and decrease
             fibroblastic activity and scar tissue formation.  Animal data
             has demonstrated that strictures formed in subjects given
             steroids have been less well structured with fewer
             inflammatory changes and less fibrin deposition.  The use of
             steroids for corrosive injury in man is a controversial
             subject which has generated a huge amount of literature.
    
             Middlekamp et al. (1969) reported thirty-two cases of
             oesophageal burns due to alkali injury, none of the patients
             with first degree burns (nineteen cases) developed
             oesophageal stricture.  One patient (out of six) with second
             degree burns and all patients with third degree burns (seven)
             developed oesophageal stricture.
    
             In another study on the use of steroids in children with
             corrosive injury of the oesophagus, of one hundred and
             thirty-one children sixty had oesophageal burns.  Of these
             burns, fifty-five were caused by known agents, 91% of which
             were alkaline.  Oesophageal stricture developed in ten of the
             thirty-one children treated with steroids and in eleven of
             the twenty-nine controls.  Nine of the ten patients in the
             steroid group had third degree burns and one had second
             degree injuries, all eleven patients in the control group had
             third degree burns. Twenty-one patients given steroids and
             eighteen controls did not develop strictures, of these

             children all but one had first or second degree injuries
             (Anderson et al., 1990).
    
             Several authors have found that it is the depth of the
             initial burn rather than the initial treatment which
             determines the outcome (Anderson et al., 1990; Moazam et al.,
             1987; Oakes et al., 1982; Webb et el., 1970).
    
             The main aim of the management of alkali injury is to reduce
             stricture formation.  The role of steroids in alkali injury
             is still the subject of much debate, however most authors
             agree that patients with first degree burns do not require
             steroids since these burns usually heal without stricture
             formation.  The difficulty here is determining the severity
             of the injury from oesophagoscopy since it is difficult to
             determine the depth of the burn and the endoscope is
             sometimes not passed beyond the first identified burn due to
             the risk of perforation.  Some burns are so severe and
             extensive that strictures may develop despite steroid therapy
             (Haller et al., 1971) and may be delayed (Middlekamp et al.,
             1969).
    
             Steroids are valuable in the management of laryngeal oedema,
             a complication of alkali ingestion.
    
             In summary, steroids are probably most effective for second
             degree or moderately severe burns (Hawkins et al., 1980;
             Klein-Schwartz  and Oderda, 1983;  Webb et al., 1970).  They
             are not necessary for first degree burns and appear to be
             ineffective in preventing stricture formation following third
             degree burns.  However, there is no clinical evidence that
             steroid therapy is more effective than non-steroid therapy in
             reducing oesophageal stricture in any patient, even those
             with second degree burns.  Some authors believe there is no
             place for steroid therapy in the management of corrosive
             injury (Di Costanzo et al., 1980; Wijburg et al., 1989).  As
             Oakes et al. (1982) state, clinicians should not feel
             compelled to institute steroid therapy for caustic
             oesophagitis simply because it is considered 'standard
             therapy'.
    
             Contraindications and problems in steroid therapy: It
             should be noted that there are definite contraindications to
             the use of steroids, these are as follows:- 
    
             a) active infection
             b) perforation of the gastrointestinal tract or secondary
             mediastinitis
             c) significant gastrointestinal bleeding
             d) history of or active ulcer
    

             Steroids depress the immune system and as a result the
             patient is more susceptible to infection.  Also steroids may
             mask the signs and symptoms of infection as well as those of
             perforation and peritonitis.  Steroid therapy may also result
             in a thin-walled oesophagus vulnerable to perforation due to
             reduced wound healing and scar formation (Cardona and Daly,
             1971). 
    
             When to begin therapy: Once the decision has been made to
             use steroids therapy should be started within 24 to 48 hours
             of the injury because the major inflammatory insult occurs
             within the first 48 hours and after this time steroids have
             little antifibroblastic activity.  Therapy started later may
             reduce scar formation but all evidence indicates that the
             best results are obtained with early institution of therapy
             (Haller et al., 1971).  The short duration of steroid therapy
             should not produce a significant reduction in intrinsic
             steroid production or alter the metabolic balance.
    
             The use of antibiotics in corrosive injury
             Antibiotics should be used in all patients with evidence of
             infection.  Some authors suggest that prophylactic
             antibiotics should be given in patients on steroid therapy
             (Adam and Birck, 1982; Howell et al., 1992), but others
             considered this unnecessary (Klein-Schwartz  and Oderda,
             1983; Wijburg et al., 1989) since the risk of infection is
             low (Knopp, 1979).
    
             Adjuntive treatment
    
             The use of H2-blockers and metoclopramide may help to prevent
             secondary acid injury to the esophagus (Haddad, 1998).

        10.2 Life supportive procedures and symptomatic/specific treatment

             See section 10.1

        10.3 Decontamination

             Gastric lavage and emesis are contraindicated because
             of the risks of further injury on re-exposure of the
             oesophagus.

        10.4 Enhanced elimination

             See section 10.1

        10.5 Antidote treatment

             10.5.1 Adults

                    There is no specific antidote.


             10.5.2 Children

                    There is no specific antidote.

        10.6 Management discussion

             See section 10.1

    11. ILLUSTRATIVE CASES

        11.1 Case reports from literature

    12. Additional information

        12.1 Specific preventive measures

             Rescuers, first-aid personnel and medical professionals
             should use appropriate protective clothing/gloves and where
             necessary employ respiratory protection.

        12.2 Other

    13. REFERENCES

        Adam JS and Birck HG. (1982)  Pediatric caustic ingestion. 
        Ann Otol Rhinol Laryngol 91:656-658
    
        Anderson KD, Rouse TM and Randolph JGH. (1990) A controlled trial
        of corticosteroids in children with corrosive injury of the
        oesophagus.  N Eng J Med 323 (10):637-640
    
        Appelqvist P and Salmo M. (1980) Lye corrosion carcinoma of the
        oesophagus. A review of 63 cases. Cancer 45:2655-2658
    
        Benirscke K. (1981) Time bomb of lye ingestion? Am J Dis Child
        135:17-18
    
        Cardona JC and Daly JF. (1971)  Current mangement of corrosive
        esophagitis.  An evaluation of results of 239 cases.  Ann Otol
        80:521-527
    
        Clausen JO, Nielsen TLF and Fogh A. (1994)  Admission to Danish
        hospitals after suspected ingestion of corrosives.  A nationwide
        survey (1984-1988) comprising children aged 0-14 years.
        Dan Med Bull 41:234-237
    
        Crain EE, Gershel JC and Mezey AP. (1984) Caustic ingestions.
        Symptoms as predictors of esophageal in jury. Am J Dis Child
        138:863-865
    

        Di Costanzo J, Noirclerc M, Jouglard J, Escoffier JM, Cano N,
        Martin J and Gauthier A. (1980) New therapeutic approach to
        corrosive burns of the upper gastrointestinal tract. Gut
        21:370-375
    
        Ford M. (1991) Alkali and acid injuries of the upper
        gastrointestinal tract. Contemporary management in critical care 1
        (3):225-249  Tobin MJ and Grenvik A (eds). Churchill
        Livingstone
    
        Gaudreault P, Parent M, McGuigan MA, Chicoine L and Lovejoy FH.
        (1983) Predicability of eosophageal injury from signs and
        symptoms: a study of caustic ingestions in 378 children.
        Pediatrics 71 (5):767-770
    
        Haller JA, Andrews HG, White JJ, Tamer MA and Cleveland WW. (1971) 
        Pathophysiology and management of acute corrosive burns of the
        esophagus: results of treatment in 285 children.  J Pediatr Surg 6
        (5):578-584
    
        Hawkins DB, Demeter MJ and Barnett TE. (1980) Caustic ingestion:
        controversies in management.  A review of 214 cases. Laryngoscope
        90:98-109
    
        Herbert K and Lawrence JC. (1989) Chemical burns. Burns 15
        (6):381-384
    
        Howell JM, Dalsey WC, Hartsell FW and Butzin CA. (1992) Steroids
        for the treatment of corrosive esophageal injury: a statistical
        analysis of past studies.  Am J Emerg Med 10:421-425
    
        Isolauri J and Markkula H. (1989) Lye ingestion and carcinoma of
        the oesophagus. Acta Chir Scand 155:269-271
    
        Kinnman J, Shin HI and Wetteland P. (1968) Carcinoma of the
        oesophagus after lye ingestion.  Report of a case in 15 year old
        Korean male. Acta Chir Scand 134:489-493
    
        Klein-Schwartz W and Oderda GM. (1983) Management of corrosive
        ingestions. Clin Toxicol Consult  5 (2):39-55
    
        Knopp R. (1979) Caustic ingestions. JACEP 8:329-336
    
        Meredith  TJ. (1996) Corrosive ingestion: how should it be
        managed? XVII International Congress of the EAPCCT Marseille June
        4-7 1996
    
        Middlekamp JN, Ferguson TB, Roper CL and Hoffman FD. (1969) The
        management and problems of caustic burns in children.  J Thorac
        Cardiovasc Surg 57:341-347
    

        Moazam F, Talbert JL, Miller D and Mollitt DL. (1987)  Caustic
        ingestion and its sequelae in children.  South Med J
        80:187-190
    
        Nuutinen M, Uhari M, Karvali T and Kouvalainen K. (1994)
        Consequences of caustic ingestions in childeren. Acta Paediatr
        83:1200-1205
    
        Oakes DD, Sherck JP and Mark JBD. (1982)  Lye ingestion.  Clinical
        patterns and therapeutic implications.  J Thorac Cardiovasc Surg
        83:194-204
    
        OœDonoghue JM, Al-Ghazal SK and McCann JJ. (1996)  Caustic soda
        burns to the extremities: difficulties in management.  BJCP 50
        (2):108-109
    
        Shikovitz MJ, Levy J, Villano D, Graver LM and Pochaczevsky R.
        (1996)  Speech and swallowing rehabilitation following devastating
        caustic ingestion: techniques and indicators for success. 
        Laryngoscope 106 (Suppl 78):1-12
    
        Webb WR,  Koutras P, Ecker RR and Sugg WL. (1970)  An evaluation
        of steroids and antibiotics in caustic burns of the esophagus. 
        Ann Thorac Surg 9:95-102
    
        Wijburg FA, Heymans HSA and Urbanus NAM. (1989)  Caustic
        esophageal lesions in childhood: prevention of stricture
        formation.  J Pediatr Surg 24 (2):171-173

    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE 
        ADDRESS(ES)

        Author:     Medical Toxicology Unit,
                    Guyœs and St Thomasœ Trust
                    Avonley Road, London SE14 5ER, UK
    
        Date:       November, 1997
    
        Review:     As for author. 1997
    
        Peer review:         INTOX meeting, March 1998, London, UK 
                             (Members of group: Drs G. Allridge, L.
                             Lubomovir, R. Turk, C. Alonso, S. de Ben, K.
                             Hartigan-Go, N. Bates)
    
        Editor:     Dr M.Ruse (September, 1998)