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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY


    ENVIRONMENTAL HEALTH CRITERIA 10





    CARBON DISULFIDE









    This report contains the collective views of an
    international group of experts and does not necessarily
    represent the decisions or the stated policy of either
    the World Health Organization or the United Nations
    Environment Programme.

    Published under the joint sponsorship of
    the United Nations Environment Programme
    and the World Health Organization

    World Health Organization

    Geneva, 1979


    ISBN 92 4 154070 2

    (c) World Health Organization 1979

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    CONTENTS

    ENVIRONMENTAL HEALTH CRITERIA FOR CARBON DISULFIDE

    1.   SUMMARY AND RECOMMENDATIONS FOR FURTHER RESEARCH
         1.1   Summary
               1.1.1   Uses and sources of exposure
               1.1.2   Populations at risk
               1.1.3   Estimation of exposure
               1.1.4   Metabolism
               1.1.5   Mechanisms of toxic action
               1.1.6   Carbon disulfide poisoning; evaluation of the
                       health risk to man
               1.1.7   Diagnosis of carbon disulfide poisoning
               1.1.8   Surveillance of exposed workers
         1.2   Recommendations for further research
               1.2.1   Analytical aspects
               1.2.2   Studies on health effects
               1.2.3   Mechanisms of toxic action

    2.   PROPERTIES AND ANALYTICAL METHODS
         2.1   Chemical and physical properties
         2.2   Analytical procedures
               2.2.1   Measurement of carbon disulfide in air
               2.2.2   Sampling methods
                       2.2.2.1   The activated charcoal tube method
                       2.2.2.2   The liquid absorption method
               2.2.3   Methods for the determination of carbon disulfide
                       2.2.3.1   Direct measurement using gas detector
                                 tubes
                       2.2.3.2   Photometric determination
                       2.2.3.3   Gas-liquid chromatographic determination
                       2.2.3.4   Continuous measurement using gas
                                 analysers
                       2.2.3.5   Determination of metabolites in urine

    3.   EXPOSURE TO CARBON DISULFIDE
         3.1   Occupational exposure
         3.2   Community exposure

    4.   METABOLISM
         4.1   Absorption
               4.1.1   Inhalation
               4.1.2   Skin absorption
         4.2   Distribution and biotransformation
               4.2.1   Balance of absorbed carbon disulfide
               4.2.2   Transport by the bloodstream
               4.2.3   Determination of carbon disulfide in blood
               4.2.4   Distribution in the organism
               4.2.5   Binding in blood and tissues

         4.3   Elimination of carbon disulfide and metabolites
               4.3.1   Elimination by breath, saliva, sweat, and faeces
               4.3.2   Excretion of carbon disulfide and metabolites in
                       urine

    5.   BIOCHEMICAL EFFECTS OF CARBON DISULFIDE
         5.1   Chelating effects of carbon disulfide metabolites
         5.2   Effects on enzyme systems
         5.3   Effects on vitamin metabolism
               5.3.1   Vitamin B6
               5.3.2   Nicotinic acid
         5.4   Effects on catecholamine metabolism
         5.5   Effects on lipid metabolism
         5.6   Interaction with microsomal drug metabolism

    6.   CARBON DISULFIDE POISONING
         6.1   Historical review
         6.2   Clinical picture of carbon disulfide poisoning
         6.3   Effects on organ systems
               6.3.1   Dermatological effects
               6.3.2   Ophthalmological effects
               6.3.3   Otological effects
               6.3.4   Respiratory effects
               6.3.5   Gastrointestinal effects
               6.3.6   Hepatic effects
               6.3.7   Renal effects
               6.3.8   Haematological effects
               6.3.9   The endocrine system
               6.3.10  Effects on the nervous system
                       6.3.10.1  Central nervous system
                       6.3.10.2  Peripheral nervous system
               6.3.11  Cardiovascular effects
               6.3.12  Carcinogenicity and mutagenicity
               6.3.13  Teratogenic effects
               6.3.14  Other effects
               6.3.15  Interactions with other chemical compounds
         6.4   Diagnosis
         6.5   Surveillance of the health of exposed workers
         6.6   Contraindications for exposure to carbon disulfide

    7.   EXPOSURE-EFFECT AND EXPOSURE-RESPONSE RELATIONSHIPS
         7.1   Validity of exposure data
         7.2   Experimental data
               7.2.1 Acute animal exposure
               7.2.2 Long-term animal exposure
         7.3   Epidemiological data
               7.3.1   Neurological and behavioural effects
               7.3.2   Cardiovascular effects
               7.3.3   Ophthalmological effects
               7.3.4   Gonadal effects

    8.   CONTROL OF EXPOSURE IN THE VISCOSE INDUSTRY

    REFERENCES

    ANNEX I    Production of viscose and its end-products

    ANNEX II   Maximum permissible concentrations for carbon disulfide
               in different countries

    NOTE TO READERS OF THE CRITERIA DOCUMENTS

    While every effort has been made to present information in the
    criteria documents as accurately as possible without unduly delaying
    their publication, mistakes might have occurred and are likely to
    occur in the future. In the interest of all users of the environmental
    health criteria documents, readers are kindly requested to communicate
    any errors found to the Division of Environmental Health, World Health
    Organization, Geneva, Switzerland, in order that they may be included
    in corrigenda which will appear in subsequent volumes.

         In addition, experts in any particular field dealt with in the
    criteria documents are kindly requested to make available to the WHO
    Secretariat any important published information that may have
    inadvertently been omitted and which may change the evaluation of
    health risks from exposure to the environmental agent under
    examination, so that the information may be considered in the event of
    updating and re-evaluation of the conclusions contained in the
    criteria documents.

    WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR
    CARBON DISULFIDE

    Participants

     Members

    Dr G. Avilova, Institute of Hygiene and Preventive Medicine, Academy
         of Medical Sciences, Moscow, USSR

    Dr A. Cavalleri, Institute of Occupational Medicine, University of
         Pavia, Pavia, Italy

    Dr D. Djuric, Institute of Occupational and Radiological Health,
         Belgrade, Yugoslavia

    Professor K. J. Freundt, Institute of Pharmacology and Toxicology,
         Faculty of Clinical Medicine, Mannheim, Federal Republic of
         Germany

    Dr S. Hernberg, Institute of Occupational Health, Helsinki, Finland

    E. Lukas, Institute of Hygiene and Epidemiology, Centre of Industrial
         Hygiene and Occupational Diseases, Prague, Czechoslovakia

    Professor A. A. E. Massoud, Department of Preventive and Industrial
         Medicine, Ein Shams University, Cairo, Egypt

    Professor W. O. Phoon, Department of Social Medicine and Public
         Health, Faculty of Medicine, University of Singapore, Singapore

    Mr V. Rose, National Institute for Occupational Safety and Health,
         Rockville, MD, USA

    Dr S. Tarkowski, Department of Biochemistry, Institute of Occupational
         Medicine, Lodz, Poland

    Professor J. Teisinger, Institute of Hygiene and Epidemiology, Prague,
         Czechoslovakia  (Chairman)

    Dr H. Thiele, Central Institute for Occupational Medicine, Berlin,
         German Democratic Republic

    Professor S. Yamaguchi, Department of Public Health, Tsukuba
         University, School of Medicine, Niihari-Gun, Ibaraki-ken, Japan

    Professor S. H. Zaidi, Industrial Toxicology Research Centre, Lucknow,
         India

     Secretariat

    A. David, Institute of Hygiene and Epidemiology, Centre of Industrial
         Hygiene and Occupational Diseases, Prague, Czechoslovakia
          (National Coordinator and Co-Chairman)

    Dr M. A. El Batawi, Chief Medical Officer, Office of Occupational
         Health, World Health Organization, Geneva, Switzerland
          (Secretary)

    ENVIRONMENTAL HEALTH CRITERIA FOR CARBON DISULFIDE

         A WHO Task Group on Environmental Health Criteria for Carbon
    Disulfide met in Prague from 13 to 20 June 1977. Dr M. El Batawi,
    Chief Medical Officer, Office of Occupational Health, opened the
    meeting on behalf of the Director-General and expressed the
    appreciation of the Organization to the Government of Czechoslovakia
    for kindly acting as host to the meeting. In reply, the Group was
    welcomed by Professor J. Teisinger, Institute of Hygiene and
    Epidemiology, Prague. The Task Group reviewed and revised the second
    draft criteria document and made an evaluation of the health risks
    from exposure to carbon disulfide.

         The first draft of the criteria document was prepared by
    Dr. Djuric, Institute of Occupational and Radiological Health, Belgrade,
    Yugoslavia, in consultation with Professor Teisinger, Dr E. Lukas,
    Institute of Hygiene and Epidemiology, Prague, Czechoslovakia, and
    several research workers in Belgrade and Prague. The second draft was
    prepared by Dr S. Hernberg, Institute of Occupational Health,
    Helsinki, Finland taking into consideration comments by Professor
    K. Freundt, Institute of Toxicology and Pharmacology, Mannheim, Federal
    Republic of Germany, Professor Sh. Goto, Osaka University, Japan,
    Dr. I. Lancranjan, Institute of Hygiene and Public Health, Clinic of
    Occupational Diseases, Bucharest, Romania, Dr J. Lieben of the
    American Viscose Division, PM Corporation, Philadelphia, USA, Dr A.
    Massoud, National Research Centre, Cairo University, Egypt, Dr A.M.
    Seppäläinen, Institute of Occupational Health, Helsinki, Finland, and
    Dr P. G. Vertin, Institute of Social Medicine, Catholic University of
    Nijmegen, Netherlands.

         The Secretariat wishes to acknowledge the collaboration of these
    experts and, in particular, to thank Dr Djuric and Dr Hernberg for
    their valuable help in all phases of the preparation of the document,
    and Dr H. Nordman, Institute of Occupational Health, Helsinki,
    Finland, for his assistance in the scientific editing.

         This document is based primarily on original publications listed
    in the reference section but much valuable information has also been
    obtained from various publications reviewing the toxicity and health
    aspects of carbon disulfide including those of the US National
    Institute of Occupational Safety and Health (NIOSH, 1977) and Brieger
    & Teisinger, ed. (1966). In addition, much useful data has been drawn
    from reports of several international symposia and meetings including:
    Zbornik radova o toksikologiji CS2, Yugoslavia, Loznica, 3-5 June
    1965; the II International Symposium on the Toxicology of Carbon
    Disulfide, Yugoslavia, Banja Kovilijaca, 25-28 May 1971; the III
    International Symposium on the Toxicology of Carbon Disulfide, Egypt,
    Cairo and Alexandria, 4-9 May 1974; and the IV International Symposium
    on Occupational Health in the Production of Artificial Fibres,
    Finland, Helsinki and Valkeakoski, 6-10 June 1977.

         Details of the WHO Environmental Health Criteria Programme
    including some terms frequently used in the documents may be found in
    the general introduction to the Environmental Health Criteria
    Programme published together with the environmental health criteria
    document on mercury (Environmental Health Criteria 1, Mercury, Geneva,
    World Health Organization, 1976), now also available as a reprint.


         The following conversion factor has been used in this document:

                     carbon disulfide            1 ppm = 3.12 mg/m3

         When converting values expressed in ppm to mg/m3 the numbers
    have been rounded up to 2 or, exceptionally, 3 significant figures.
    Where concentrations were expressed as ppm in the original
    publication, this value has been given in parentheses together with
    the converted value.

    1.  SUMMARY AND RECOMMENDATIONS FOR FURTHER RESEARCH

    1.1  Summary

    1.1.1  Uses and sources of exposure

         By far the most important use of carbon disulfide in industry is
    in the production of viscose rayon fibres. It is also used, to some
    extent, as a solvent in various industrial processes including the
    refining of paraffin and petroleum, and more recently in the
    production of flotation agents and herbicides. However, the risk of
    being exposed to high concentrationsa of carbon disulfide during
    these processes is small compared with that in the viscose industry.
    Viscose rayon fibres are used in the production of rayon filament
    textile yarn, rayon tire yarn, rayon stable fibre and Cellophane film.
    In these processes, carbon disulfide exposure occurs concomitantly
    with exposure to hydrogen sulfide. The amounts of carbon disulfide and
    hydrogen sulfide vapour liberated depend on the process. For every
    kilogram of viscose used, about 20-30 g of carbon disulfide and 4-6 g
    of hydrogen sulfide will be emitted. About 0.6-1.0 kg of viscose is
    used per hour in the different processes involved in the production
    of textile yarn. However, exposure to carbon disulfide is usually
    highest in connection with the production of staple fibre and
    Cellophane, where the equivalent amounts of viscose used are
    approximately 70-100 kg and 1800-2000 kg per hour, respectively.

    1.1.2  Populations at risk

         Carbon disulfide is a typical industrial toxic chemical and
    exposure is almost exclusively confined to occupational situations. In
    theory, any worker engaged in processes using carbon disulfide may be
    exposed to some degree. However, in practice, only workers in the
    viscose rayon industry are exposed to concentrations high enough to
    have deleterious effects on health. The exposure of the general
    population living in the vicinity of carbon disulfide-emitting
    industries cannot be assessed at present, because information is
    inadequate.

    __________

     a Throughout the document the word concentration refers to mass
      concentration unless otherwise stated.

    1.1.3  Estimation of exposure

         Exposure to carbon disulfide can be estimated either by direct
    measurement of air concentrations or by the determination of carbon
    disulfide metabolites in the urine of exposed individuals. Air samples
    can be taken either at fixed sites, or from the breathing zone of the
    workers. Sampling at fixed sites is recommended for engineering
    purposes, while sampling from the breathing zone is indicated for the
    assessment of personal exposure.

         Monitoring at fixed sites is best done by continuous measurement
    with gas analysers based on electrical conductivity or light
    absorption in the infrared region. Gas detector tubes may be used for
    preliminary screening, since the procedure is rapid and simple, but
    their usefulness is limited because of lack of accuracy and a high
    detection limit; thus, this procedure should always be complemented by
    more accurate methods.

         Personal exposure is best monitored by samples collected from the
    breathing zone of the workers, using portable samplers. The carbon
    disulfide is adsorbed on activated charcoal and later determined by
    gas chromatography. Absorption in liquids is not possible, when using
    portable samplers. Depending on desorption efficiency and the type of
    gas chromatograph used, determination of carbon disulfide
    concentrations below 1 mg/m3 is possible. Furthermore, hydrogen
    sulfide does not cause interference.

         The method most extensively used for the indirect assessment of
    personal exposure is the iodine-azide test in which the concentration
    of carbon disulfide metabolites present in the urine is measured. The
    "chronometric" iodine-azide test, based on the time elapsing from
    adding the iodine-azide reagent to the urine until decolorization of
    the iodine solution takes place, offers a simple method to be used at
    the plant level, but its rather high detection limit restricts its use
    to exposure levels in excess of 50 mg/m3. Titrimetric modification of
    the same test increases sensitivity and allows assessment of exposure
    at levels down to 10 mg/m3.

         Because of the poor correlation with carbon disulfide
    concentrations in air as well as for analytical reasons, the
    concentration of carbon disulfide in blood is not a useful test of
    exposure.

    1.1.4  Metabolism

         Inhalation is the principal route of absorption of carbon
    disulfide in man, equilibrium between the carbon disulfide contents of
    inhaled and exhaled air being reached in about 1-2 h. At this point,
    retention is about 40-50%. Absorption through the skin is a much less
    important route than inhalation and other routes are negligible.

    Carbon disulfide is distributed in the organism by the blood stream.
    It is taken up by the erythrocytes and plasma in the blood in the
    ratio of 2:1. It is readily soluble in fats and lipids and binds to
    amino acids and proteins; hence, it disappears rapidly from the blood
    stream and has a high affinity for all tissues and organs. Because of
    the rapid elimination of carbon disulfide, the distribution pattern in
    the human organism has not been fully elucidated. Ten to 30% of
    absorbed carbon disulfide is exhaled, less than 1% is excreted in the
    urine, and the remaining 70-90% undergoes biotransformation before
    excretion in the urine in the form of metabolites.

    1.1.5  Mechanisms of toxic action

         The biochemical mechanisms of the adverse effects of carbon
    disulfide are largely unknown. However, a number of possible
    mechanisms have been suggested including:

          (a) A chelating effect of the metabolites on various essential
    trace metals;

          (b) Inhibition of some enzymes (this may be explained, to some
    extent, by chelation, but the nature of other mechanisms is not yet
    known);

          (c) Disturbance of the vitamin metabolism (experimental
    evidence in animals has shown an impairment of vitamin B6 and
    nicotinic acid metabolism);

          (d) Disturbance of the catecholamine metabolism;

          (e) Disturbance of the lipid metabolism;

          (f) Interaction with the microsomal drug metabolizing system
    (the liver toxicity may be, at least, partly explained by the
    destruction of cytochrome P-450 via the oxidative desulfuration of
    carbon disulfide).

    1.1.6  Carbon disulfide poisoning; evaluation of the
           health risk to man

         Carbon disulfide can cause both acute and chronic forms of
    poisoning. Massive, short-term exposure to concentrations of about
    10 000 mg/m3 or more can cause "hyperacute" poisoning, characterized
    by rapid falling into coma and, eventually, death. Acute and subacute
    poisoning is associated with short-term exposure to concentrations of
    3000-5000 mg/m3 accompanied by predominantly psychiatric and
    neurological symptoms such as extreme irritability, uncontrolled
    anger, rapid mood changes, euphoria, hallucinations, paranoic and
    suicidal tendencies, and manic delirium. Exposure over many years may
    produce the syndrome of chronic poisoning manifested by a variety of

    symptoms and signs arising from manifold adverse effects on different
    organ systems. Because of the lack of reliable retrospective data on
    exposure levels, dose-effect and dose-response relationships are
    extremely difficult to establish, and the no-observed-effect-level is
    unknown for most effects.

         Psychiatric signs and symptoms indicative of adverse effects on
    the central nervous system following prolonged exposure to high
    concentrations of carbon disulfide include restlessness, excitation,
    and loss of temper with gradual development of anxiety, depression,
    and paranoic tendencies. The development of chronic encephalopathy has
    been associated with exposure to levels of 150 mg/m3 or more over a
    period of several years. Psychological and behavioural changes have
    been recorded following exposure to levels ranging from 30-120 mg/m3
    for more than 6 years, and increases in the frequency and severity of
    such symptoms as headache, impairment of memory, rapid mood changes,
    paraesthesia, and fatigue have been noted at concentrations ranging
    from 20-90 mg/m3. As poisoning progresses further, neurological
    symptoms become more predominant. Both pyramidal and extrapyramidal
    symptoms may develop indicating impairment of the central nervous
    system.

         Symmetric polyneuropathy primarily affecting the nerves of the
    lower extremities and characterized by paraesthesia, dysaesthesia,
    fatiguability, and diffuse pain, sometimes with hyperaesthesia or
    hypersensitivity of the muscles, constitutes a well known syndrome.
    Recent studies indicate that peripheral neurological dysfunction such
    as the reduced conduction velocity of peripheral nerves may follow
    prolonged exposure to carbon disulfide concentrations in the range of
    30-90 mg/m3. Sensory polyneuropathy with increased pain threshold has
    been reported following 10-15 years of exposure to concentrations as
    low as 10 mg/m3.

         Vascular atherosclerotic changes are also caused by long-term
    exposure. Studies in Finland, Norway, and the United Kingdom have
    shown that carbon disulfide promotes the development of coronary heart
    disease and that exposure to levels ranging from 30 to 120 mg/m3, for
    more than 10 years, appears to increase coronary mortality.

         Ophthalmological changes of various types, such as increased
    pressure, retrobulbar neuritis, etc. were formerly connected with
    severe forms of poisoning but, under present conditions of exposure,
    such findings are uncommon. However, an increased frequency of retinal
    microaneurysms, related to the duration and intensity of exposure, has
    been found in Japanese workers. No such abnormalities have been
    diagnosed, with certainty, in European workers, in spite of
    well-controlled comparative studies.

         Effects on the endocrine system include a reduction in adrenal
    activity attributable to reduced secretion of corticotrophine,
    impairment of spermatogenesis, and disturbance of the hormonal balance
    in women, evidenced by menstrual irregularities, spontaneous
    abortions, and premature deliveries. Moreover, the thyroid function
    may be altered, probably due to impairment of the
    hypothalamic-hypophyseal system. The most sensitive endocrine changes,
    i.e., depression of blood progesterone, increase of estriol, and
    irregular menstruation may occur at concentrations as low as
    10 mg/m3, whereas increases in spontaneous abortions and premature
    births have been reported in association with an exposure level of
    30 mg/m3.

         Gastrointestinal symptoms including dyspeptic complaints,
    gastritis, and ulcerative changes have been found in workers, heavily
    exposed to carbon disulfide.

    1.1.7  Diagnosis of carbon disulfide poisoning

         The effects of carbon disulfide are nonspecific, making
    individual diagnosis a matter of probability based on the confirmation
    of exposure, the presence of symptoms and signs compatible with carbon
    disulfide exposure, and the exclusion of other diseases. In workers
    with ascertained exposure, carbon disulfide poisoning should be
    suspected whenever subjective and neurasthenic symptoms, signs of
    peripheral neuropathy, psychological disturbances, or vascular changes
    are present. The diagnosis in acute forms of poisoning is
    straightforward, whereas the insidious development of adverse effects
    in chronic carbon disulfide poisoning makes early detection difficult.
    The probability of an accurate diagnosis increases as the number of
    abnormalities present increases. One recent study suggests that a
    positive diagnosis can be made only if changes in the choroidal
    circulation are found and provided that these occur in conjunction
    with polyneuropathy, or behavioural changes, or both.

    1.1.8  Surveillance of exposed workers

         For the early detection of adverse effects and for the continuous
    surveillance of exposed workers, medical examinations should be
    carried out once or twice yearly. The following examinations are
    recommended for a pre-employment check:  (a) thorough medical
    history;  (b) clinical and neurological examination;
     (c) electromyogram (EMG) examination; especially conduction velocity
    measurements;  (d) psychological tests;  (e) measurement of the
    blood pressure;  (f) electrocardiography; and  (g) serum cholesterol
    determinations.

         All or some of these examinations should be repeated regularly
    during the supervision of exposed workers, whenever exposure exceeds
    half the maximum permissible concentration. It is recommended that
    personal exposure rather than background exposure should be measured.
    For this purpose, either personal samplers, or the iodine-azide test
    should be employed. The iodine-azide test should be carried out from 2
    to 12 times a year depending on the level of exposure. Recommendations
    for early detection and prevention of adverse effects should, of
    course, be combined with technical and administrative measures for the
    protection of the health of exposed workers. The adoption of a maximum
    permissible concentration of carbon disulfide in the air is considered
    indispensable, and it is equally important to take all measures needed
    for achieving and maintaining conditions that will keep exposure below
    this level.

    1.2  Recommendations for Further Research

    1.2.1  Analytical aspects

         In the field of occupational hygiene technology there is a need
    to:

          (a) Improve and harmonize the methods of assessment of carbon
    disulfide in the work environment with a view to facilitating the
    comparability of data;

          (b) to improve, use, and harmonize personal sampling techniques
    in epidemiological studies; and

          (c) to further investigate the relationship, if any, between
    exposure as measured by personal sampling, and the iodine-azide test.

    1.2.2  Studies on health effects

         There is a need for internationally co-ordinated research on
    exposure-response relationships using, as far as possible, harmonized,
    experimental and epidemiological methods.

         It is advisable to undertake comparative studies on the
    relationships between carbon disulfide concentrations and coronary
    artery disease both in countries with a high, and countries with a low
    prevalence of the disease to find out whether or not the present
    information from some industrialized countries, such as Finland, is
    applicable to countries with a low prevalence of coronary artery
    disease.

         The possible carcinogenicity, teratogenicity, and mutagenicity of
    carbon disulfide should be studied.

         The effects of continuous exposure to low levels of carbon
    disulfide, such as may be found in the neighbourhood of factories, are
    unknown. Studies are recommended to elucidate exposure levels and any
    health risks associated with such exposure, and to introduce control
    measures.

    1.2.3  Mechanisms of toxic action

         The mechanisms of the toxic action of carbon disulfide are still
    hypothetical and further studies concerning the biochemical basis of
    these effects deserve high priority.

    2.  PROPERTIES AND ANALYTICAL METHODS

    2.1  Chemical and Physical Properties

         Carbon disulfide (CS2) when pure, is a colourless, mobile,
    refractive solution of sweetish aromatic odour, similar to that of
    chloroform. However, the crude technical product is a yellowish liquid
    with a disagreeable odour of decaying radishes.

         Carbon disulfide evaporates at room temperature and the vapour is
    2.62 times heavier than air (one litre of vapour weighs 3.017 g).
    Carbon disulfide vapour forms a highly explosive mixture with air.
    Furthermore, liquid carbon disulfide may produce a static electric
    charge that can initiate an explosion. Thus, it must be handled with
    the greatest caution, and should never come into contact with an
    electric charge or spark, a flame, or even high temperatures. Carbon
    disulfide is spontaneously flammable at 130-140°C, and fire
    extinguishers of the foam type must always be available, when it is
    handled.

         Because of its solubility in fats and lipids, carbon disulfide is
    widely used as a solvent for fats, lipids, resins, rubber, sulfur
    monochloride, white phosphorus, and some other substances.

         Some basic physical and chemical properties of carbon disulfide
    are summarized in Table 1.

    Table 1.  Physicochemical data on carbon disulfide.a
                                                               

    Synonym                       carbon disulphide, carbon
                                    bisulphide
    Formula                       CS2
    Relative molecular mass       76.14
    Melting point                 -111.53° C
    Boiling point                 46.3° C
    Density                       1 263 g/cm3 at 20° C
    Water solubility              0.2 g/100 ml at 20° C
    Vapour density (air = 1)      2.64
    Flash point                   below -30° C (closed cup)
    Explosive limits (% by        lower 1.0%
      volume in air)              upper 50.0%
    Vapour pressure at (28° C)    53.3 kPa (400 mmHg)
                                                               

    a  From: Weast, R. C. (1970); Faith et al. (1965).

    2.2  Analytical Procedures

    2.2.1  Measurement of carbon disulfide in air

         Control of exposure depends, to a great extent, on the
    measurement of carbon disulfide concentrations in air.

         Samples of carbon disulfide may be extracted either by the
    activated charcoal tube method or by the liquid absorption method.

         The following methods are recommended for the measurement of
    carbon disulfide:

          (a) direct measurement using gas detector tubes;

          (b) photometric determination of carbon disulfide samples taken
    by the liquid absorption method;

          (c) gas-liquid chromatography of carbon disulfide samples taken
    by the activated charcoal tube method;

          (d) continuous measurement by gas analyser.

    2.2.2  Sampling methods

    2.2.2.1  The activated charcoal tube method

         This method of sampling is preferable because the sample can be
    taken from the breathing zone of the worker (see for example Truhaut
    et al., 1972) and because, when combined with the biological
    iodine-azide test (section 2.2.3.5), it offers the best measure of
    personal exposure to carbon disulfide. The sampling device, which
    consists of a charcoal tube fastened to the worker's shoulder and a
    pump fastened to the belt, is small enough to be worn for the whole
    working period without discomfort.

         The carbon disulfide, which is absorbed by activated carbon in
    the tube, is later desorbed by a solvent and determined by gas
    chromatography (section 2.2.3). To determine the time-weighted average
    concentration of carbon disulfide, the volume of air sampled should be
    large enough to allow the determination of concentrations below the
    threshold limit value (TLV). A sampling period of 15 minutes should be
    used for the determination of maximum or ceiling concentrations. An
    advantage of this sampling method is that the presence of hydrogen
    sulfide does not impair sampling efficiency (McCammon et al., 1975).
    Further information concerning possible interference with sampling
    efficiency can be found in reports by McCammon et al. (1975) and NIOSH
    (1977).

    2.2.2.2  The liquid absorption method

         The liquid absorption method can only be used for the
    determination of carbon disulfide concentrations at fixed sites. The
    principle of the method is that air is drawn through the absorption
    liquid using two fritted bubblers in series. The carbon disulfide in
    the air reacts with the liquid, which is an ethanolic solution of
    copper salt and diethylamine. Hydrogen sulfide, present in the air,
    must be trapped on cotton-wool treated with lead acetate before the
    air enters the absorption solution (Bagon et al., 1973).

    2.2.3  Methods for the determination of carbon disulfide

    2.2.3.1  Direct measurement using gas detector tubes

         This method of measurement is based on a reaction between the
    tested gas and a specific reagent mixture. For carbon disulfide, the
    indicating layer in the detector tube contains a combination of a
    copper salt and an alkylamine that yields a copper-
    dialkyldithiocarbamate complex with carbon disulfide. A known
    volume of air is drawn through the tube. The length of the coloured
    zone is a measure of the concentration. Detector tube systems provide
    a rapid, inexpensive, and simple method for evaluating the level of a
    contaminant in the industrial environment, the relative standard
    deviation of which is about 20-30%. However, the results of this
    method are only approximate and, if measurements indicate that air
    contaminant levels are excessive, additional measurements should be
    made by more accurate methods.

    2.2.3.2  Photometric determination

         The principle of this colorimetric method is that carbon
    disulfide reacts in an ethanolic solution with diethylamine and a
    copper salt to give a yellow-brown metallic complex of
    diethyldithiocarbamate. The colour of the solution is directly
    proportional to the concentration of carbon disulfide (Department of
    Employment and Productivity, 1968).

         The carbon disulfide concentration in the sample can be
    determined using a spectrophotometer at 420 nm. Five mg of carbon
    disulfide per m3 of air may be determined by this method. Hydrogen
    sulfide causes interference and should be removed by the method
    described in section 2.2.2.2 (Cullen, 1964).

    2.2.3.3  Gas-liquid chromatographic determination

         Gas chromatography in combination with the activated charcoal
    sampling method (section 2.2.2.1) is widely used for the determination
    of personal exposure to carbon disulfide. A method using a gas
    chromatograph equipped with a flame photometric detector and a sulfur
    filter has recently been described in detail (NIOSH, 1977). The assay
    was validated over a range of 45.6-182.3 mg of carbon disulfide per
    m3 of air, at an atmospheric temperature and pressure of 22°C and
    102.1 kPa (766 mmHg), respectively, using a 6 litre sample. With this
    concentration range, the coefficient of variation was 0.059
    corresponding to a standard deviation of 5.6 mg/m3, at a carbon
    disulfide concentration of 93 mg/m3. However, the detection of much
    smaller amounts is possible using this method, if the desorption
    efficiency is adequate (NIOSH, 1977). It must be emphasized that any
    compound having the same retention time as the analyte may cause
    interference and that, if this possibility exists, separation
    conditions (column packing, temperature, etc.) should be adjusted
    accordingly.

    2.2.3.4  Continuous measurement using gas analysers

         Some types of gas analysers are convenient for the continuous
    monitoring of carbon disulfide in workroom air. The measurements can
    be carried out at one or several fixed sampling sites depending on the
    construction of the equipment.

         Analysers suitable for continuous monitoring include:

          (a) Analysers based on electrical conductivity in which an air
    flow is conducted through a suitable absorbing solution. The gas to be
    measured reacts with the solution and changes its electrical
    conductivity according to the concentration of the gas.

         In the case of carbon disulfide, the gas must first be oxidized
    in a combustion oven, the determination is then based on the reaction
    of carbon dioxide or sulfur dioxide with the absorbing solution.

          (b) Analysers based on light absorption in the infrared region
    in which the measuring effect is based on the specific radiation
    absorption of heteroatomic gases in the infrared spectral range
    between 2.5 and 12 µm wavelength. Absorption occurs at strictly
    separated frequencies that are associated with the natural vibrations
    of the molecules.

         When measuring low concentrations of carbon disulfide using
    infrared analysers, some other gases, especially water vapour, can
    cause interference. The interference can be eliminated and the
    sensitivity improved, if the carbon disulfide is first oxidized in a
    combustion oven to sulfur dioxide and the latter measured by
    infrared-analyser.

         Numerous systems for continuous gas monitoring have been
    developed; detailed information concerning the measurement of carbon
    disulfide by this method can be found in Schütz (1970), Leithe (1971),
    Verdin (1973), Weigman (1973).

    2.2.3.5  Determination of metabolites in urine

         Since there is only a poor, if any, correlation between carbon
    disulfide concentrations in blood and air, and only 1% or less of
    absorbed carbon disulfide is excreted unmetabolized into the urine,
    there is no basis for using the determination of carbon disulfide in
    either blood or urine as an exposure test (section 4.2.3 and 4.3.2).
    In contrast, good results have been obtained using the concentration
    of metabolites of carbon disulfide in the urine as a measure of
    exposure.

          (a) The iodine-azide test is based on the finding of Yoshida
    (1955) that the iodine-azide reaction:

                        2NaN3 + I2 -> 3N2 + 2NaI

    is catalysed by a metabolite present in the urine of animals exposed
    to carbon disulfide. Subsequently, it was found that the C-SH and C-S
    groups act as catalysts in the reaction, and a quantitative test was
    developed based on the time interval between adding the iodine-azide
    reagent to urine and the decolorization of the iodine solution, as
    measured by a stop watch (Vasak, 1963; Vasak et al., 1963). In order
    to simplify the test, the time was corrected according to the
    creatinine concentration to avoid the collection of 24-h urine
    samples. This time served as a basis for the calculation of the
    exposure coefficient, which was indirectly proportional to the
    concentration of carbon disulfide metabolites excreted in the urine.
    Vasak et al. (1967) later elaborated a diagram for the evaluation of
    the average concentration of carbon disulfide during the shift.
    Provided that the urine is not too dilute, i.e., the creatinine
    concentration is not much below 2.25 mg/ml, exposure may be considered
    negligible if decolorization of the iodine-azide reagent does not take

    place within 3 h. The "chronometric" iodine-azide test may be
    successfully used on workers, when the average exposure is above
    50 mg/m3 (Djuric et al., 1965). However, recent data from Sweden
    indicate that a short decolorization time in the iodine-azide test may
    occur in some workers exposed to 30-40 mg/m3, suggesting individual
    differences in the reaction to carbon disulfide (Kolmodin-Hedman,
    1976).

         A modification of the "chronometric" test was developed by
    Jakubowski (1968, 1971). The modified procedure was not based on the
    time of reaction, but on measurements of the amount of iodine used for
    titration of carbon disulfide metabolites catalysing the iodine-azide
    reaction in 1 ml of urine and calculated for a standard creatinine
    concentration of 1.5 mg/kg. With this method, it was possible to
    assess exposure to levels as low as 10 mg of carbon disulfide per m3
    of air with a precision of ±20%.

          (b) A method for the determination of thiourea was developed by
    Pergal et al. (1977a), based on the colorimetric determination of a
    complex produced in a reaction between thiourea present in the urine
    and potassium ferrocyanide (K4FeCN6) present as a reagent in an acid
    media. Levels of thiourea excretion between 0.001 and 0.1 mg/ml could
    be determined by this method. Preliminary results showed that the
    amount of thiourea in the urine sampled at the end of the working
    shift was not strongly correlated with the results of the iodine-azide
    test. It is necessary to study the excretion dynamics of this
    metabolite to establish if this method can be used as an exposure
    test. So far, the results suggest that the excretion of this
    metabolite reflects the rate of carbon disulfide metabolism rather
    than recent exposure (Pergal et al., 1977a).

    3.  EXPOSURE TO CARBON DISULFIDE

    3.1  Occupational Exposure

         Carbon disulfide was first used as a solvent in 1851 as a
    phosphorus solvent in the manufacture of matches. During the 19th
    century, it was used as a solvent for fats, lacquers, and camphor, for
    the refining of jelly, paraffin, and petroleum, and in the extraction
    of oil from olives, palmstones, bones, and rags. In the latter half of
    the century, it was used extensively in the vulcanization of rubber.
    These applications still prevail to some extent and, today, it is also
    used in the production of flotation agents, herbicides, rubber
    accelerators, and neoprene cement, and in the fumigation of grain.
    However, by far the most important use of carbon disulfide is in the
    production of viscose rayon fibres.

         The industrial production of viscose, which began in 1906,
    quickly expanded all over the world, particularly during and after
    World War I. The synthesis of other artificial fibre,; after World War
    II slowed clown this expansion, but rayon fibres are still of
    considerable industrial importance. As viscose rayon production is the
    most important source of exposure to carbon disulfide, a more detailed
    description of the technological process and the exposure hazards that
    may be associated with various stages of production has been given in
    Annex I. The brief account given here highlights the processes
    associated with the highest risk of exposure.

         Carbon disulfide is introduced into viscose production during the
    so-called process of xanthation, where it is added to shredded and
    oxidized alkali cellulose to form sodium cellulose xanthate. Although
    exposure to carbon disulfide at this stage is mechanically controlled,
    exposure to high concentrations may still occur. The sodium cellulose
    xanthate is dissolved in caustic soda to produce viscose that can be
    further processed either by spinning to form textile yarn, tire yarn,
    or staple fibre, or by casting to form Cellophane. Carbon disulfide,
    and to a lesser extent hydrogen sulfide, are evolved during spinning
    and casting, and exposure to high concentrations of carbon disulfide
    can occur during doting and when filaments break. Carbon disulfide is
    further emitted in the cutting of rayon filaments for staple fibre,
    and in the washing and drying processes. Because of the high input of
    viscose, carbon disulfide emissions are highest in the production of
    staple fibre and Cellophane.

    3.2  Community Exposure

         At the present time, very little information is available
    concerning exposure to carbon disulfide outside the workplace or the
    effects on the general population. Although concentrations outside the
    workplace are expected to be much lower than those found inside,
    special consideration must be given to the possibility that
    individuals in poor health or the very young may be exposed and also
    that workers, who are exposed to carbon disulfide at work may also be
    exposed during non-working hours if they live close to their place of
    work.

         In 1976, Peyton et al. reviewed the literature concerning
    environmental studies of carbon disulfide and carbonyl sulfide. Both
    compounds are emitted by man-made, as well as natural sources.
    Although carbon disulfide appears to be relatively stable in the
    atmosphere, oxidation leads to the formation of sulfur dioxide, carbon
    monoxide, and carbonyl sulfide. It has been suggested that carbonyl
    sulfide itself elicits a toxic response in man because of partial
    decomposition to hydrogen sulfide in the lungs and bloodstream.

         From the limited data available, it appears that individuals
    living close to workplaces where carbon disulfide is used can be
    exposed to high enough concentrations to result in measurable uptake.
    When 70 children living 400 m from a factory discharging carbon
    disulfide into the atmosphere were compared with a control group of 30
    children living 15 km from the factory, physical and psychological
    examinations did not show any health disorders in the exposed group
    even though urine concentrations of carbon disulfide indicated
    increased uptake compared with the controls (Helasova, 1969).
    Environmental measurements were taken for both hydrogen sulfide and
    carbon disulfide. Ninety-two out of 127 measurements of carbon
    disulfide concentrations in air were higher than 0.01 mg/m3.

         By applying data on workplace exposure to conditions in the
    general environment, Peyton et al. (1976) recommended that limiting
    long-term average concentrations to 0.3 mg of carbon disulfide per m3
    of air should be sufficient to protect the general population against
    long-term health effects. In the USSR, the maximum allowable
    concentration for carbon disulfide in the ambient air is 0.03 mg/m3
    with an allowable 24-h average of 0.005 mg/m3 (Bajkov, 1963). In
    addition, the USSR has also established an allowable level of carbon
    disulfide in waterways (prior to treatment) of 1.0 mg per litre
    (Vinogradov, 1966).

    4. METABOLISM

    4.1  Absorption

         Inhalation and skin contact are the only significant routes of
    absorption of carbon disulfide. The only way carbon disulfide may
    enter the human organism through ingestion is by accidental (or
    intentional) intake.

    4.1.1  Inhalation

         Inhalation represents the main route of carbon disulfide
    absorption in occupational exposure. Data reported earlier by
    Teisinger & Soucek (1952), namely that, in spite of considerable
    variation between individuals, absorption seemed to be proportional to
    the concentration of carbon disulfide in inhaled air, were confirmed
    by Demus (1967).

         Toyama & Kusano (1953) studied the absorption of carbon disulfide
    through the lungs of rabbits. They found that equilibrium in the
    carbon disulfide contents of inhaled and exhaled air was reached after
    90-150 min of exposure, and that 70-80% was retained at equilibrium.
    Inhalation studies have also been performed on human volunteers, but
    the data obtained have been diverse, even controversial (Teisinger &
    Soucek, 1949; Teisinger, 1954; Brieger, 1961, 1967; Djuric, 1963,
    1967; Davidson & Feinleib, 1972). It was reported by Madlo & Soucek
    (1953) that equilibrium in man was reached during the first 90-120 min
    of exposure and that, at this stage, the retention of carbon disulfide
    was about 30% of the amount present in the inhaled air. However, in a
    number of Japanese studies, Tazuka (1955) found that equilibrium was
    reached 30-60 min after the beginning of exposure, Toyama & Harashima
    (1962), after about 180 min, and Tahara (1961), at the end of a
    working shift of 8 h (480 min). The discrepancies can probably be
    explained by differences in exposure conditions.

         In studies by Teisinger & Soucek (1949), higher retention was
    observed in volunteers exposed for the first time to carbon disulfide
    than in continuously exposed workers. In volunteers, equilibrium was
    reached after 120 min of exposure. An initial retention of 80% fell to
    45%, when equilibrium was reached. Equilibrium in industrial workers
    was already reached after 45-60 min. Harashima & Masuda (1962)
    obtained similar results with exposed workers but found a retention of
    65% at equilibrium. Average retentions of 41% after the first 60 min
    and 48% after 240 min of exposure were reported by Petrovic & Djuric
    (1966).

         Thus, the majority of authors agree that, in man, an equilibrium
    between the carbon disulfide concentrations in inhaled and exhaled air
    is reached during the first 60 min of exposure. The percentage
    retained at equilibrium appears to be about 40-50% of the amount of
    carbon disulfide in the inhaled air and depends on both the
    concentration of carbon disulfide in the air and the partition
    coefficient between blood and tissues. This percentage is lower in
    continuously exposed workers than in volunteers exposed for the first
    time to carbon disulfide. This difference should be taken into account
    in the planning of inhalation studies as well as in the interpretation
    of the results.

    4.1.2  Skin absorption

         As an organic solvent, carbon disulfide can be expected to pass
    through the skin and this has been confirmed in a number of studies.

         Dutkiewicz & Baranowska (1967) studied absorption from an aqueous
    solution through the skin of immersed hands. The solution contained
    0.33-1.67 g of carbon disulfide per litre and, after 1 h, the quantity
    absorbed ranged from 0.23 to 0.78 mg/cm2 of skin. The authors
    calculated that immersion of a hand for 1 h in a washing bath in a
    viscose rayon plant could result in the absorption of 17.5 mg of
    carbon disulfide into the organism.

         It is obvious that workers exposed to carbon disulfide solution
    and vapour will absorb some through the skin and that, though these
    amounts will be less than the quantities inhaled, they will still be
    important and should be considered in the evaluation of total
    exposure.

    4.2  Distribution and Biotransformation

    4.2.1  Balance of absorbed carbon disulfide

         In animal experiments, where carbon disulfide was administered
    into the gastrointestinal tract, most of it was eliminated in the
    faeces and only a small part was excreted by exhalation (Soucek,
    1957). However, after intraperitoneal injection, rats and guineapigs
    exhaled about 55% and 70%, respectively, of the amounts administered
    (Soucek, 1959, 1960a,b).

         Studies in man, as summarized by Soucek (1957), show that 10-30%
    of the carbon disulfide absorbed into the body is exhaled and that
    less than 1% is excreted unchanged in the urine; thus, 70-90%
    undergoes biotransformation and is excreted in the form of
    metabolites. Demus (1964) reached similar conclusions. About 10% of
    the absorbed carbon disulfide represents a body burden that is
    excreted slowly in the urine, mainly in the form of metabolites. In
    contrast to these studies, Dutkiewicz & Baranowska (1967) reported
    that, when carbon disulfide was absorbed through the skin, only 3% was
    exhaled.

    4.2.2  Transport by the bloodstream

         There are differences among animal species with regard to the
    affinity between carbon disulfide and blood. The affinity is higher in
    rats than in guineapigs (Soucek, 1959, 1960a) and this is quite in
    accordance with the differences in exhalation rates after
    intraperitoneal injection, referred to in section 4.2.1. The
    disappearance of carbon disulfide from the circulation can be
    accelerated by the administration of a mixture of fresh air and 5%
    carbon dioxide; this results in a more rapid disappearance of narcotic
    effects (Soucek, 1959).

         In man, the carbon disulfide that is not exhaled is distributed
    in the body by the bloodstream, twice as much being taken up by
    erythrocytes as by the plasma (Soucek & Pavelkova, 1953). Carbon
    disulfide disappears quickly from the blood because of its affinity
    for lipid-rich tissues and organs. However, traces of carbon disulfide
    have still been found in the blood of exposed workers 80 h after
    termination of exposure (Soucek & Pavelkova, 1953).

    4.2.3  Determination of carbon disulfide in blood

         Bartonicek (1957, 1958, 1959) showed that the determination of
    carbon disulfide in blood did not give reproducible results and that
    the correlation between carbon disulfide concentrations in blood and
    air was very weak or non-existent. Thus, determination of the
    concentration of carbon disulfide in the blood is not a useful test of
    exposure. The reasons for these discrepancies are explained by the
    results of studies by Bartonicek (1957, 1958, 1959) on "free" and
    "bound" carbon disulfide (section 4.2.4).

    4.2.4 Distribution in the organism

         Soucek (1960a) established that the partition coefficients for
    carbon disulfide from air to blood and from blood to organs were 2.8
    and about 100, respectively. This explains the rapid disappearance of
    carbon disulfide from the blood (section 4.2.2).

         The solubility in lipids and fats, and binding to amino acids and
    proteins, explains the affinity of carbon disulfide for all tissues
    and organs. However, at the beginning of absorption, some initial
    preference for some organs seems to exist. Animal experiments have
    given various results concerning the order of affinity for different
    organs, but these may be explained by interspecies differences, by
    differences in the mode of administration or both. These aspects have
    been studied in animals only, since even postmortem studies in man are
    impracticable because of the rapid elimination of carbon disulfide.
    McKee (1941) first performed such experiments and results obtained up
    to 1954 have been reviewed by Teisinger (1954). In studies on
    guineapigs by Strittmatter et al. (1950) using labelled carbon
    disulfide, initial accumulation occurred in the liver followed by
    uniform distribution in the organism after some days. The following
    order of initial prevalence of carbon disulfide in rats was
    established by Merlevede (1951): liver, bile, kidneys, heart,
    adrenals, brain. Teisinger (1954) found the largest amount of carbon
    disulfide in the brain of guinea-pigs and Madlo & Soucek (1953)
    demonstrated its presence in the peripheral nerves of rats.

         In studies on the distribution of carbon disulfide labelled with
    35S, radioactivity was retained in the brain for 2 days (Bussing et
    al., 1953; Büssing & Sonnenschein, 1954).

         Bartonicek (1957) found that "total" carbon disulfide accumulated
    initially in the adrenals, blood, and brain of exposed rats. At the
    same time, he observed the existence of both "free" and "bound" forms
    in the body. "Free" carbon disulfide denotes the fraction of carbon
    disulfide dissolved in body fluids and "bound" carbon disulfide, the
    fraction that has reacted with amino acids to give thiocarbamates, a
    reaction that is reversible. This form is acid labile. It has been
    shown by De Matteis & Seawright (1973) that the sulfur released during
    the process of desulfuration of carbon disulfide can form covalent
    bonds with other sulfur radicals. By determining "free" and "bound"
    carbon disulfide separately, Bartonicek (1957) obtained another order
    of initial accumulation. "Free" carbon disulfide disappeared quite
    quickly from the organs following an exponential curve and reached
    very low values, 10-16 h after the termination of exposure, while the
    "bound" form decreased irregularly. Thus, according to Bartonicek
    (1958, 1959), "free" carbon disulfide accumulates in the liver,
    muscles, spleen, blood, lungs, brain, kidneys, and heart while "bound"
    carbon disulfide accumulates in the blood, spleen, liver, lungs,
    heart, muscles, kidneys, and brain. Gradually more uniform
    distribution takes place. The existence of 2 forms with quite
    different initial affinities for blood and organs, could explain the
    controversial results obtained earlier and the poor correlation
    between carbon disulfide concentrations in the blood and air (section
    4.2.3).

    4.2.5  Binding in blood and tissues

         According to Teisinger (1954), in 1910, Siegfried & Weidenhaupt
    proved by  in vitro experiments that carbon disulfide was bound to
    glycine in blood in alkaline medium, producing glycine-dithiocarbamic
    acid characterized by free -SH groups. These authors stated that
    similar reactions took place with phenylalanine, sarcosine, and
    asparagine. Chromatographic and spectrophotometric studies have shown
    that amino acids of the blood plasma react with carbon disulfide to
    form dithiocarbamic acid and a cyclic compound of the thiazolinone
    type (Soucek & Madlo, 1953; Madlo, 1953; Yoshida, 1955; Cohen et al.,
    1959). Bobsien (1954) demonstrated the binding of carbon disulfide to
    euglobulin and albumin through -SH groups; he found that binding to
    pseudoglobulin was negligible. The binding of carbon disulfide to
    cysteine, methionine, and glutathione in the blood was established by
    Büssing (1952), but the nature of the binding was not stated.

         Using human blood, Soucek & Madlo (1953) established  in vitro,
    that carbon disulfide was bound to amino acids in the blood by a
    first-order reaction, the half-time of which was 6.5 h. Various acids
    and formaldehyde blocked this reaction, producing dithiocarbamic acid
    and thiazolinone. In further  in vitro studies, the same authors
    (Soucek & Madlo, 1954, 1955, 1956) found that, at pH 7.3-8.3 and at a
    temperature of 37°C, carbon disulfide was quantitatively bound to
    albumin but not to gammaglobulin. The product formed possessed free-SH
    groups that could be determined by titration with iodine chloride. The
    product was very stable, not hydrolysing even at 100° C. On the other
    hand, the product formed after the binding of carbon disulfide to
    amino acid did not show such stability. Soucek (1957) showed that the
    same processes took place  in vivo.

         The binding of carbon disulfide to proteolytic enzymes (trypsin,
    pepsin, chymotrypsin) forming a labile compound similar to
    dithiocarbamic acid was also reported by Soucek et al. (1957) and
    Soucek (1959). Soucek & Madlo (1955) assumed that the formation of
    dithiocarbamic acid took place in the blood and the liver, and that
    the compound formed then appeared in the liver, adipose tissues,
    blood, and, in small quantities, in the brain and muscles.


    4.3  Elimination of Carbon Disulfide and Metabolites

    4.3.1  Elimination by breath, saliva, sweat, and faeces

         Some basic data on the exhalation of absorbed carbon disulfide
    have already been discussed (section 4.2.1). The process takes place
    in 3 phases. In the first phase, there is rapid elimination of the
    carbon disulfide absorbed on the mucosa of the lungs and upper part of
    the tract. In a second slower phase, exhalation of carbon disulfide
    released from the blood occurs. In the third, very slow phase, carbon
    disulfide released from tissues and organs is exhaled. Each phase can
    be presented as a separate curve with a different angle (Soucek &
    Pavelkova, 1953). In experiments on animals, De Matteis & Seawright
    (1973) established that a significant part of the carbon, released
    from the carbon disulfide by a desulfuration process, was exhaled as
    carbon dioxide.

         It was reported by Merlevede (1951) that small quantities of
    carbon disulfide were excreted in the saliva and sweat. Harashima &
    Masuda (1962) demonstrated the excretion of "free" carbon disulfide
    through the skin of exposed workers, stating that, sometimes, the
    amounts excreted by this route were as much as 3 times higher than the
    amounts of unmetabolized carbon disulfide excreted in the urine.

         It is generally accepted that the elimination of inhaled carbon
    disulfide in the faeces is negligible.

    4.3.2  Excretion of carbon disulfide and metabolites in urine

         Less than 1% of absorbed carbon disulfide is excreted unchanged
    in the urine but about 70-90% of retained carbon disulfide is
    metabolized and excreted in the urine in the form of various
    metabolites (Soucek, 1957).

         A number of experimental studies on rats, dogs, and guineapigs
    have shown that carbon disulfide is excreted in the form of inorganic
    sulfates into the urine (Billet & Bourlier, 1944; Strittmatter et al.,
    1950). Using labelled carbon disulfide, Strittmatter et al. (1950)
    showed that, in guinea-pigs, 30% of intravenously injected carbon
    disulfide was metabolized to form such end-products. Jakubowski (1968,
    1971) isolated 3 metabolites, and Kopecky (1973) identified
    2-mercapto-thiazoline-4-carbonyl acid in the urine of exposed rats.

         In contrast with the results obtained in animal studies,
    Merlevede (1951) did not observe any increase in the total sulfate
    concentration in the urine of exposed workers and registered only a
    relative increase in the ethereal fraction. This was corroborated by
    Delic et al. (1966) and Djerassi & Lambroso (1968). Delic et al.

    (1966) studied the urinary excretion of sulfates in 111 workers, 52 of
    whom were exposed to high concentrations of carbon disulfide, i.e.,
    100-1000 mg/m3, 36 to concentrations below 150 mg/m3 and 23 to
    concentrations below 30 mg/m3. In the most heavily exposed group,
    15.5% of the workers showed an increased excretion of total sulfates
    (3.8-6 g/litre). On the other hand, an equally high percentage (15%)
    of workers exposed to levels below 30 mg/m3 displayed a similar
    increase (3-3.2 g/litre); 5.6% of the workers exposed to
    concentrations below 150 mg/m3 also showed an increased excretion.
    Thus, there was no correlation between excretion of toted sulfates and
    exposure. A relative increase in the ethereal (organic) fraction of
    sulfates that was evident in 60% of all the workers was also unrelated
    to exposure level. The results appeared to suggest that a conjugation
    process of some carbon disulfide metabolites took place rather than an
    oxidation to inorganic sulfates.

    FIGURE 1

         The responsibility of metabolites for the discoloration of iodine
    azide remained hypothetical until Pergal et al. (1972a,b) isolated 3
    metabolites from human urine and identified 2 of them as thiourea and
    mercaptothiazolinone; thiourea is by far the most important of these
    metabolites. Later, Pergal et al. (1977a) developed a quantitative
    method for the micro-determination of thiourea in the urine of exposed
    workers or of alcoholics treated with tetraethylthiuramdisulfide
    (TETD, Disulfiram, Antabuse). The authors suggested that the third
    metabolite was 2-mercapto-thiazoline-4-carbamic acid (Pergal et al.,
    1977b). Tetraethylthiuramdisulfide is metabolized in a way that
    liberates carbon disulfide (Fig. 1). Consequently, alcoholics treated
    with this agent are exposed to carbon disulfide and its metabolites.
    Skalicka (1967) and Novak et al. (1968) measured the iodine-azide
    reaction and determined diethyldithiocarbamates (DDC) in the urine of
    alcoholics treated with TETD. These results led Djuric et al. (1973)
    to use TETD as a test for the evaluation of the metabolic rate of
    sulfur compounds in the organism of workers, the so-called "antabuse
    test".

         Studies on the microsomal metabolism of carbon disulfide in the
    liver of rats revealed that it was desulfurated to form
    carbonylsulfide and that this was further oxidized, yielding carbon
    dioxide which was exhaled (De Matteis & Seawright, 1973; De Matteis,
    1974; Dalvi et al., 1974).

         Data from human and animal studies on ethereal sulfate excretion
    (Magos, 1973) have shown that bivalent sulfur represents a small part
    of retained carbon disulfide, probably less than 5%. The major pathway
    leads to the formation of sulfates that are excreted in urine.

    5.  BIOCHEMICAL EFFECTS OF CARBON DISULFIDE

         From the chemical point of view, carbon disulfide is highly
    reactive with nucleophilic reagents characterized by the presence of a
    group with a free pair of electrons in the molecule. The most
    important nucleophilic groups are mercapto (-SH), amino (-NH2) and
    hydroxy (-OH) groups (Vasak & Kopecky 1967). However, physiological pH
    values do not favour these reactions (Kopecky, 1977, private
    communication).

         According to the chemical structure of compounds participating in
    the reactions, carbon disulfide will produce dithiocarbamic,
    trithiocarbonic, or xanthogenic acid. If carbon disulfide reacts with
    an organic compound with 2 nucleophilic groups, a cyclic compound of
    the thiazolinone type is formed (see Fig. 2).

         The majority of biochemically important compounds, such as amino
    acids, biogenic amines, and sugars, contain these nucleophilic groups
    and, thus, may react with carbon disulfide. This is true of a large
    number of substances existing in the organism.

         A number of possible mechanisms of the effects of carbon
    disulfide on the organism have been postulated including:

          (a) the chelating effect of carbon disulfide metabolites on
    various metals, essential for the functioning of enzymes;

          (b) the effect of carbon disulfide on enzymatic systems;

          (c) disturbances of vitamin metabolism;

          (d) impairment of catecholamine metabolism;

          (e) changes in lipid metabolism;

          (f) interaction with microsomal drug-metabolizing enzyme
    systems.

    FIGURE 2

    5.1  Chelating Effects of Carbon Disulfide Metabolites

         The hypothesis of the chelating effect of carbon disulfide
    metabolites was advanced by Cohen and coworkers and was based on
    experiments on rabbits (Cohen et al., 1958; Paulus et al., 1957;
    Scheel et al., 1960; Scheel, 1965, 1967). Considerable shifts were
    found in the copper and zinc contents of various tissues, especially
    in the nervous tissue, in rabbits poisoned by carbon disulfide. The
    concentration of copper in the brain and spinal cord of animals killed
    2 weeks after final exposure was less than half of that in the
    controls. On the other hand, the zinc level in exposed rabbits was 20%
    higher than that in the control animals. In general, pathological
    examination of the tissues did not indicate any changes, except in the
    kidneys and in the spinal cord, which showed marked degeneration of
    the axis of the cylinder. The Purkinje cells of the cerebrum also
    showed signs of degeneration.

         The following hypothesis, based on an observation that the levels
    of metal ions in tissues were altered by exposure to carbon disulfide,
    was formulated by Scheel (1967):

         -- carbon disulfide reacts with the amino groups of amino acids
    and proteins to form thiocarbamate in blood and tissues, as was stated
    by Soucek & Madlo (1956);

         -- thiocarbamates, possessing sulfhydryl groups, may chelate
    polyvalent inorganic ions. Because of the low dissociation of the
    product, they would, thus, interfere with cellular metabolism.

         -- when such interference becomes sufficiently limiting, the body
    would respond by oxidizing fat and general loss in body-weight would
    occur;

         -- ultimately, as the metabolic limitation increases, cellular
    death and loss of associated function would occur, producing signs of
    tissue injury.

         Since the entire hypothesis rests on chelation of metal ions, it
    should be possible to prevent the occurrence of such an effect by
    supplying an excess of metal ions in the diet of animals exposed to
    carbon disulfide (Scheel et al., 1960; Scheel, 1967). Such a
    protective effect is claimed to have been achieved by Scheel (1967).

         The hypothesis of a chelating effect has been supported by the
    results of other studies including those of Andreeva (1970), who
    reported an increase in zinc and copper excretion in exposed rats, and
    Lukas et al. (1974), who found increased copper levels in the
    peripheral nervous tissue of exposed rats. A decreased level of
    ceruloplasmin in rats with experimental carbon disulfide
    polyneuropathy was reported by Lukas et al. (1975). This decrease was

    related to the intensity and extent of the electromyographic signs of
    polyneuropathy. Gadaskina & Andreeva (1969) and Cimbarevic (1970)
    noticed a decrease in ceruloplasmin activity in workers exposed to
    carbon disulfide for more than 10 years. However, in other studies,
    the ceruloplasmin levels in exposed workers were in the normal range
    (Andruszczak, 1967; Kujalova, 1973). Andruszczak (1967) found
    increased ceruloplasmin levels in patients suffering from chronic
    carbon disulfide poisoning.

         Increased excretion of trace metals in the urine of workers
    exposed to carbon disulfide was not observed in studies by Djuric et
    al. (1967). Hernberg & Nordman (1969), and Hernberg et al. (1969).
    However, these negative results do not necessarily exclude a chelating
    effect, since exposure may have been too low. Thus, the more recent
    results of El Gazzar et al. (1973) showing a temporary increase in the
    zinc contents of all serum protein fractions as well as in urinary
    excretion may reflect the effects of a higher exposure level than in
    the previous studies.

         It is known that copper and zinc ions are essential for the
    prosthetic groups of many enzymes. The neurotoxic action of carbon
    disulfide and its interference with the activity of many enzymes could
    easily be explained by chelating effects. Zinc is required for the
    activity of enzymes such as lactic acid dehydrogenase (EC 1.1.1.27)a,
    carbonic anhydrase (EC 4.2.1.1), glutamate dehydrogenase (EC 1.4.1.2),
    and alcohol dehydrogenase (EC 1.1.1.1). Copper, on the other hand,
    represents a cofactor of pyridoxol, a form of vitamin B6.

         Copper is required for the proper functioning of enzymes such as
    cytochrome  c oxidase (EC 1.9.3.1), the coenzyme A dehydrogenase
    system, and dopamine ß hydroxylase (EC 1.14.17.1). The loss of copper
    from the spinal cord is accompanied by cellular damage, producing
    tissue degeneration. Disturbances of the central and peripheral
    nervous systems, resulting from carbon disulfide exposure, could be
    connected with the loss of copper due to chelation and consequent
    inhibitory effects on enzyme systems (Scheel, 1967).

                   

    a The numbers within parentheses following the names of enzymes are
      those assigned by the Enzyme Commission of the Joint IUPAC-IUB
      Commission on Biochemical Nomenclature.

    5.2  Effects on Enzyme Systems

         Inhibition of monoamine-oxidase (EC 1.4.3.4) (MAO) activity
    occurs as soon as exposure of an animal to carbon disulfide begins,
    but it is reversible (Magistretti & Peirone, 1961; Lazarev et al.,
    1965). The mechanism of inhibition is not yet clear, but it is known
    that MAO contains a copper pyridoxal complex. Vasak & Kopecky (1967)
    found a decrease in catecholamine in the urine of exposed rats. This
    result suggests the possibility that carbon disulfide forms a compound
    with catecholamine which cannot be split by MAO. However, Magos &
    Jarvis (1970b), who also exposed rats to carbon disulfide, did not
    find any inhibition of MAO. They suggest that Vasak & Kopecky's (1967)
    finding could be explained by the inhibition of dopamine ß
    hydroxylase.

         Alkaline phosphatase (EC 3.1.3.1) activity was inhibited in the
    tissues and serum of rabbits exposed for more than 22 weeks to high
    concentrations of carbon disulfide, i.e., concentrations up to about
    2350 mg/m3 (750 ppm) (Cohen et al., 1959). Chervenka & Wilcox (1956)
    did not find any influence of carbon disulfide on derivatives of
    chymotrypsinogen or on succinate dehydrogenase (EC 1.3.99.1) activity
    and Minden et al. (1967) did not register any effects on glycolytic
    enzymes, Kreb's cycle enzymes, and transaminases in experimental
    animals.

         No changes in glycolysis were found in the brain tissue of rats
    after either acute or chronic exposure to carbon disulfide (Tarkowski
    & Cremer, 1972; Tarkowski, 1973). Changes in the brain free amino acid
    metabolism observed in rats exposed to a carbon disulfide
    concentration of 2400 mg/m3 for 15 h included reductions in the
    levels of glutamic delta-amino butyric acids. These effects were
    accompanied by decreased activity of brain glutamate decarboxylase
    (EC 4.1.1.15) (Tarkowski, 1974).

         Both, acute and chronic exposures of animals to carbon disulfide
    result in changes in mitochondrial respiration and oxidative
    phosphorylation. Respiration of the brain mitochondria was partly
    inhibited in rats exposed to carbon disulfide (Tarkowski & Sobczak,
    1971); cytochrome oxidase activity was also inhibited (Tarkowski,
    Wronska-Nofer, 1966). Oxidative phosphorylation in the mitochondria
    was partly inhibited and partly uncoupled, and was accompanied by a
    reduction in the activity of adenosinetriphosphatase (EC 3.6.1.3)
    (Tarkowski & Sobczak, 1971).

         Gregorczyk et al. (1975a,b) did not find any changes in liver
    enzymes, proteins, and free amino acids in rats exposed to a carbon
    disulfide concentration of 1300 mg/m3 for 12-26 weeks, and 5 and 10 h
    daily. The authors concluded that carbon disulfide was not hepatotoxic
    under such exposure conditions; this seems to be supported by the fact
    that they did not find any changes in the blood serum enzymes
    (Gregorczyk et al. 1975a,b).

         Decreased activity of triosephosphate dehydrogenase (EC 1.2.1.9),
    lactate dehydrogenase, and glycerophosphate dehydrogenase found in the
    muscles of rats with developed neuropathy was accompanied by an
    increase in hexokinase (EC 2.7.1.1) activity (Lukas et al., 1977).

         Further studies should establish which enzymes are inhibited by
    exposure of the organism to carbon disulfide, at what levels of
    exposure, and the inhibition of which enzyme systems would present a
    significant health hazard.

    5.3  Effects on Vitamin Metabolism

    5.3.1  Vitamin B6

         There are 3 forms of vitamin B6, i.e., pyridoxol, pyridoxal, and
    pyridoxamine, that play the role of coenzymes in various enzyme
    systems. These 3 forms are in equilibrium because they are
    enzymatically converted into each other (Fig. 3). The binding of one
    form of vitamin B6 will block the reactions of the enzymes containing
    the remaining forms. Vasak & Kopecky (1967) reported that carbon
    disulfide reacted  in vitro with pyridoxamine to form a salt of
    pyridoxamine dithiocarbamic acid. Some authors think that this process
    could also occur  in vivo, causing inhibition of the enzyme systems
    in which vitamin B6 is involved as a coenzyme. Disturbance of
    pyridoxol metabolism during chronic intoxication was shown in
    experiments on rats by Kujalova (1971). After the tryptophan load
    test, excretion of xanthurenic acid increased in exposed animals while
    excretion of pyridoxol acid decreased.

         The temporal development and the severity of this disturbance
    depended on the diet given to the animals in question (Kujalova, 1971;
    Gorny, 1974). Pyridoxol deficiency due to carbon disulfide
    intoxication could be eliminated in the animals by giving a diet rich
    in pyridoxol (10 times the normal dietary level). However, this diet
    did not prevent the development of neuropathy (Lukas, 1970) or
    influence the deterioration in motor activity in rats (Frantik, 1970;
    Teisinger, 1971).

    FIGURE 3

         That pyridoxol deficiency might result from carbon disulfide
    intoxication was proved by Gorny (1971), who showed that the pyridoxal
    phosphate concentration decreased in the serum of acutely intoxicated
    rats. Furthermore, increases have been reported in nicotinamides, the
    metabolites of nicotinic acid (Nofer & Wrofiska-Nofer, 1966) and in
    hydroxyindolacetic acid (a metabolite of serotonine) (Abuczewicz et
    al., 1971) in the urine of rats exposed to carbon disulfide. All these
    substances are derived from tryptophan.

         In a review on the mechanisms of chronic carbon disulfide
    poisoning, Teisinger (1971) concluded that disturbance of vitamin B6
    metabolism was obvious but that it did not play a major role in the
    pathogenesis of nervous tissue lesions.

         Transaminases are sensitive to vitamin B6 deficiency. Thus,
    metabolic pathways in which transaminases are involved may be
    inhibited. This is the case in tryptophan metabolism, where it is
    manifested by increased excretion of xanthurenic acid in both man
    (Tintera et al., 1972) and rat (Fig. 4) (Abramova, 1967).

    FIGURE 4

    5.3.2  Nicotinic acid

         Exposure to carbon disulfide resulted in increased excretion of
    methyl nicotinamide, a nicotinic acid metabolite, in the urine of rats
    (Liniecki, 1960; Wrofiska-Nofer et al., 1965). An increase in serum
    lipids during the exposure of rabbits and rats to carbon disulfide was
    prevented by administration of nicotinic acid (Nofer & Wrofiska-Nofer,
    1966; Wrofiska-Nofer, 1970). The biochemical background of this
    phenomenon is still obscure, but a hypothesis based on the
    interference of carbon disulfide with pyridine nucleotide and
    nicotinamide metabolism has been advanced (Nofer & Wrofiska-Nofer,
    1966). However, feeding nicotinic acid to the exposed animals did not
    prevent the development of neuropathies in these experiments.

         As the increase in urinary excretion of nicotinamide metabolites
    did not occur at the cost of the systematic pool of
    nicotinamide-adenine dinucleotides, Wrofiska-Nofer et al. (1970)
    suggested that it reflected an increase in the whole turnover rate.
    The mechanism of the process was not clarified but it may be assumed
    that an increase in the synthesis via tryptophan occurs.

    5.4  Effects on Catecholamine Metabolism

         Disturbance of the catecholamine metabolism can play a part in
    many pathological processes. In studies on rats acutely intoxicated
    with carbon disulfide, significant changes were found in the brain
    catecholamine metabolism (Magos & Jarvis, 1970b; Magos, 1975). There
    was a decrease in the level of noradrenaline accompanied by an
    increased concentration of dopamine. Inhibition of dopamine
    ß-hydroxylase, an essential enzyme in catecholamine metabolism, was
    demonstrated  in vivo in studies on rats by Magos (1975), and  in
    vitro by McKenna & Di Stefano (1975). Magos (1975) advanced a theory
    concerning the central role played by catecholamine disturbances in
    carbon disulfide pathology, especially where central nervous system
    changes were involved, and in cardiovascular pathology. Cavalleri et
    al. (1977) suggested that this could also explain the involvement of
    the endocrine system.

    5.5  Effects on Lipid Metabolism

         Disturbance in the lipid metabolism has long since been linked
    with carbon disulfide exposure. Increased levels of serum lipids, free
    and total cholesterol, and ß-lipoproteins have been reported in
    rabbits exposed to carbon disulfide (Paterni et al., 1958; Cohen et
    al., 1959; Prerovska et al., 1961). Harashima et al. (1960) reported
    elevated total and esterified cholesterol levels in the serum of
    heavily exposed workers, whereas workers exposed to levels of about
    15-60 mg/m3 (5-19 ppm) displayed normal serum cholesterol
    concentrations. Elevated cholesterol levels were also found in exposed
    workers by Manu et al. (1971) and in patients with previous exposure

    to carbon disulfide (the patients had not been exposed for several
    years) by Graovac-Leposavic et al. (1977). Higher levels of serum
    lipids and especially cholesterol may be due to an increased rate of
    synthesis in the liver and to the inhibition of the degradation of
    lipids (Wrofiska-Nofer, 1969; Laurman & Wronska-Nofer, 1977). The fact
    that elevated cholesterol levels have not been found consistently may
    be explained by the different exposure levels in different studies
    (Toyoma & Sakurai, 1967). Bittersohl & Thiele (1977) found that a
    higher frequency of cholesterol values exceeding 6.72 mmol/litre
    (260 mg/dl) in workers exposed to carbon disulfide was strongly
    correlated with the duration of exposure.

         A decreased clearing factor activity was found by Ruikka (1959)
    in workers exposed to carbon disulfide and Martino et al. (1963, 1964)
    reported an elevated ß-lipoprotein fraction in the serum of exposed
    workers.

         Changes in the lipid metabolism found in the aorta tissue may
    contribute to the development of atheromatic changes in blood vessels
    (Wrofiska-Nofer, 1976).

         An increase in serum lipids during the exposure of rabbits to
    carbon disulfide was prevented by administration of nicotinic acid
    (Nofer & Wrofiska-Nofer, 1966) and in rats (Wrofiska-Nofer, 1970)
    (section 5.3.2).

    5.6  Interaction with Microsomal Drug Metabolism

         An important feature of the liver toxicity caused by carbon
    disulfide seems to be the destruction of cytochrome P-450 (Bond & De
    Matteis, 1969). There is evidence that this effect is due to the
    oxidative desulfuration of carbon disulfide by mixed-function oxidases
    (De Matteis & Seawright, 1973). The resulting, highly reactive, sulfur
    becomes covalently bound to the microsomal protein (Dalvi et al.,
    1974; De Matteis, 1974; Jarvisalo et al., 1977), mainly to the
    apoprotein of cytochrome P-450 (Neal et al., 1976; Jarvisalo & De
    Matteis, 1977; Savolainen et al., 1977a). It is possible that the
    liberated sulfur is the real toxic agent in liver toxicity arising
    from carbon disulfide exposure.

         Experiments on rats have shown that exposure to carbon disulfide
    in concentrations up to 1250 mg/m3 (400 ppm) for 8 h is followed by
    an increase in microsomal RNA content and in total protein in the
    hepatic microsomal fraction and also increased incorporation of
    2,4-3H-L-phenylalanine in liver microsomes (Freundt et al., 1974b).
    Such changes follow the action of inducing agents, such as
    phenobarbital, in the microsomal enzyme system. It has, therefore,
    been suggested that carbon disulfide may have an inducing as well as
    an inhibiting effect on mixed-function oxygenases. However, there is
    no real evidence of such an effect at present (Freundt, 1977).

    6.  CARBON DISULFIDE POISONING

    6.1  Historical Review

         At the end of 1850, several physicians observed cases of strange
    nervous and mental diseases, the origin of which remained obscure. In
    1856, Delpech, reported 24 cases of carbon disulfide poisoning and
    confirmed the diagnosis by animal experiments (Delpech, 1856a,b). In
    1863, he reported 80 more cases of "carbon disulfide neurosis"
    (Delpech, 1863). Cases of chronic poisoning were also reported in
    England by Bruce (1884) and Foreman (1886). Laudenheimer (1899)
    described carbon disulfide poisoning in German vulcanization shops,
    stirring public opinion by drawing attention to about 50 cases of
    "insanity". As further cases were reported in the USA (Jump & Cruice,
    1904; Francine, 1905), the need for hygienic improvement in work
    places was recognized. The first epidemic of carbon disulfide
    poisoning due to the vulcanization process ended at the beginning of
    the 20th century. At the same time, the viscose rayon industry started
    to develop and expanded rapidly. Sporadic cases of carbon disulfide
    poisoning in the viscose industry were reported between 1900 and 1930
    (Quarelli, 1928) but the problem became serious in the 1930s.
    Raneletti (1933), Quarelli (1934) and others described cases of
    psychotic and polyneurotic disorders and extrapyramidal disturbances
    (Audio-Gianotti, 1932; Teisinger, 1934).

         In Japan, the viscose rayon industry was established in 1916 and,
    in 1929, the first cases of carbon disulfide poisoning were reported
    by Tokuhara, followed by other authors (review by Kubota, 1967). Many
    cases of poisoning were also described in the USA (Hamilton, 1925,
    1940; Bashore et al., 1938). The so-called Pennsylvania study by Gordy
    & Trumper (1938) resulted in the establishment of the first TLV of
    20 ppm adopted by the American Standards Association (1941). As the
    hygienic standard in this industry improved, the incidence of severe
    poisoning decreased. However, during World War II, the hygienic
    situation in the expanding viscose industry deteriorated and severe
    poisoning again became common.

         During and after World War II, many cases of carbon disulfide
    poisoning were reported, mainly from Italy (e.g., Vigliani et al.,
    1944; Vigliani, 1946) but also from Belgium (Langelez, 1946; Merlevde,
    1951) and Finland (Noro, 1944). After World War II, the viscose rayon
    industry spread to many developing countries, where the whole sequence
    of degrees of exposure was repeated. In the developed countries,
    attention is now focused on slowly developing symptoms due to
    long-standing exposure to relatively low concentrations.

    6.2  Clinical Picture of Carbon Disulfide Poisoning

         Carbon disulfide intoxication has been classified as hyperacute,
    acute, subacute, and chronic.

         Hyperacute poisoning occurs in extreme cases of massive exposure
    for a short time to concentrations of about 10 000 mg/m3 or more. The
    victim quickly falls into a coma and eventually dies. Acute and
    subacute poisoning occurs with short exposure to carbon disulfide
    concentrations ranging from 3000-5000 mg/m3 with predominantly
    psychiatric and neurological signs and symptoms such as extreme
    irritability, uncontrolled anger, rapid mood changes including maniac
    delirium and hallucinations, paranoic ideas, and suicidal tendencies.
    Other symptoms include memory defects, severe insomnia, nightmares,
    fatigue, loss of appetite, gastrointestinal troubles, asthenia, and
    interference with sexual functions, such as impotency.

         The symptoms and signs of chronic carbon disulfide poisoning were
    described by Vigliani (1946, 1961) and the following classification of
    the different syndromes was suggested by Nesswetha & Nesswetha (1967):

         -- psychoses characterized by manic and depressive symptomatology
    and disorientation;

         -- polyneuropathy of the lower extremities, with diminished or
    completely absent Achilles and patellar tendon reflexes, sensory
    disturbances in a glove-stocking distribution, diminished faradic and
    galvanic excitability, and decrease of the motor and sensory
    conduction velocity in the peripheral nerves;

         -- disturbances of the gastrointestinal tract in the form of
    chronic, hyper- and hypoacidic gastritis and duodenal ulceration;

         -- myopathy of the calf muscles;

         -- neurasthenic syndrome with disturbances in the autonomous
    nervous system,

         -- optic neuritis;

         -- atherosclerotic vasculoencephalopathy; the principal forms
    being bulbar-paralytic, hemiplegic, or extrapyramidal.

         The typical mental deterioration has been called an organic
    psycho-syndrome, which may be due to general cerebral atherosclerosis,
    to direct toxic action upon the brain cells, or to both.

         The pattern of carbon disulfide poisoning has changed with
    improvements in hygienic standards in industry. However, when the
    viscose industry is established in a country with no former
    experience, there is always the risk of severe poisoning; this has
    occurred many times.

    6.3  Effects on Organ Systems

    6.3.1  Dermatological effects

         Liquid carbon disulfide represents a severe irritant for both the
    skin and mucosa. Hueper (1936) found blisters in viscose rayon workers
    and also in experimental animals that often resembled second and third
    degree burns.

    6.3.2  Ophthalmological effects

         Studies on the ophthalmological effects of carbon disulfide in
    animals have mostly been of a histological nature. In 1899, Koester
    observed changes in the retinal ganglia. Seto (1958) found vacuolar
    degeneration and tigrolysis in the retina, and atrophy of the optic
    nerve in rabbits exposed to a carbon disulfide concentration of about
    3700 mg/m3 for 1-3 h.

         Ophthalmological examinations in man are informative because it
    is possible to observe the visual capacity and to study the changes in
    the vessels of the ocular fundus directly. According to the literature
    (e.g., Nunziante-Cesaro et al., 1952; Savic, 1967) the following
    effects have been observed:

         -- changes in the motility of the eyelids;

         -- changes in the sensitivity of the cornea and conjunctiva;

         -- changes in the motility of the ocular bulbus;

         -- changes in convergency and accommodation;

         -- morphological changes in the fundus such as focal haemorrhage,
    exudative changes, atrophy of the optic nerve, retrobulbar neuritis,
    microaneurysms, and sclerotic changes of the blood vessels;

         -- functional changes, e.g., disturbances of colour vision,
    adaptation to the dark, reaction of the pupil to light, accommodation,
    and decrease in visual accuracy.

         Most of the effects mentioned above have resulted from heavy
    exposure. Many that were observed decades ago, when the observations
    often lacked comparison materials, are open to criticism. Nowadays,
    under prevailing working conditions such grave changes are rarely, if
    ever, seen.

         Increased systolic and diastolic blood pressure in the retinal
    arteries and damage to the arterial walls have been reported (Maugeri
    et al., 1966d; Goto et al., 1971). Maugeri et al. (1966d, 1967)
    studied the arterial pressure in 107 workers who had been exposed to
    carbon disulfide at concentrations ranging from 200-500 mg/m3, with
    peak concentrations of up to 900 mg/m3, for 1-9 years. Using an
    ophthalmodynamographic method, the authors found an average increase
    in both systolic and diastolic pressures in exposed workers of about
    18.4/14.7 kPa (138/110 mmHg) compared with controls which averaged
    15.3/11.6 kPa (115/87 mmHg). The increase was more marked for the
    diastolic pressure than for the systolic. Measurement of the pressure
    of the ophthalmic arteries may be a test that needs further evaluation
    in the light of the demonstrated disturbance of the brain
    catecholamine metabolism induced by carbon disulfide.

         Savic (1967) studied changes in the nervous system of the eyes of
    young workers exposed to carbon disulfide levels of 100-400 mg/m3.
    Changes were observed but only after a long period of exposure
    (>5 years) (Hotta & Savic, 1972). Retinal microaneurysms have been
    reported in a high proportion of Japanese viscose rayon workers (Goto
    & Hotta, 1967; Goto et al., 1971; Sugimoto et al., 1976). In one
    study, the prevalences of microaneurysms as judged by fundus
    photography, were 8% and 2% among exposed and unexposed male workers,
    respectively (Goto & Hotta, 1967). In a subsequent study (Hotta &
    Goto, 1971; Goto et al., 1971), a prevalence of 56% of microaneurysms
    was found in the exposed group (241 subjects) and 15% in a control
    group (30 subjects). The extremely high prevalence in the exposed
    groups in these studies was due to biased selection of the subjects;
    one-half of them were selected for examination because of known
    microaneurysms revealed by ophthalmoscopy. Later studies by the same
    team did not show such a high prevalence (Sugimoto et al., 1976), but
    a statistically significant difference between exposed and unexposed
    subjects still persisted. Retinaopathy was found in 89 out of 289
    carbon disulfide workers (31%), but only in 2 out of 49 controls (4%).
    The frequency of retinopathy was correlated with both the duration and
    the intensity of exposure (Sugimoto et al., 1976). It has been
    suggested that the retinal microaneurysms found in Japanese workers
    were related to the diabetogenic action of carbon disulfide (Goto et
    al., 1971). However, microaneurysms are generally associated with
    hypoxia and, though they may occur in advanced cases of diabetes, they
    are not, by any means, specific for the disease. Thus, to ascribe the
    excess of aneurysms found in Japanese studies to subclinical diabetes
    caused by carbon disulfide is not justified. It is more likely that
    they were caused by a direct effect on the retinal vessels, possibly
    in association with local hypoxia coacting with ethnic or
    environmental factors.

         The results of recent Finnish studies do not tally with the
    Japanese findings. Out of 100 exposed men and 97 controls, only 3
    exposed and 2 control subjects showed 1-5 microaneurysms, and one
    exposed subject showed more than 5 (Raitta et al., 1974). Furthermore,
    general narrowing of the arteries and calibre irregularity were so
    common in the fundus of both the exposed and control subjects that
    plain ophthalmoscopy did not have any discriminatory value in this
    study. A subsequent Japanese-Finnish study showed that the differences
    in values obtained in the 2 studies were true differences and were not
    caused by inter-observer variation (Sugimoto et al., 1977).

         The most interesting finding in a study by Raitta et al. (1974)
    was the high frequency of delayed peripapillary filling that occurred
    in 68 exposed and 38 unexposed men. The findings of Raitta & Tolonen
    (1975), suggest that studying the microcirculation of the ocular
    fundus by fluorescein-angiography and oculosphygmography would help in
    the early detection of carbon disulfide effects, especially since the
    vessels can be observed directly in their natural state.
    Ophthalmoscopy is indicated for the examination of patients suspected
    to be suffering from carbon disulfide poisoning and for following-up
    such patients, but it is too prone to inter-and intra-observer
    variation to be used routinely by plant physicians for regular health
    checks. Fundus photography eliminates some of this variation, but its
    evaluation should be standardized. The diagnosis of retinal
    microaneurysms requires a fundus angioscreenography, but this method
    is recommended for research purposes only.

         It should be added that a mixture of carbon disulfide, hydrogen
    sulfide and sulfuric acid mist from an acid bath caused
    keratoconjunctivitis in exposed workers (Savic & Jovicic, 1965). This
    phenomenon is called "spinner's eye".

    6.3.3  Otological effects

         Sulkowski & Latkowski (1969) observed that exposure to carbon
    disulfide impaired hearing ability. The authors examined 60 workers
    occupationally exposed to carbon disulfide for between one year and
    more than 10 years. The workers were below 50 years of age.
    Audiometric examinations showed impairment of hearing of the receptory
    type in more than 50 workers and also a decreased ability to
    distinguish sound intensity within the range 1.5-3.0 dB. This
    suggested a central and supracochlear localization of the impairment.
    Electronystagmographic examinations performed by these authors
    disclosed reduced excitability of the vestibular apparatus, suggesting
    an extralabyrinthine localization of the lesion. Loss of sensitivity
    to high frequency tones has also been attributed to carbon disulfide
    exposure (Zenk, 1970). Since noise levels are often very high in
    viscose rayon plants, it is possible that the lesions found may be at
    least partly due to this cause. Vestibular symptoms, as manifested by
    vertigo and nystagmus may also be present in carbon disulfide
    intoxication (Zenk, 1967, 1970).

    6.3.4  Respiratory effects

         Carbon disulfide is a known irritant, but few data exist about
    its effects on the respiratory system (Zenk, 1967). Ranelletti (1933)
    described chronic cough as a consequence of the irritant effect of
    carbon disulfide, but it is necessary to take into consideration the
    irritative effects of hydrogen sulfide and sulfuric acid mist and of
    other irritants present in the air of viscose rayon plants. The
    findings of Massoud et al. (1971) i.e., cough, phlegm, wheezing,
    dyspnoea, precordial pain and palpitations, may also have been due to
    such mixed exposure rather than to carbon disulfide alone.

    6.3.5  Gastrointestinal effects

         Gastrointestinal symptoms are common among heavily exposed
    workers and patients with carbon disulfide poisoning. Bashore et al.
    (1938) found a prevalence of such symptoms of 25%, Vigliani (1954),
    28%, Karajovic et al. (1964), 66%, Lysina (1967), 27%, and Hass et al.
    (1967), 27%. Since such symptoms occur among unexposed people too,
    especially in shift work, the figures listed cannot be attributed
    exclusively to carbon disulfide exposure (Knave et al., 1974). A
    higher prevalence of gastrointestinal disorders and liver and bile
    duct dysfunction was observed in 2 groups of workers (800 and 492
    subjects, respectively) exposed to very low carbon disulfide
    concentrations (4-12 mg/m3) than in a control group of 453 unexposed
    workers. The prevalence in the 2 exposed groups was 4.7 and 5.6%,
    respectively, and that in the control group, 2.2% (Murashko, 1975).
    Later, Bittersohl & Thiele (1977) found a prevalence of 22.7% of
    gastrointestinal changes in 309 exposed shift workers as opposed to
    5.9% in 345 unexposed shift workers.

         Based on histological studies of the gastric mucosa of 75 workers
    exposed to carbon disulfide, Hassman et al. (1967) suggested
    classification into 5 groups: normal gastric mucosa, superficial
    gastritis, chronic gastritis with incipient atrophy, chronic atrophic
    gastritis, and gastritis of undetermined type. Duodenal ulceration was
    only found in 2 out of 75 subjects in this study. Of the workers
    examined, 11% had dyspeptic complaints and gastritis was verified in
    60% of the cases. A similar figure (66%) was found by Karajovic et al.
    (1964).

    6.3.6  Hepatic effects

         Exposure to carbon disulfide has caused fatty degeneration and
    haemorrhages of the liver in animals (Bashore et al., 1938).
    Experimental studies on rats have shown that pretreatment with a drug
    that stimulates liver microsome enzyme activity alters the degree of
    liver damage on exposure to carbon disulfide. Thus, Bond et al. (1969)

    reported necrosis in the livers of rats that had been pretreated with
    phenobarbital and subsequently received a single oral dose of carbon
    disulfide (1 ml/kg body weight) but not in rats treated only with
    carbon disulfide. Moreover, only pretreated rats displayed hydropic
    degeneration of the liver. Magos & Butler (1972) found that starvation
    potentiated the effect of phenobarbital in rats subsequently treated
    with carbon disulfide, and that the resulting hydropic degeneration
    was reversible. Similar results were obtained by Freundt et al.
    (1974a), when they administered a single oral dose of 1 ml of carbon
    disulfide per kg body weight to rats pretreated with phenobarbital.
    However, no degenerative changes in the liver were observed in
    pretreated rats following exposure by inhalation to carbon disulfide
    at about 60 mg/m3 (20 ppm) and 620 mg/m3 (200 ppm) for up to 7 days.
    In experiments performed on rats with short-term (8-h) exposure to
    carbon disulfide at concentrations ranging from 62-1250 mg/m3
    (20-400 ppm), the energy potential of the organism was damaged mainly
    because of a reversible augmentation of hepatic glycolysis (Kürzinger
    & Freundt, 1969; Freundt & Kürzinger, 1975).

         The possible effects of carbon disulfide on the liver have been
    discussed in numerous reports of clinical observations. Some authors
    deny that exposure to carbon disulfide results in toxic effects in the
    liver, some claim degenerative changes of the hepatocytes, and others
    state that sclerotic changes are produced under conditions of chronic
    exposure. Such controversial observations can be explained by
    nonuniformity in approach to the method of examination. Vidakovic et
    al. (1965a) examined workers hospitalized because of chronic carbon
    disulfide poisoning. The exposure of these workers had been extremely
    high, ranging from 1400-2200 mg/m3 (Petrovic & Djuric, 1965).
    Functional disturbances of the liver and fatty degeneration of
    hepatocytes were found but no necrotic changes were observed.

         Pirotskaja (1972) examined the protein-forming function of the
    liver in workers (40 women and 6 men) who had been exposed to carbon
    disulfide for 5 years. At first, the workers were exposed to a carbon
    disulfide concentration of 90 mg/m3 but later, concentrations ranged
    from 8-14 mg/m3. All exposed subjects were between 30 and 40 years of
    age. The mean concentrations on cystine, thyroxine, methionine,
    valine, leucine, and tryptophan in serum showed statistically
    significant increases in comparison with a control group.
    Statistically valid decreases occurred in the levels of glutamic acid,
    aspartic acid, olanine, and lysine. The levels of histidine, arginine,
    and serine did not differ from those in the control group. There was a
    correlation between these changes and the clinical signs of carbon
    disulfide intoxication. There was no difference in the serum contents
    of total protein in the exposed and control groups.

    6.3.7  Renal effects

         Some authors have drawn attention to nephrosclerosis in autopsies
    of patients with carbon disulfide poisoning (Uehlinger, 1952; Yamagata
    et al., 1966; Sbertoli et al., 1969), but this could be ascribed to a
    general atherosclerotic process induced by carbon disulfide. For
    example, in the cases studied by Uehlinger (1952), typical
    glomerulosclerosis of the Kimmelstiel-Wilson type was established in 4
    patients, while the fifth showed arteriosclerotic injury of the
    kidney. Obviously renal involvement represents a very late consequence
    of heavy, protracted carbon disulfide exposure, since
    Graovac-Leposavic & Jovicic (1971) reported that only one patient with
    persistent kidney insufficiency had ever been diagnosed in a large
    viscose rayon plant employing several thousands of workers. In another
    study of viscose rayon workers, Hemberg et al. (1971) found a slight
    but statistically significant rise in the mean plasma creatinine
    concentration compared with a control group. All values were within
    "normal" limits, however.

    6.3.8  Haematological effects

         Brieger (1949) studied the bone marrow of exposed rats and found
    retarded maturation of the erythrocytes. Mild anaemia, a slight
    decrease in the haemoglobin concentration, slight reticulocytosis,
    eosinophilia, and hypercoagulability of the blood have also been
    recorded in exposed rats (Vidakovic et al., 1965b).

         Ivanova (1967) found a moderate decrease in the haemoglobin
    concentration and erythrocyte count in men with only slight exposure
    to carbon disulfide. Such results cannot be attributed to carbon
    disulfide effects, but rather to poor standardization of the study
    conditions, since significant haematological changes in the peripheral
    blood were not observed, even in highly-exposed workers (Vidakovic &
    Andjelkovski, 1965; Fahim et al., 1973). Thus, it has not been
    confirmed that carbon disulfide causes anaemia or polyglobulia. It is
    probable that the anaemia mentioned in some clinical reports reflects
    malnutrition or some other nonoccupational cause, perhaps even
    defective study design, rather than an effect of carbon disulfide.

         The effects of carbon disulfide on blood coagulation mechanisms
    are discussed in section 6.3.14.

    6.3.9  The endocrine system

         Damage to the endocrine structures with functional alterations
    was described in animals by Ranelletti as early as 1931, and by
    Audio-Gianotti in 1932. Impaired sexual function in patients with
    carbon disulfide poisoning was reported by Gordy & Trumper (1938),

    Langelez (1946), and Vigliani (1946). Vesce et al. (1953) observed a
    decrease in 17-ketosteroids excretion in the urine of exposed rabbits.
    This phenomenon was confirmed in studies on exposed workers by
    Fruscella (1962) and Olienacz et al. (1964). Most of these
    observations were made on workers belonging to older age-groups and
    the confounding effect of age was not controlled. Cavalleri & Zuccato
    (1965), however, obtained the same results taking the age factor into
    account.

         In 1965, a joint Italian-Yugoslav group began an investigation on
    young workers in a Yugoslav viscose rayon plant. The workers were
    classified according to duration of exposure to carbon disulfide. The
    average ages of various groups ranged from 26 to 33 years and they
    were exposed to average carbon disulfide concentrations of about
    200-500 mg/m3 with peak concentrations of up to 900 mg/m3. The
    excretion of 17-ketosteroids in the urine showed a linear decrease
    with the duration of exposure (Cavalleri et al., 1966a,b, 1967). The
    decrease in excretion of 17-hydroxycorticosteroids was most marked in
    workers with short exposure and did not decrease any more as exposure
    continued. The excretion of androsterone appeared to decrease
    progressively with duration of exposure, probably in a linear fashion;
    that of etiocholanolone did not show any uniform pattern (Cavalleri et
    al., 1966c,d). Urinary excretion of testosterone and gonadotropin
    luteinizing hormone was also reduced in workers exposed to
    concentrations of 100-400 mg/m3 for 2-12 yearsa. Lancranjan et al.
    (1971) reported a decrease in 17-ketosteroid and
    17-hydroxycorticosteroid excretion in the urine of exposed workers.

         The thyroid function has been studied in exposed workers by
    determination of serum thyroxine (Cavalleri et al., 1971; Cavalleri,
    1975; Massoud et al., in press). Decreases reported in thyroxine
    levels suggest a reduction of thyroid activity.

         Mild hypothyroidism was reported in 8% of exposed workers in
    studies by Lancranjan (1972). This effect may be primary or may be due
    to inhibition of the hypothalamus-hypophysis axis. A decrease in
    thyrotropin-stimulating hormone, observed in human subjects given
    tetraethylthiuram, favours the hypothesis of an impairment of the
    hypothalamic-hypophyseal system (Cavalleri et al., 1977).

                 

    a Exposure data submitted by Professor Cavalleri as private
      communication to the Task Group.

         When the thyroid function is inhibited, disturbances in the lipid
    metabolism will appear. A well-known manifestation of subclinical
    hypothyreosis is elevation of the serum cholesterol level, which in
    turn may contribute to the vascular changes typical of carbon
    disulfide poisoning. The isolation and identification of two
    metabolites, thiourea and mercaptothiazoline, may help to explain the
    mechanism (Pergal et al., 1972a,b). Neither of these metabolites is
    directly toxic, but both may have some influence on thyroid activity.
    In fact, drugs containing substances of the thiourea and
    mercaptothiazolinone type are used in the treatment of
    hyperthyroidism.

         Lancranjan et al. (1969, 1972), reported hypospermia,
    asthenospermia, and tetratospermia in the spermatic liquid of young
    exposed workers, confirming the gonadal injury reported by Cavalleri
    et al. (1965).

         Disturbances were found in the ovarian function of 500 young
    females, exposed to concentrations of carbon disulfide of around
    20 mg/m3, and of 209 women exposed to a concentration of less than
    10 mg/m3 (Vasiljeva, 1973). In a comparison with a group of 429
    unexposed women, menstrual flow durations of more than 5 days occurred
    in 18% of the first group and in 11% of the second compared with 5% in
    the control group. Irregular menstruation occurred in 8% of those
    exposed to 20 mg/m3 as opposed to 2% in the comparison group. Other
    menstrual disorders followed a similar pattern, and were correlated
    with the length of exposure. When vaginal smears were examined from
    subsamples, cellular disturbances were most frequent in the group with
    highest exposure. A biochemical study of the sex hormones in the urine
    confirmed the vaginal-smear findings. Hence, even rather low exposure
    to carbon disulfide appeared to induce hormonal and functional
    disturbances in young women. Other studies corroborate these findings
    (Petrun, 1967, Finkova et al., 1973).

         In a study of 380 women exposed to around 30 mg/m3, Petrov
    (1969) found more pregnancy complications than in a control group of
    191 women. Spontaneous abortions occurred in 14% of the exposed, and
    7% of the unexposed women. "Threatened pregnancy terminations" also
    occurred more frequently in the exposed women than in the controls
    (26% and 13% respectively). Exposed women gave birth prematurely
    significantly more frequently than controls (9% and 3%, respectively).

         It has been reported in several studies that carbon disulfide
    produces primary damage at the hypothalamic-hypophyseal level
    (Cavalleri et al., 1965; Lancranjan et al., 1971; Maugeri et al.,
    1971; Cavalleri, 1972). The hypothalamus produces the releasing
    factors that stimulate the hypophysis to synthesize and release
    polypeptide hormones, which in turn stimulate the target glands in
    question. The impairments found would, therefore, represent a
    secondary consequence.

         Thus, carbon disulfide causes several disturbances of the
    endocrine systems that can be summarized as follows:

         -- a reduction of adrenal activity that can be repaired by ACTH
    administration and can therefore be ascribed to reduced secretion of
    corticotrophin;

         -- a reduction of the endocrine activity of the testis and
    impairment in spermatogenesis possibly due to direct gonadal damage;
    this finding could explain the decrease in "libido" and "potentiae"
    often found in exposed workers;

         -- disturbances in the hormonal balance in women, resulting in
    menstrual irregularities, spontaneous abortions, and premature births;

         -- impairment of thyroid function, which could be primary or due
    to a deficiency in the thyrotropin-stimulating hormone (TSH) or the
    TSH releasing factor or both.

    6.3.10  Effects on the nervous system

    6.3.10.1  Central nervous system

         In experimental animals, carbon disulfide causes destruction of
    the myelin sheet and axonal changes in both the central and peripheral
    neurons. Degenerative changes have been observed in the cortex, basal
    ganglia, the thalamus, the brain stem, and the spinal cord (Wiley et
    al., 1936; Ferraro et al., 1941; Lewey et al., 1941; Fischer &
    Michalova, 1956; Drogicina, 1968).

         The mechanism by which carbon disulfide causes these changes has
    not been elucidated, however. Mitochondrial enzymes may be inhibited
    (Tarkowski & Wrofiska-Nofer, 1966; Tarkowski & Sobczak, 1971), and the
    tyrosine and catecholamine metabolism may be disturbed (Magos et al.,
    1974). The content of free glutamine increases as a result of carbon
    disulfide exposure (Efremova & Uzbekov, 1968; Tarkowski & Cremer,
    1972). Such changes were observed with acute experimental poisoning,
    but chronic, repeated exposure did not produce gross changes
    (Tarkowski, 1973).

         Horvath & Mikiska (1957) followed the electroencephalographic
    changes in rabbits exposed to carbon disulfide and found a transitory
    decrease in the amplitude of basic and superimposed beta rhythms.

         The results of animal experiments have to be extrapolated to man
    with extreme caution; however, many data obtained from animal studies
    are in good agreement with clinical observations in man. Like other
    narcotic agents, carbon disulfide produces a clinical symptomatology
    of irritation and excitation on one hand, and inhibited psychomotor
    activity, psychological alterations, insomnia, hypersomnia, loss of
    consciousness and death, on the other.

         In acute poisoning, the first typical signs from the central
    nervous system (CNS) are excitation, euphoria, and aggressive
    behaviour. Subacute and chronic cases are first characterized by
    neurotic signs of unrest, excitation, and loss of temper. Gradually
    the patient becomes depressive, anxious, paranoiac and sometimes there
    is a suicidal tendency. Nightmares, apathy, loss of initiative,
    vegetative disturbances, and headache are common symptoms (Melissinos
    & Jacobides, 1967; Mihail et al., 1968). In the further course of
    chronic intoxication, neurological signs become prominent. Both
    diffuse cortical and focal symptoms from the subcortical grey matter
    and extrapyramidal system are typical (Teisinger, 1934). Typical
    Parkinson symptomatology with bradykinesia, bradylalia, muscle
    rigidity, tremor, and increased elementary postural reflexes is
    similar to that in arteriosclerotic or postencephalitic parkinsonism
    (Nakamura et al., 1974). Psychic, pyramidal and extrapyramidal
    symptomatology, including signs from other parts of the brain
    (vestibular, cerebellar) give a picture compatible with diffuse
    effects, described under the term of "toxic encephalopathy".
    Furthermore, nervous involvement in general may be reflected as
    changes in the sensitive branch of the trigeminal nerve, in the
    function of the III, IV, and VI cranial nerves, and in the sympathetic
    and parasympathic nerves of the eye.

         Disturbances in cerebral circulation probably explain some of the
    manifestations of neurotoxicity. Vigliani et al. (1944) demonstrated
    hyalinosis of the arterioles and precapillaries histologically, a
    finding that fits into the picture of general atherosclerosis caused
    by carbon disulfide. Thus, the vascular changes described by Vigliani
    (1961) as "encephalovasculopathia sulfocarbonica", are probably
    responsible for many of the manifestations of central nervous system
    pathology.

         On the other hand, authors of some recent publications have tried
    to explain some mechanisms by direct interference of carbon disulfide
    and its metabolites in the system of enzymatic processes in the brain.
    Morphological studies indicate that long axons in the spinal cord are
    preferentially destroyed in chronic carbon disulfide poisoning
    (Szendzikowski et al., 1973).

         The typical neuropathological picture includes an increase in
    neurofilaments, and secondary effects on the myeline sheath (Juntunen
    et al., 1974). Biochemical studies have shown that oxidative
    desulfuration also take place in the brain (Savolainen et al., 1977b),
    and that the highest specific binding of the liberated sulfur is
    detected in spinal cord axons (Savolainen & Vainio, 1976). It appears
    that most of the liberated sulfur binds to neurofilaments that are
    essential to normal axon functions (Savolainen et al., 1977c). Thus,
    there is evidence of a direct toxic action upon the nervous system.

         The results reported by Abramova (1967), Vasak & Kopecky (1967),
    and others (section 5.3.1) regarding inhibition of the vitamin B6
    metabolism, might explain some changes in the peripheral myelin sheet
    and even some effects on the central nervous system. The consequences
    of vitamin B6 inhibition, or interference with the transamination of
    glutamic acid and inactivation of pyridoxamine could, perhaps, produce
    irritative cortical symptomatology, including epileptiform cramps.
    Furthermore, studies showing interactions between carbon disulfide
    and, tissue respiration; depression of cytochrome oxidase, succinic
    dehydrogenase, alkaline phosphatase, and dopamine-ß-hydroxylase; and
    influence of inhibitors of serum elastase (EC 3.4.21.11), suggest that
    besides a purely vascular etiology, it is plausible to consider a
    direct toxic interference of carbon disulfide with tissue metabolism
    (section 5.2). In fact, direct toxic effects of carbon disulfide on
    peripheral nerve cells (Szendzikowski et al., 1973), and on the
    myoneural junctions (Juntunen et al., 1977) have been shown in
    animals. The central nervous system may react in the same manner.

         From all these considerations, it can be concluded that the
    effects of carbon disulfide on the nervous system may be influenced by
    many factors. The method most often used for the study of cerebral
    involvement in man is electroencephalography (EEG). However, studies
    on carbon disulfide poisoning are rare. Early studies emphasize the
    frequent occurrence of very flat records among subjects chronically
    exposed to carbon disulfide (Krolikowska & Rucinska, 1959). More
    recently, Seppäläinen & Tolonen (1974) found 21 abnormal EEGs in an
    exposed group comprising 54 viscose workers compared with only 6 in a
    control group of 50 paper-mill workers. Thiele & Wolf (1976) found EEG
    changes in 52% of a group of 139 spinning workers. The abnormalities
    consisted of slight, diffuse slow-wave abnormalities, slight to
    moderately severe focal slow-wave abnormalities and even spike and
    wave discharges in 3 exposed men. Thus, mild brain dysfunctions were
    clearly more prevalent in the exposed group than in the control. EEG
    findings among 250 workers with longstanding occupational exposure to
    carbon disulfide (mean exposure 11.2 years) were recently described by
    Styblva (1977) and compared with the EEGs of 61 healthy controls and
    47 patients suffering from cerebral arteriosclerosis. Increased
    frequency of abnormal EEGs was found in 33.2% of the exposed workers,
    compared with 6.6% in the control group ( P < 0.01). The most
    frequent abnormalities among the exposed workers were episodic theta
    activity (33%) and diffuse abnormality (30%) (it was not, however,
    indicated or even deducible from the data presented, how these
    percentages had been calculated, i.e., from which population they were
    taken). Local abnormalities were rare. Local EEG abnormalities

    predominated in patients with cerebrovascular disease. The episodic
    activity in the EEG was considered to reflect the direct toxic effects
    of carbon disulfide on mesodiencephalic structures. The author
    proposed that diffuse abnormality could be a manifestation of
    vasculoencephalopathy resulting from toxic changes in the small
    diameter vessels. The frequency of alpha activity tended to be lower
    among exposed workers and this was considered to indicate a cerebral
    metabolic disorder due to carbon disulfide exposure.

         Studies on the behavioural and psychological effects of carbon
    disulfide exposure have indicated disturbances in deep subcortical
    structures, namely vegetative centres, and more diffuse cortical
    involvement. The methods used have included diagnostic interviews,
    behavioural observations (mainly on experimental animals), and
    psychological test batteries.

         Both structured and unstructured interviews of human subjects
    showed differences in the clinical pictures of carbon disulfide
    poisoning at rather high concentrations i.e., about 950-2400 mg/m3
    (300-760 ppm) and at much lower concentrations i.e., around
    20-50 mg/m3 (7-30 ppm) over a long period of exposure. At high
    concentrations, symptoms of headache, muscle pain, fatigue,
    paraesthesia, and general weakness were consistently reported (Gordy &
    Trumper, 1940; Manu et al., 1970). At lower levels of exposure, fewer
    complaints of muscular pain and overall weakness were noted, the main
    symptoms being headache, memory impairment, rapid mood changes,
    insomnia, paraesthesia, and fatigue (Seppäläinen et al., 1972; Lilis,
    1974).

         Standardized batteries of tests yield results that are directly
    quantifiable and comparisons can be made between groups at different
    exposure levels and control groups. Using this method, Hänninen (1971)
    presented 3 groups of workers with different exposures and clinical
    profiles (unexposed, exposed without clinical symptoms, and poisoned).
    The results suggested that syndromes of latent and manifest carbon
    disulfide poisoning differ in quality as well as in intensity, i.e.,
    "clinically manifested poisoning is characterized by lowered
    vigilance, diminished intellectual activity, diminished rational
    control, retarded speed, and motor disturbances, whereas traits
    indicative of depressive mood, slight motor disturbances, and
    intellectual impairment are characteristic of latent poisoning"
    (Hänninen, 1971). Analysis of intercorrelations among test sources for
    each of the 3 groups resulted in substantially different factor
    structures across the 3 groups. This supports the contention that
    behavioural differences between groups exposed to different
    concentrations are qualitative as well as quantitative (Hänninen,
    1974). Naturally, the extent to which such distinctions are, in fact,
    true, depends on the number of false-positive diagnoses in the
    poisoned group (i.e., how many patients with other diseases had been
    classified as cases of carbon disulfide poisoning), and, since this

    aspect could not be evaluated, it may be premature to accept the
    qualitative changes found as real facts. As to the quantitative
    changes, it is self-evident that their severity must be correlated
    with the degree of poisoning, at least on a group basis. The
    specificity of the psychological and behavioural examination increases
    when other sub-clinical signs of carbon disulfide exposure, such as
    EEG and EMG findings are present.

         Hänninen & Mäenpää, as reviewed by Tolonen (1974), applied the
    same type of tests to 97 exposed male viscose rayon workers (mean
    exposure time 15 years) and 96 age-and-sex matched controls from a
    paper mill with no history of exposure to carbon disulfide. The most
    distinct difference was in the retardation of psychomotor speed, where
    the relative risk was 2.2 ( P = 0.02). As a whole, 40% of the exposed
    and 25% of the control group showed "poor" performance, as defined
    according to criteria published by Tolonen (1974). These results show
    a clear group difference; however, the test battery has a low
    specificity for carbon disulfide, as could be seen from the high
    number of "false positive" results.

         Recently, Hänninen and her co-workers increased the specificity
    of the test battery, reducing the number of tests on the basis of
    information gathered from new analytical approaches applied to results
    of 206 exposed and 152 unexposed men, examined in 1972. According to a
    multiple discriminant analysis, the most specific variables for carbon
    disulfide effects were those indicating retarded speed, retarded
    emotionality and energy, and psychomotor disturbances (Hänninen et
    al., 1978). Another approach, starting from test results classified as
    abnormal, resulted in similar conclusions (Tolonen et al., 1976). Now,
    the test battery can be restricted to a few rather specific tests
    applicable to suspected cases of poisoning that can also be used at
    periodic health examinations.

         Analogous results concerning the depressing effects of carbon
    disulfide on psychological performance and behaviour have been
    reported by Foa et al. (1976), Gherase (1976), Schneider (1976),
    Tuttle et al. (1976)a and Hakky (1977).

         Foa et al. (1976) demonstrated an exposure-effect relationship by
    comparing workers from 2 plants with different degrees of exposure. A
    relationship between exposure time and performance was demonstrated by
    Schneider (1976), but the role of age as a confounding factor could be
    excluded for 2 test variables only.

                 

    a Tuttle, T. C., Wood, G. D., & Grether, C. B. (1976) Behavioral and
      neurological evaluation of workers exposed to carbon disulfide
      (CS2). Unpublished report submitted to NIOSH (National Institute for
      Occupational Safety and Health) by Westinghouse Electric Corporation,
      Behavioral Services Center, Columbia, MD, USA, 156 pp.

         From these data, it can be concluded that, at rather low exposure
    levels, psychological test results are almost the only way of
    assessing involvement of the central nervous system. Relationships may
    exist between psychological impairment and EEG abnormalities, but
    further studies are needed to clarify this point.

    6.3.10.2  Peripheral nervous system

         Many authors have studied the neuropathy and myelopathy of
    animals exposed to carbon disulfide (Fischer & Michalova, 1956;
    Higashida et al., 1959; Scheel, 1967; Frantik, 1970; Luke,, 1973;
    Szendzikowski et al., 1973; Wrofiska-Nofer et al., 1973; Seppäläinen &
    Linnoila, 1975, 1976). Destruction of the myelin sheet has been the
    most prominent finding, but axonal changes have also been observed. In
    the muscle fibres, atrophy of the denervation type occurred secondary
    to the polyneuropathy. Some species differences in susceptibility to
    carbon disulfide have been found. Cats and rabbits tolerated only low
    concentrations of carbon disulfide. On the other hand, polyneuropathy
    in rats was produced only with exposure to extremely high
    concentrations (1200-2400 mg/m3). The slowing of nerve conduction
    velocity in the sciatic nerve in rabbits and rats preceded clinical
    symptoms such as clumsiness and later on, paresis. In rabbits,
    electromyographic abnormalities suggested the presence of myelopathy
    together with peripheral neuropathy (Seppäläinen & Linnoila, 1975,
    1976). Neuropathological studies (Linnoila et al., 1975) showed severe
    morphological alterations in the lateral and anterior funiculi of the
    spinal cord in addition to pronounced axonal alterations in the
    peripheral nerves of rabbits.

         Lukas (1970, 1973) established by electromyography (EMG) that the
    development of neuropathy in the rat was influenced by dose, duration
    of exposure, physical conditions, and the nutritional state of the
    animal. This confirms the long-standing clinical belief that the
    individual constitution bears some relationship to the quantity and
    quality of the effects of carbon disulfide (Djuric, 1967, 1971; Djuric
    et al., 1973; Goto et al., 1971).

         The protective effects of some substances have also been studied
    in animals. The addition of zinc and copper salts (Scheel, 1967;
    Lukas, 1970), and of pyridoxine to the diet (Frantik, 1970; Luke,,
    1970) did not change the toxic effects of carbon disulfide but
    improved the biochemical consequences of the intoxication, for example
    by decreasing the excretion of xanthurenic acid with urine (Kujalova &
    Tintera, 1970). Addition of nicotinic acid (Wrofiska-Nofer, 1970)
    provided some protection against the effects of carbon disulfide lipid
    metabolism. The clinical picture of carbon disulfide intoxication in

    man is mainly based on toxic polyneuropathy (Bashore et al., 1938;
    Vigiliana, 1954, 1961; Lukas, 1969; Lukas & Hromadka, 1977; Milkov et
    al., 1970; Seppäläinen et al., 1972; Seppäläinen & Tolonen, 1974;
    Seppäläinen, 1977; Gilioli et al., 1977). The subjective complaints
    include paraesthesia, dysaesthesia, and fatiguability and diffuse
    pains of the lower extremities. Sometimes irritative signs are
    prevalent and sometimes the patients have a feeling of local
    hyperaesthesia, or hypersensitivity on palpation in the muscles of the
    lower limbs.

         Distribution of the complaints is mostly symmetrical, and,
    objectively, there is hyporeflexia. Klimkova-Deutschova (1965) pointed
    out the characteristic dissociation of the patellar reflex response,
    which is normal or increased, with a decreased or absent Achilles
    tendon reflex. As the neuropathy develops, changes first appear in the
    sensitive fibres of the lower extremities, later reaching the upper
    extremities. (Lukas, 1969; Lukas & Hromadka, 1977). Hyperaesthesia is
    mostly of a "sock" character, but sometimes it is also diffuse.
    Palpation of the nerve roots and sometimes of the whole muscle groups
    is painful. Today, the development of symptoms seldom reaches the
    stage of motor paresis and, consequently, atrophic changes
    (amyotrophy) are rare. The same is true of vasomotoric changes.
    Amyotrophy has been described in the earlier literature in the area of
    the triceps surae and quadriceps muscles of the legs, as well as in
    the small muscles of the hand, the thenat, the hypothenar, and in the
    interosseal muscles.

         It has also been suggested that cells in the spinal cord are
    injured (Manu et al., 1970; Seppäläinen et al., 1972). On the other
    hand, disturbances in myoneural function have resulted in
    myastheniform signs (Seppäläinen et al., 1972).

         Needle electromyography and measurement of the motor conduction
    velocities of peripheral nerves have proved to be sensitive methods
    for detecting early nerve damage, even in neurologically normal,
    exposed workers (Lukas, 1969; Manu et al., 1970; Seppäläinen et al.,
    1972; Lilis, 1974; Seppäläinen & Tolonen, 1974; Knave et al., 1974;
    Thiele & Wolf 1976; Lukas et al., 1977). The EMG abnormality most
    often found consists of a reduced number of motor units at maximal
    contraction and an increase in the duration of motor unit potentials
    and fibrillation. The maximum motor conduction velocities (MCV) are
    lower, especially in the leg nerves, and the distal latencies are
    prolonged. However, the most sensitive test for peripheral nervous
    involvement appears to be the conduction velocity of the slower fibres
    of the ulnar and deep peroneal nerves, and that of the H-reflex in the
    region of tibia] nerve (Lukas, 1969, 1977; Seppäläinen & Tolonen,
    1974; Gilioli et al., 1977). In a recent epidemiological study
    (Seppäläinen & Tolonen, 1974) comprising 118 male viscose rayon
    workers and 100 control subjects from a paper mill, the most important
    findings were as follows: the conduction velocities in the nerves of

    the exposed men were generally slower than those of the controls. The
    most distinct differences (all  P values smaller than 0.01) were
    obtained for the conduction velocity of the slower fibres of the ulnar
    and deep peroneal nerves, the MCV of the deep peroneal and posterior
    tibial nerves, and the motor distal latency of both the median and
    ulnar nerves. The exposed group in this study was predominantly
    composed of clinically "well" men, exposed for a number of years
    (median 15) to carbon disulfide plus hydrogen sulfide concentrationsa
    of about 60-190 mg/m3 (20-60 ppm) in the 1950s, about 30-95 mg/m3
    (10-30 ppm) in the 1960s, and mainly below 60 mg/m3 (20 ppm) during
    the last years. A little more than half of the men were still exposed
    at the time of examination, the rest were working in "clean"
    departments.

         Different types of nervous system symptoms and findings among 51
    Swedish viscose factory workers were evaluated by Knave et al. (1974).
    The iodine-azide test was used as a measure of exposure intensity. The
    comparison group consisted of 51 subjects matched for sex and age.
    Symptoms of peripheral nervous dysfunction (e.g., restless legs,
    cramps, pain, and numbness) were over-represented among workers,
    especially the combination of these symptoms. Only one neurological
    sign-namely tremor-showed a higher prevalence in the exposed than in
    the control group. The authors measured only the maximal MCV of the
    median nerve and found minor slowing in this MCV when the duration of
    employment was between 5 and 30 years, but not after shorter exposure.

         The prognosis of carbon disulfide polyneuropathy has not been
    considered to be too poor. According to one follow-up study of exposed
    workers, electroneuromyographic abnormalities tend to ameliorate if
    the exposure level decreases or exposure is stopped (Seppäläinen,
    1977). A tendency for repair and restitution of lost functions has
    also been demonstrated experimentally in animals (Lukas, 1970;
    Seppäläinen & Linnoila, 1975, 1976).

         However, it has been shown that, even after periods of 10-15
    years without exposure, abnormal conduction velocity values may be
    found in workers with previous carbon disulfide poisoning or previous
    long-term exposure to carbon disulfide (Seppäläinen et al., 1972).
    This corresponds with the experience of Gilioli et al. (1977), who
    found the reduction in conduction velocity to be irreversible. In
    another study, Seppäläinen (1977) described an amelioration in the EMG
    findings when carbon disulfide exposure was reduced or stopped.

                 

    a Exposure levels in studies by Hernberg et al. (1970, 1973, 1976),
      Raitta et al. (1974), Tolonen (1974), Tolonen & Seppäläinen (1974),
      and Tolonen et al. (1975) refer to combined concentrations of carbon
      disulfide and hydrogen sulfide. Hydrogen sulfide concentrations were
      about 10% of the carbon disulfide concentrations (Hernberg et al.,
      1970).

    6.3.11  Cardiovascular effects

         A number of studies have shown that carbon disulfide causes
    vascular changes in various organs of experimentally exposed animals
    (Lewey, 1941; Guarino & Arcello, 1954; Paterni et al., 1958). In man,
    evidence of vascular changes caused by long-term exposure, has been
    accumulating since World War II. Attinger (1948) was the first to
    describe such changes in 5 autopsy cases. Further clinical and autopsy
    studies showed clearly that carbon disulfide was a vasotropic poison
    (Uehlinger, 1952; Attinger, 1954; Vigliani & Pernis, 1955; Crepet et
    al., 1956; Rechenberg, 1957; Maugeri et al., 1966a,b; Prerovska &
    Roth, 1968; Maugeri et al., 1971; Prerovska & Zvolsky, 1973).

         According to Vigliani & Pernis (1955) the "vasculopathia
    sulfocarbonica" appears in 2 forms, namely in cerebral arteries
    causing encephalopathy, and in the renal arteries causing nephropathy
    and hypertension. The syndromes that follow these types of vascular
    damage have already been described in sections 6.2, 6.3.7, and
    6.3.10.1. Autopsy studies have revealed that sclerosis is prevalent in
    large and middle-size arteries and hyalinization in arterioles and
    capillaries. These changes appear in the blood vessels of all organs
    but they are particularly prominent in the central nervous system and
    kidneys.

         Vascular changes due to carbon disulfide exposure are similar to
    those produced with atherosclerosis due to age. Thus, the picture in
    older persons is confused by the influence of age. The carbon
    disulfide induced vasculopathy is therefore best studied in young
    persons with a sufficiently long exposure time. With this in mind, a
    joint Italian/Yugoslav team selected 104 young workers (age around
    30-35 years) with more than 10 years' exposure for closer study
    (Maugeri, et al., 1966a,b; Maugeri et al., 1971; Taccola et al.,
    1971). Of these, 28 were invalids due to carbon disulfide poisoning.
    Organic changes in blood vessels were discovered, mostly in the
    invalids, by means of cerebral rheography. The results obtained
    suggested progression of such changes even after the termination of
    exposure. Using peripheral rheography, plethysmography, and
    oscillography, the authors established functional vasoconstriction in
    the arteries of the upper and lower extremities. Organic alterations
    of the sclerotic type were rare and mainly appeared after prolonged
    exposure and in the lower extremities.

         During the last 10 years or so, it has become increasingly
    evident that long-standing exposure to carbon disulfide promotes
    coronary heart disease, even under circumstances where clinical
    poisoning is uncommon. Of the several attempts made to connect carbon
    disulfide exposure with coronary heart disease, only a few have
    complied with necessary methodological requirements. The first such

    investigation was a careful mortality study in Britain published by
    Tiller et al. (1968). They found a 2.5-fold excess mortality in
    viscose rayon workers exposed to carbon disulfide for 10 years or
    more, compared with that of other workers. The same study demonstrated
    that, in the 3 plants studied, coronary mortality was proportionally
    higher among workers engaged in the viscose spinning process than in
    other workers, men living in the locality, and the national statistics
    derived from the Registrar General's tables. Similar results have been
    obtained from Norway, where a 3-fold excess mortality from coronary
    heart disease was found among workers, aged 35-54 years, compared with
    unexposed workers in other departments (Mowé, 1971).

         A prospective study that was initiated in 1967 in Finland, showed
    that the 5-year mortality in a cohort of 343 male viscose rayon
    workers exposed to about 30-95 mg/m3 (10-30 ppm) was almost 5-fold
    (14 deaths compared with 3) that of an unexposed comparison cohort
    from a nearby paper mill. Other causes of death were evenly
    distributed (Hernberg et al., 1970, 1973). The incidence of nonfatal
    first myocardial infarctions was almost 3 times that in the comparison
    cohort (11 compared with 4) (Tolonen et al., 1975). In a continuation
    of the follow-up extending to 8 years, the cumulative incidence rate
    for mortality from coronary heart disease was 5.8% in the exposed
    group and 2.6% in the comparison group, giving a rate difference of
    3.2% (Hernberg et al., 1976; Nurminen, 1976). Between the sixth and
    ninth years of follow-up, no further excessive mortality was observed,
    probably because most (81%) of the originally exposed workers were no
    longer exposed to carbon disulfide and also overall concentrations of
    carbon disulfide had decreased to less than 30 mg/m3 (10 ppm). This
    positive trend was promising with regard to coronary heart disease:
    the prognosis of exposed workers improved with improved occupational
    hygienic measures and with a reduction in the length of exposure over
    a lifetime.

         Anamnestic angina was more prevalent both in 1967-68, and at
    re-examination in 1972, whereas there were no great differences in
    coronary electrocardiographic findings (Hemberg et al., 1970; Tolonen
    et al., 1975) as coded by the "Minnesota Code" (Blackburn et al.,
    1960). These results showed that the greatest effect of carbon
    disulfide on coronary arteries was on the production of fatal
    infarctions (relative risk 4.8) followed in reducing order by all
    infarctions, fatal and nonfatal (relative risk 3.7), nonfatal
    infarctions (relative risk 2.8), angina (relative risk 2.2), and
    coronary ECGs (relative risk 1.4). In other words, the more serious
    the outcome, the greater the relative risk. The interpretations may be
    that exposure to carbon disulfide not only worsens the prognosis of
    existing coronary heart disease but increases the incidence of new
    cases. However, it is not certain that this mode of action operates in
    countries where coronary heart disease is less common than in Finland.

    Coronary heart disease has a multifactorial etiology, and the pattern
    described above may be noticeable only when a sufficient number of
    other coronary risk factors are present at the same time. In fact,
    some other studies have shown a more distinct excess of coronary ECGs
    (Goto & Hotta, 1967; Cirla et al., 1972). It is possible that both
    dose-dependent, methodological, and even geographical factors may be
    responsible for the discrepancies reported so far. For example, it may
    be that the pattern of excess coronary heart disease differs in
    different populations, depending on the concomitant prevalence of
    other coronary risk factors such as elevated blood lipids and
    hypertension.

         A joint analysis of the prevalence of angina pectoris, exercise
    ECGs, and blood pressure measurements in Finnish and Japanese workers
    exposed to carbon disulfide and in 2 unexposed control groups
    supported this view (Tolonen et al., 1976). Angina was rare and
    evidence of past infarction nonexistent in both exposed and unexposed
    Japanese men; in the Finnish exposed and unexposed groups the
    prevalence of angina was 15 and 10%, respectively. The prevalence of
    coronary ECGs was almost equal among the exposed and unexposed men in
    both the Japanese and the Finnish groups. Angina plus coronary ECGs as
    evidence for coronary heart disease occurred with a prevalence of nil
    for both exposed and unexposed Japanese, and 5 and 2% for the exposed
    and unexposed Finnish groups, respectively. The study did not yield
    any evidence of an excess in any of the variables examined among the
    exposed Japanese workers. However, a follow-up study of this group is
    necessary to shed more light on the possibility of excess morbidity
    and mortality from coronary heart disease. Vertin (1977) did not find
    any significant differences in coronary heart diseases, ECG changes,
    serum cholesterol concentrations, and arterial pressure in workers
    exposed to carbon disulfide concentrations of about 30-95 mg/m3
    (10-30 ppm) compared with a control group.

         Carbon disulfide vasculopathy may be due to the combined action
    of several biochemical and physiological disturbances, namely:

          (a) changes in lipid metabolism (section 6.3.9);

          (b) disturbances in the coagulation mechanism (section 6.3.14);

          (c) elevation of blood pressure (Hemberg et al., 1970; Sakurai,
    1972; Tolonen et al., 1975);

          (d) subclinical hypothyroidism (Cavalleri et al., 1971);

          (e) a toxic effect on the myocardium, either direct or through
    interference with the catecholamine metabolism (Magos, 1972).

         However, much work remains to elucidate the mechanism of carbon
    disulfide-induced atherosclerosis. In particular, coronary heart
    disease has a multicausal origin and is closely related to the
    saturated fat intake of the population. Furthermore, its incidence is
    influenced by a large number of other risk factors, such as smoking,
    diabetes, and physical inactivity. A combination of 2 or more risk
    factors greatly increases the incidence. Thus, it may be postulated
    that carbon disulfide will only become evident as a coronary risk
    factor in the presence of other risk factors.

    6.3.12  Carcinogenicity and mutagenicity

         No reports are available that indicate any carcinogenic or
    mutagenic effects of carbon disulfide.

    6.3.13  Teratogenic effects

         Only a weak teratogenic effect appeared in rats following
    low-level exposure to a combination of hydrogen sulfide and carbon
    disulfide (Bariljak et al., 1975).

         A marked impairment (increase in early embreonal mortality,
    reduction in fetal weight, malformations in the brain and limbs,
    behavioural deviation) in the prenatal development of 2 successive
    generations was produced in rats exposed to carbon disulfide
    concentrations of 100 and 200 mg/m3 throughout the period of
    gestation (Tabacova et al, 1977).

    6.3.14  Other effects

         The literature is contradictory concerning the effects of carbon
    disulfide on blood coagulation. Saita & Gattoni (1957) found a slight
    decrease in factor VII and prothrombin in exposed workers. On the
    other hand, Moreo & Candura (1960) and De Nicola et al. (1962)
    reported hypercoagulability in the blood of experimental animals, a
    finding that was later confirmed in studies of exposed workers by
    Candura et al. (1962), Saita et al. (1964), and Danilova (1968). An
    increase in fibrinolysis was found by De Nicola et al. (1962) in
    animals suffering from acute poisoning. In contrast, Candura et al.
    (1962) found decreased fibrinolysis in workers exposed to carbon
    disulfide.

         The coagulation mechanism in highly-exposed young workers in a
    viscose factory was studied by Visconti et al. (1966a,b,c, 1967). They
    found protracted coagulation, retarded production of active
    thrombotastin, decreases in plasminogen and in the activity of
    plasmin, and a decrease in antiheparinic activity in workers exposed
    for up to 9 years. These disturbances were most pronounced during the
    first years of exposure.

         Visconti et al. (1966a) supposed that carbon disulfide could
    affect blood coagulation either directly by interfering with the
    system itself, or indirectly, by liver injury. Different routes of
    entry, differences in the level and duration of exposure and in the
    distribution of carbon disulfide in the organism, and also
    interspecies differences are probably responsible for the confusing
    results.

         It has been reported that the glucose metabolism is disturbed by
    carbon disulfide both in experimental animals (rabbits) (Hara, 1958)
    and in exposed workers (Goto et al., 1971). There are also a few
    clinical studies reporting an increased occurrence of diabetes in
    patients suffering from severe carbon disulfide poisoning (Austoni &
    d'Agnolo, 1957; Finulli & Ghislandi, 1959; Ferrero, 1969). Lack of
    proper control groups renders the interpretation of these results
    difficult.

    6.3.15  Interactions with other chemical compounds

         The combined effects of carbon disulfide with other chemical
    compounds were first reported by Lazarev et al. (1965) who indicated
    that repeated exposure to a concentration of carbon disulfide of
    3900 mg/m3, for 2 h per day, over a period of 20-30 days considerably
    prolonged both the hexobarbital sleeping time and alcohol retention
    time in rats and mice (see also section 6.3.6).

         Carbon disulfide caused reversible inhibition of the oxidative
    drug metabolism in rat liver endoplasmic reticulum (Bond et al., 1969;
    Freundt & Dreher, 1969; Freundt & Kuttner, 1969; Freundt & Henschler,
    1971; Freundt, 1973; Sokal, 1973; Freundt et al., 1974b, 1975, 1976).
    This effect was also produced in man after exposure to a carbon
    disulfide concentration of about 30 mg/m3 (10 ppm) over a 6-h period
    (Mack et al., 1974); the treatment led to a rapidly reversible but
    significant decrease in the oxidative  N-demethylation of the
    analgesic, aminopyrine.

         Simultaneous exposure to carbon disulfide and ethanol resulted in
    an increase in blood acetaldehyde in rats and man that was considered
    to be a consequence of the inhibition of aldehyde dehydrogenase by
    carbon disulfide (Freundt & Netz, 1973; Freundt & Lieberwirth, 1974;
    Freundt, 1974; Freundt et al., 1976). In 12 healthy male volunteers, a
    50% increase in blood acetaldehyde was noted following exposure to a
    carbon disulfide concentration of about 60 mg/m3 (20 ppm) for 8 h
    with simultaneous ingestion of ethanol in orange juice at a
    concentration that maintained the blood ethanol level at about 0.8%.
    However, no signs of an "antabuse syndrome" were observed under these
    experimental conditions (Freundt et al., 1976).

    6.4  Diagnosis

         Since all isolated effects are nonspecific, individual diagnosis
    becomes a matter of probability based on:  (a) the ascertainment of
    exposure;  (b) the demonstration of signs and symptoms of poisoning
    and the combination in which they occur; and  (c) the exclusion of
    other diseases.

         The changes due to carbon disulfide exposure described in
    sections 6.2-6.3.15 affect so many different organ-systems that, in
    considering the etiology of a single case, the probability of it being
    caused by carbon disulfide increases in proportion to the number of
    these signs and symptoms present. Although, in 1941, Lewey drew
    attention to the importance of the concomitant occurrence of different
    neuropsychiatric and vascular effects, as well as to their connection
    with the severity of the disease, there have been few, if any, studies
    systematically analysing the knowledge that has emerged since then.
    For this reason it is difficult to find quantitative data. However,
    carbon disulfide poisoning should always be suspected when a viscose
    worker presents with subjective, neurasthenic symptoms, signs of
    peripheral neuropathy, psychological disturbances, and vascular
    changes in the cerebral, coronary, renal, or peripheral systems. When
    exposure to toxic levels of carbon disulfide occurs, the following
    chronological effects can usually be expected: the appearance of
    neurasthenic symptoms accompanied by psychological behavioural
    changes; signs of peripheral nervous system involvement as shown by
    electromyographic changes, initially mainly in the afferent fibres but
    later in the motor fibres; simultaneous disturbances in the central
    nervous system may appear but may be more difficult to detect
    objectively than the lesions of the peripheral nervous system. Another
    early finding is a decrease in the level of serum thyroxine that is
    probably due to damage of the hypothalamic-hypophyseal axis (section
    6.3.9). Cardiovascular damage appears after longer periods of
    exposure. The appearance and severity of the above-mentioned signs and
    symptoms are related to the level of the uptake and to the duration of
    exposure to carbon disulfide. The changes are also dependent on the
    individual constitution and health status of exposed workers.

         In the differential diagnosis of true cases, atherosclerosis due
    to other causes should be considered including, postencephalitic or
    atherosclerotic Parkinsonism, brain tumours, syphilis, multiple
    sclerosis, and psychiatric diseases of other origins such as endogenic
    depression, schizophrenia, and alcoholism. Peripheral polyneuropathy
    should be distinguished from that due to alcoholism, diabetes, and
    other toxic agents.

         The subclinical stage is, by definition, more difficult to
    identify. First, the presence of pathological symptoms and signs must
    be established, which requires sensitive techniques. Second, the
    causal connection between an established symptom or sign and carbon

    disulfide exposure should be shown. Both aspects pose great
    difficulties because of the nonspecificity of the manifestations and
    their vagueness in the initial stages. So far, the only attempt to
    approach this problem in a systematic way has been made by Tolonen
    (1974).

         He studied 97 men exposed to carbon disulfide in a viscose
    factory and 96 controls of the same age from a paper mill. The mean
    age was 48 years (range 33-67 years), and the mean exposure time was
    15 years (range 1-27 years). The intensity of background exposure
    ranged from about 60 to 125 mg/m3 (20 to 40 ppm) in the 1950s and
    then from about 30-95 mg/m3 (10-30 ppm). Personal exposure data were
    not available. The group comprised both completely "healthy" workers
    as well as some partly incapacitated patients with past poisoning.
    About half of the men were still exposed to carbon disulfide, the rest
    being employed in "clean" departments. The groups underwent many
    examinations including:  (a) examination of the heart (positive =
    history of verified myocardial infarction, and/or "Minnesota Codes"
    I1-3, IV1-3, V 1-3, VIII3, VIII3 , XI1-3-5-7, and/or typical angina):
     (b) psychological testing (section 6.3.10.1);  (c) measurement of
    the conduction velocities of 8 peripheral nerves (polyneuropathy was
    considered to exist when 2 or more nerves showed reduced conduction
    velocities) and  (d) examination of the circulation of the ocular
    fundus (the criterion for disturbed circulation was delayed
    peripapillary filling -- circumferential, segmental, or both). The
    occurrence of isolated and combined signs is shown in Table 2.

         As many as 59% of the exposed and 29% of the unexposed men were
    affected by more than one disorder under study but most combinations
    of disorders occurred more frequently in the exposed group; a
    combination of 3 abnormalities was 3 times more common in the exposed
    group than in the controls and a combination of all 4 abnormalities
    occurred only in the exposed group. Only 5% of the exposed subjects
    compared with 31% of the controls were without any abnormalities.
    Since disturbances in the choroidal circulation were present in all
    cases of excess "morbidity" (68% of the exposed, Raitta et al., 1974),
    it seems that this abnormality represents the earliest manifestation
    of carbon disulfide toxicity, at least, of those considered here.

         Thus, it can be postulated that a positive diagnosis of carbon
    disulfide poisoning can only be made if changes in the choroidal
    circulation have been observed and providing that exposure has
    extended over 10 years or more, with an intensity of the magnitude of
    about 30-90 mg/m3 (10-30 ppm). The estimated probability that a
    combination of findings is of occupational origin is the excess
    morbidity over total morbidity. The results also showed that the
    etiological role of carbon disulfide could be demonstrated with
    greater probability, the greater the number of abnormalities present
    at the same time.

         The necessity to ascertain exposure is so obvious that it should
    not need to be mentioned. It should be stressed that recent experience
    has shown the importance of evaluating personal, as opposed to
    background exposure, since the former may be only weakly correlated
    with the latter. Personal exposure can be measured using personal
    samplers, or by the iodine-azide test. The latter has been claimed to
    discriminate particularly sensitive workers (whose test does not
    return to normal after 16 h away from exposure) (Graovac-Leposavic et
    al., 1967).

        Table 2.  Prevalence (%) of coronary heart disease (CHD), delayed
              peripapillary circulation (EYE), polyneuropathy (PN) and
              behavioural symptoms (BS), their combinations in subjects
              in the exposed and control groups, and the differences
              between the groups.a

                                                                        
                          Exposed     Group       Difference =
                          (N = 97)    control     excess morbidity
                                      (N = 96)
                                                                        

    Free of disease           5          31
    CHD only                  4           9             -5
    EYE only                 19          19              0
    PN only                   6           6              0
    BS only                   7           6              1

    CHD + EYE                 4           4              0
    CHD + PN                  1           1              0
    CHD + BS                  1           2             -1
    EYE + PN                 12           5              7
    EYE + BS                  7           4              3
    PN + BS                   4           5             -1

    CHD + EYE + PN            9           0              9
    EYE + PN + BS            11           5              6
    CHD + PN + BS             2           1              1
    CHD + EYE + BS            2           2              0

    CHD + EYE + PN + PS       6           0              6
                                                                        
    Total                   100         100             26
                                                                        

    a  From: Tolonen (1974).

    
    6.5  Surveillance of the Health of Exposed Workers

         Considering the early manifestations of chronic carbon disulfide
    effects and the factors that may influence the appearance and the
    severity of such effects (section 6.4), the following examinations are
    recommended for health surveillance:

          (a) Clinical neurological investigation;

          (b) Electroneuromyographic (ENMG) examination wherever possible
    (especially the conduction velocity test, which should be carried out
    on several nerves);

    Additional tests that may give valuable information include:

          (a) Psychological and behavioural testing with a narrow battery
    of well validated tests;

          (b) Serum thyroxine measurement repeated at least once a year;

          (c) Blood pressure measurements;

          (d) Electrocardiography (preferably an exercise ECG);

          (e) Fundus photography (in some countries);

          (f) Blood lipid pattern estimation, if the exposure level is
    high;

          (g) Electroencephalography (EEG), if there are special
    indications;

         These tests should be performed at the pre-employment examination
    and subsequently at regular intervals to detect early deviation from
    baseline values. Changes observed in the same individual over a period
    of time may suggest a relationship with carbon disulfide uptake.

         Depending on the intensity of exposure, the iodine-azide test
    should be carried out from 2-12 times a year, both immediately after
    the work shift and the next morning. Those with positive tests should
    be seen by the plant physician, since a pathological test in the
    morning is a warning of incipient poisoning (Graovac-Leposavic et al.,
    1967). In addition to this, medical examinations should be made once
    or twice a year. They should comprise a thorough history and a
    neurological examination.

         When suspect signs of early carbon disulfide effects appear, the
    worker should be removed from exposure to a "clean" job. In the light
    of the new findings concerning coronary heart disease, the removal of
    workers who develop coronary risk factors, such as hypertension,
    hypercholesterolaemia, and ECG changes may be indicated, irrespective
    of their etiology. In some plants, there is the practice of regular
    periods of work in a clean atmosphere, e.g., every sixth month, or of
    extra vacations in the winter.

         Some authors believe in the importance of the diet of exposed
    workers. However, the protective effect of various diets and
    supplements for man remains unclear. Scheel (1965) claimed that
    addition of zinc and copper salts to the diet of exposed rats had a
    protective effect against carbon disulfide exposures. A diet poor in
    proteins, especially amino acids containing sulfur, but enriched in
    vitamin B6 and glutaminic acid was suggested by Agronovskij &
    Goloscapov (1972). Lukas (1973) established that rats on an "optimal"
    diet were more resistant to the effects of carbon disulfide than rats
    on a normal diet. In the first group, the signs of intoxication
    appeared after a longer time and the effects were less marked than in
    the second group.

         At the present time, the only recommendation that can be given in
    the case of man is that workers should be provided with a diet
    containing sufficient amounts of energy foods to provide the required
    joules, proteins, vitamins, and trace elements. This recommendation is
    of particular importance in countries where such dietary requirements
    are not necessarily fulfilled normally. However, basing the preventive
    programme mainly on diets or drugs should be condemned, since the
    fundamental question is that of technical improvements.

    6.6  Contraindications for Exposure to Carbon Disulfide

         An inborn error of metabolism manifesting itself as an abnormal
    iodine-azide reaction in subjects working under conditions of high or
    moderate carbon disulfide exposure (less than, 50 mg/m3) should be
    considered an absolute contraindication for exposure.

         Other contraindications for working in an environment containing
    carbon disulfide include those common to all other toxic exposures
    such as youth (below 18 years), pregnancy, concomitant chronic disease
    such as psychiatric neurological, cardiac, renal, and pulmonary
    diseases, and any condition that prevents the use of respirators, etc.

         In addition, contraindications based on the specific toxicity of
    carbon disulfide include diseases of the metabolic system, such as
    liver disease and endocrine disorders. Any neurological or psychiatric
    disorder is also a contraindication, including vegetative dystony and

    psychic lability. A history of gastritis and peptic ulcer is a
    relative contraindication, depending, for instance, on whether or not
    there will be shift work and on the intensity of exposure. Recently,
    attention has been focused on to what extent the presence of coronary
    risk factors should be regarded as a contraindication; no strict
    recommendations can be given, but as a general rule the presence of
    several of these in an individual, or alternatively strongly abnormal
    values for one risk factor, should be regarded as contraindications
    (the strongest coronary risk factors apart from age itself are
    elevated serum cholesterol or triglycerides, heavy cigarette smoking,
    hypertension, and diabetes). In the evaluation of these and other
    contraindications, the exposure intensity and hygienic conditions
    should, of course, be taken into consideration.

         The employment of women in work places with carbon disulfide
    exposure is a special problem.

         Considering the studies referred to in section 6.3.9, it is
    advisable to exclude pregnant women from carbon disulfide exposure.
    The same is true for lactating women and for those with expressed
    disturbances of menstruation and habitual abortion.

    7.  EXPOSURE-EFFECT AND EXPOSURE-RESPONSE RELATIONSHIPS

    7.1  Validity of Exposure Data

         In general, valid exposure data are available only from
    experimental studies on animals. Almost all epidemiological studies
    have failed to document the exposure levels pertinent to the effects
    studied. There is a universal lack of retrospective exposure data that
    usually renders the assessment of the relationship between chronic
    effects and the exposure levels responsible for their occurrence
    impracticable. Furthermore, even when exposure data are available,
    they often consist of occasional short-time measurements from fixed
    sites that are not necessarily representative of the workers'
    exposure. It is, therefore, extremely difficult, if not impossible, to
    establish exposure-effect or exposure-response curves for carbon
    disulfide, based on epidemiological evidence. Even the relation of
    isolated findings reported in the literature, to given exposure levels
    is difficult. Thus, the attempts in this document, to relate the
    intensity of exposure to the intensity and frequency of effects must
    be regarded with caution.

    7.2  Experimental Data

    7.2.1  Acute animal exposure

         Acute exposure to carbon disulfide in animal experiments by
    inhalation or by intramuscular or intraperitoneal injection has
    provided information regarding the mechanism of carbon disulfide
    toxicity, but it is difficult to apply this information to the
    industrial exposure of man.

    7.2.2  Long-term animal exposure

         Several experiments on the inhalation of carbon disulfide have
    been performed on different types of animals. In most of these
    studies, exposure was to carbon disulfide only, but in a few, a
    combination of carbon disulfide and hydrogen sulfide was used.

         The concentrations of carbon disulfide ranged from
    0.1-2330 mg/m3 and those of hydrogen sulfide, from 0.1-140 mg/m3;
    the exposure periods ranged from 30 min per day to 6 h per day for up
    to 15 months.

         The reactions to such exposures included increased mortality,
    teratogenic changes, testicular lesions, aspermatogenesis, engorged
    blood vessels, weakness, paralysis, lethargy, weight changes,
    metabolic changes, behavioural changes; sometimes there were no

    observed effects. Some of the effects resembled lesions found in
    exposed workers; others did not bear any relationship to those arising
    from human exposure (Wakatsuki & Higashikawa, 1959; Goldberg et al.,
    1964; Minden et al., 1967; Yaroslavski, 1969; Frantik, 1970; Gondzik,
    1971; Misiakiewicz et al., 1972; Szendzikowski et al., 1973; Bariljak
    et al., 1975; Seppäläinen & Linnoila, 1976; Tabacova et al, 1977). The
    considerable differences in ranges of concentrations and periods of
    exposure used in these experiments make conclusions regarding
    exposure-effect and exposure-response curves impossible. This
    regrettable situation emphasizes the need for international
    coordination of toxicological experiments to make comprehensive
    scientific evaluation possible.

    7.3  Epidemiological Data

         All studies so far reported have been from the viscose rayon
    industry, where exposure to carbon disulfide occurs together with
    exposure to hydrogen sulfide. However, generally, the levels of carbon
    disulfide are at least one order of magnitude higher than those of
    hydrogen sulfide, and most authors have attributed the health effects
    found to carbon disulfide rather than to hydrogen sulfide exposure.

         Only some of the various effects reviewed in section 6 can be
    related to exposure levels. The following section contains a brief
    review of exposure-effect and exposure-response data for neurological,
    cardiovascular, ocular, and gonadal effects.

    7.3.1  Neurological and behavioural effects

         Severe acute neurological effects such as psychosis and paralysis
    occur when exposure exceeds 1500-3000 mg/m3 (500-1000 ppm) (Vigliani,
    1954). Chronic encephalopathy may develop with long-standing exposure
    to 150 mg/m3 (50 ppm) or more (Vigliani, 1954). More subtle
    neurological changes, detectable by neurophysiological examination or
    psychological testing, have been reported at lower concentrations. For
    example, slowing of nerve conduction velocities and prolonged distal
    latencies of several nerves have been found among viscose rayon
    workers with a median exposure time of 15 years to combined
    concentrations of carbon disulfide and hydrogen sulfide of
    60-190 mg/m3 (20-60 ppm) in the 1950s, 30-95 mg/m3 (10-30 ppm) in
    the 1960s, and mainly below 60 mg/m3 (20 ppm) during the years
    preceding the examination (Seppäläinen & Tolonen, 1974). The same
    workers were also studied for psychological performance (Tolonen,
    1974). The most distinct difference compared with a control group was
    found in the retardation of psychomotor speed. As a whole, "poor"
    performance, as defined by Tolonen (1974), occurred 1.6 times more
    frequently among the exposed workers. These results suggest that

    concentrations around 60-90 mg/m3 (20-30 ppm) can produce
    psychological disturbances. In an indirect way, Tuttle et al.a
    corroborated this view by being able to relate behavioural test scores
    to other indices of neurological health, thought to occur under
    similar exposure conditions, but because no exposure data were
    available, their findings are not directly applicable in the
    exposure-effect sense.

         According to Martynova et al. (1976), an excess of functional
    nervous disorders was found among 108 workers exposed to carbon
    disulfide concentrations about 8-11 mg/m3 (maximum approximately
    20-25 mg/m3), for 10-15 years, compared with 390 control subjects.
    For example, sensory polyneuritis was much more frequent and the
    threshold for pain was significantly higher in the exposed group.

         These studies indicate that background concentrations below about
    60 mg/m3 (20 ppm) may cause neurological dysfunction.

    7.3.2  Cardiovascular effects

         Severe vascular effects manifesting themselves as
    vasculoencephalopathy and renal atherosclerosis developed with
    long-term exposure to carbon disulfide concentrations exceeding
    150-300 mg/m3 (50-100 ppm) (Vigliani, 1954; Nofer et al., 1961).
    Excess incidence of coronary heart disease has been reported with
    longstanding exposure to concentrations averaging 30-125 mg/m3
    (10-40 ppm) (Hernberg et al., 1970, 1973, Tolonen et al., 1975). The
    mortality rate from coronary heart disease appeared to be most
    affected while the incidence of milder manifestations such as angina
    and ECG-changes was less influenced. In fact, most studies, published
    so far, have failed to reveal any difference in the prevalence of
    ECG-findings between exposed and unexposed workers (Tolonen et al.,
    1976).

         Quite recently, Vertin (1977) reported no difference between the
    incidence of coronary heart disease found in control subjects and that
    in workers exposed to about 30-95 mg/m3 (10-30 ppm) suggesting a
    no-observed effect level for coronary heart disease in this range.
    This finding does not necessarily contradict those referred to above;
    possibly, the true exposure levels responsible for the excess coronary
    heart disease in the Finnish studies were higher than those in
    Vertin's study. It is probable that, in general, differences in actual
    personal exposure levels in the studies-not necessarily those levels
    measured and reported -- account for seeming discrepancies in results
    and that exposure data are inadequate in most published studies.


                 

    a Tuttle et al., 1976. Unpublished report. (See footnote to section
      6.3.10.1.)

         Differences in blood pressure have been reported by Hernberg et
    al. (1970) and Tolonen et al. (1975) between workers exposed to a
    carbon disulfide concentration of about 60 mg/m3 (20 ppm) and
    unexposed subjects, and by Martynova et al. (1976) in workers exposed
    for 10-15 years to concentrations of about 10 mg/m3. These findings
    indicate that effects upon the vascular system begin at low exposure
    levels.

    7.3.3  Ophthalmological effects

         Among Japanese workers, the occurrence of retinal microaneurysms
    was related to the duration of exposure (Sugimoto et al., 1976). The
    exposure levels in earlier Japanese studies were not reported; in
    present studies they are probably of the order of 60 mg/m3 (20 ppm).
    The findings of retinal microaneurysms appears to be confined to
    Japanese workers, since, according to a recent joint study, no such
    effect could be demonstrated in Finns (Sugimoto et al., 1977). In
    contrast, Finnish workers showed delayed peripapillary filling and
    wider calibre of retinal arteries compared with control subjects
    (Raitta et al., 1974). Exposure conditions under which these changes
    occurred are described in section 6.3.2 and indicate that haemodynamic
    changes in the ocular circulation are induced as early as coronary
    effects.

    7.3.4  Gonadal effects

         The results of Vasiljeva (1973), Petrov (1969), and Finkova et
    al. (1973) suggest that carbon disulfide concentrations below
    10 mg/m3 (3 ppm) may cause disturbances in the ovarian function of
    young females, resulting in menstrual disorders, pregnancy
    complications, and spontaneous abortions. Given that the exposure
    measurements reported are comparable with those of other studies, it
    would seem that these would be the earliest detectable type of effects
    in human beings.

         A summary of the most relevant exposure-effect and exposure-
    response findings is given in Table 3.

        Table 3.  Some exposure-effect and exposure-response relationships
              for long-term exposure of man to carbon disulfide.
                                                                                             

    Concentration  Exposure  Symptoms & signs                        Reference
    (mg/m3)        time
                   (years)
                                                                                             

    10             5-10      Blood progesterone depressed,           Vasiljeva (1973)
                             estriol increased, irregular
                             menstruation;
    10             10-15     Sensory polyneuritis, increased         Martynova et al. (1976)
                             pain threshold;
    30             >3        Spontaneous abortions twice as          Petroy (1969)
                             common and premature births 3
                             times as common as in controls;
    30-120         >10       Coronary mortality about 5 times        Tolonen et al. (1975)
                             that in controls, life expectancy       Hernberg et al. (1973)
                             decreased 0.9-2.1 years depending       Nurminen (1976)
                             on age; nonfatal infarctions 2.6        Hernberg et al. (1970)
                             times more frequent than in controls;
                             angina pectoris about twice as
                             prevalent as in controls; slightly
                             higher systolic and diastolic blood
                             pressure than in controls;
    30-120         >6        Peripheral nervous and CNS              Seppäläinen & Tolonen
                             dysfunction, conduction velocities      (1974); Tolonen (1974)
                             slowed, psychological changes;
    100-140        2-12      Decrease of testosterone and            Cavalleri et al. (1970)
                             gonadotrophin LH in urine;
    200-500        1-9       Ophthalmic pressure 18.4/14.7           Maugeri et al. (1966,
                             vs 15.3/11.6 kPa (138/110 vs            1967)
                             115/87 mmHg) in controls;
    500-2500       0.5       Polyneuritis, myopathy acute            Vigliani (1946)
                             psychoses
                                                                                             

    
    8.  CONTROL OF EXPOSURE IN THE VISCOSE INDUSTRY

         Technical and administrative measures for the protection of the
    health of workers exposed to carbon disulfide in the production of
    viscose rayon include:

         -- exchange of production methods (substitution or elimination);

         -- enclosure and local exhaust ventilation of the technological
    process;

         -- dilution (general) ventilation of the work room;

         -- isolated and well-ventilated rooms for process control
    operators and for rest periods;

         -- use of personal respiratory protective equipment under certain
    hazardous circumstances and,

         -- rotation of workers periodically to areas free from carbon
    disulfide exposure.

         New developments such as the SINI viscose process make it
    possible to reduce the total consumption of carbon disulfide to 70-80%
    of that used in conventional processes (Sihtola, 1976). Occupational
    health aspects must be taken into consideration at the planning stage
    in the construction of new plants.

         Enclosure of processes and machines is the second most effective
    means of technical prevention. This technique should be applied in the
    sulfidizing process and for spinning and washing machines. Possible
    leakages in closed systems should be controlled by gas detectors. The
    air removed from the processes by the exhaust ventilation should be
    transported to a recovery system. The benefits of such a system are
    both economic, since the plant has an interest in the recovery of
    useful material, and hygienic, as the possibility of the pollution of
    both the working rooms and the environment around the factory is
    reduced. The air removed by exhaust ventilation is compensated with
    pure air, which is brought to working sites by ventilation systems.

         It is not possible to protect the workers in all situations by
    ventilation systems alone. In certain circumstances, the workers may
    be exposed to very high concentrations of carbon disulfide, in which
    case respiratory protective devices must be used. The type of
    respirator may vary from a chemical cartridge (organic vapour)
    respirator, used for low concentrations, to supplied air or
    self-contained breathing devices for very high concentrations. It is
    also important to provide special isolated rooms with a slightly
    positive pressure, compared with the work area contaminated with
    carbon disulfide, for process control workers and for rest pauses.

         Another factor of concern in the control of exposure and uptake
    of carbon disulfide involves skin absorption resulting from direct
    contact with the liquid. Where workers may come into contact with
    liquid carbon disulfide, appropriate protective clothing, such as
    synthetic rubber gloves and goggles or face shields, should be worn.

         If carbon disulfide is spilled, potential sources of ignition
    should be eliminated immediately, spark-proof ventilation provided,
    and the spill cleaned up. A small spill should generally be allowed to
    evaporate under conditions of good air circulation. However, large
    spills should be covered with water and flushed into a retention basin
    under a water layer. Carbon disulfide should not be drained into a
    sewer system because of the possibility of an explosion.

         In addition to these control methods, data obtained through the
    biological monitoring of exposed workers can be used to determine
    excessive uptake situations that require additional control measures.
    The procedure for biological monitoring is discussed in section 6.5.

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    Annex I

    PRODUCTION OF VISCOSE AND ITS END-PRODUCTS

         The technological process of viscose rayon production, which is
    schematically presented in Annex I Fig. 1, can briefly be described in
    the following way:

          (a) Cellulose pulp arrives at the factory in the form of sheets
    which are placed in a hydraulic press or pulverized and steeped in a
    solution of caustic soda to form alkali cellulose;

          (b) the alkali cellulose is shredded to form crumbs to
    facilitate aging and xanthation;

          (c) after storage in aging tanks until the right level of
    polymerization has been reached, the crumbs are placed in mechanical
    churns;

          (d) in a separate operation, sulfur is melted and poured onto
    glowing charcoal where it reacts to give carbon disulfide. The liquid
    carbon disulfide is stored in special tanks that are protected against
    flames, static electricity, and heat;

          (e) the liquid carbon disulfide, which is gradually metered
    into the mechanical churns, reacts with the alkali cellulose to form
    orange crumbs consisting of colourless cellulose xanthate and orange
    sodium trithiocarbonate (Na2CS3);

          (f) these crumbs are dissolved in caustic soda solution to give
    a viscose solution;

          (g) the viscose is stored in aging tanks, filtered, de-aerated,
    and then pumped into the spinning tanks where it is forced through
    spinnerets that are submerged in a solution of sulfuric acid (H2SO4)
    and sodium and zinc sulfates (Na2SO4-ZnSO4). Filaments are formed
    by coagulation of the viscose when partial decomposition of the
    cellulose xanthate and the trithiocarbonate takes place, according to
    the reactions:

         (1) ROCS + H2SO4-ROH + NaHSO4 + CS2
                SNa

         (2) Na2CS3 + H2SO4 - H2S + CS2 + Na2SO4

         During this process, considerable quantities of carbon disulfide
    and hydrogen sulfide vapours are liberated representing a danger to
    the exposed workers. It is important that reaction (2) should proceed
    much more quickly than reaction (1) during spinning, so that
    practically all the hydrogen sulfide is already formed in the spinning
    bath or immediately over it, and the part of the carbon disulfide that
    is supplied by the xanthate is mainly freed outside the spinning bath
    in the acid yarn and/or in further treatments. The quantities of
    carbon disulfide and hydrogen sulfide vapours that are liberated
    depend on the process and the end-use of the rayon product.

         The following products may be produced from viscose:  rayon
     filament textile yarn used in the textile industry in linings and
    furniture fabrics;  rayon filament tire yarn used as reinforcing
    material in the carcass and belt of tires;  rayon staple fibre
    combined in textile fabrics with natural or synthetic fibres, such as
    cotton or polyester; and  Cellophane film, used for packaging.

         On leaving the spinning bath,  textile rayon yarn may be:

          (a) wound up on acid spools on the spinning machine above the
    spinning bath;

          (b) formed into a cylindrical acid cake in a centrifugal pot
    also incorporated in the spinning machine; or

          (c) continuously transported through the regeneration, washing,
    and drying treatments and then wound up as the finished product.

         During spinning, the spinning machines are more or less
    hermetically sealed. However, during doffing or when filament breaks
    occur, the worker must open the "windows" or covers. At such times,
    hydrogen sulfide and carbon disulfide vapours escape into the air. All
    hydrogen sulfide is formed in the spinning bath or immediately over
    it. Most of the carbon disulfide will be absorbed in the acid spool or
    cake: and either be retained for a long time or be immediately freed
    in a hot acid bath. Consequently, hydrogen sulfide will mainly be
    found in the atmosphere of the machine and the acid baths, whereas
    carbon disulfide also occurs in the departments where the acid spools
    and cakes undergo further treatment (storage room, washing and drying
    departments). In spool spinning, the worker has to lean over the
    spinning bath to perform the doting and spinning-in operations. In
    cake spinning, doffing takes place either at the front of the machine,
    under conditions that are roughly the same as for spool spinning, or
    at the rear of the machine, where the worker is not forced to breathe
    in the machine atmosphere.

    FIGURE 5

         Approximately 50% of the quantity of carbon disulfide that was
    originally added is present in the spool and is recovered by steaming.
    The cake contains less carbon disulfide because the centrifugal,
    motion of the pot removes a certain amount.

          Tire yarn is mostly spun in glass tubes, where the viscose is
    in direct contact with the spinning bath. The bath acid drains to the
    sealed spinning tanks via return pipes and the yarn is run through a
    hot acid bath, where the xanthate is largely decomposed. This second
    hot acid bath may either be incorporated in the spinning machine or
    installed outside it. In both cases the concentration of carbon
    disulfide over this bath is high and, when a yarn breaks, the worker
    may be exposed to the vapours.

         After leaving the hot acid bath, the yarn is either  (a) wound
    on large acid spools;  (b) made into cakes in centrifugal pots or
     (c) run through washing and drying sections.

          Staple fibre, like textile filament yarn, is mostly spun in an
    open bath. However, hydrogen sulfide and carbon disulfide
    concentrations are much higher, because of the large amounts of
    viscose used per unit time and per spinning position. The thick tow is
    treated in a separate sealed hot-acid bath (as in tire yarn spinning)
    for further regeneration and large amounts of carbon disulfide are
    freed in the process. After this stage, the cable is cut and more
    carbon disulfide is emitted. The staple fibre is then washed and dried
    continuously and carbon disulfide emissions are much lower.

          Cellophane casting takes place on a continuous machine. The
    sheet is cast in an open casting bath, like the spinning bath in
    textile filament spinning. The Cellophane sheet then passes through a
    number of baths in which decomposition, washing, bleaching, and drying
    take place. In Cellophane casting, large quantities of viscose are
    pressed into relatively small acid and second baths. As a result,
    hydrogen sulfide and carbon disulfide emissions are very high over a
    relatively small surface area.

         The following data and Annex 1 Table 1 give some insight into the
    emissions of hydrogen sulfide and carbon disulfide in the different
    processes:

         For every kg of yarn, staple fibre, or Cellophane, some 10-12 kg
    of viscose is fed into the spinning or casting bath.

         1 kg of viscose will give approximately: 20-30 g CS2
                                                  4-6 g H2S

    (i.e., about 5 times more CS2 than H2S)

    Viscose inputs in the spinning or casting machine per hour per
    position are:

         textile yarn                       0.6-1.0 kg
         tire yarn                           10-12 kg
         staple fibre                        70/100 kg
         Cellophane                        1800-2000 kg

    Total amounts of vapours and gases (in grams) that can be liberated
    per hour per position are:

                                 CS2                       H2S
         textile yarn           20-25                     3-5
         tire yarn             225-250                   40-50
         staple fibre         1000-1500                 200-300
         Cellophane         38 000-42 000             9000-10 000


        Annex 1.  Table 1.  Percentage emissions of carbon disulfide and hydrogen
                        sulfide during the formation of viscose products.

                                                                                   
                    Acid bath   Spinning machine   In the spool, cake,
                    tanks       over first and     tow, or Cellophane
                                second baths       after the baths
                                                                                   

    textile yarn      35               55           10       H2S
                                       25           65       CS2
    tire yarn         15             5-55           15       H2S
                                                    25       CS2
    staple fibre      45               40           15       H2S
                       8            12-45           35       CS2
    Cellophane        15               70           15       H2S
                      25               55           20       CS2
                                                                                   
    
    Annex II

    MAXIMUM PERMISSIBLE CONCENTRATIONS FOR CARBON DISULFIDE IN
    DIFFERENT COUNTRIES

         Chronic manifest poisoning can be prevented in the viscose rayon
    industry by maintaining the carbon disulfide concentrations below
    60 mg/m3 (20 ppm). However, recent studies have shown that
    gynaecological cardiovascular, neurological, and neurophysiological
    effects can still be detected under such conditions (sections 6.3.9,
    6.3.10, 6.3.11, 7.3). It appears that a time-weighted average (TWA) of
    30 mg/m3 (10 ppm) is the lowest level at which most of these effects
    can be found. However, it has been reported in some studies from the
    USSR that gynaecological, cardiovascular, and neurological disorders
    may occur at even lower levels. It seems possible that most toxic
    effects could be prevented by keeping carbon disulfide levels,
    expressed as background TWAs, below 30 mg/m3 (10 ppm). The levels for
    personal exposure may prove to be different but too few data are
    available, at present, to make any definite statements.

         If the effect is severe, as in the case of coronary deaths, it is
    prudent to apply a safety margin for that effect. The need for such a
    safety margin must be considered separately in each, case. Both, the
    new NIOSH recommendation (NIOSH, 1977) and the USSR maximum allowable
    concentration (MAC) value include safety margins. Most other countries
    have not yet considered it necessary or practically feasible to adapt
    safety margins. Table 1 in this annex presents permissible exposure
    levels for a number of countries.

         Based on results of studies on man and animals, the USSR has
    adopted an MAC value of 1 mg/m3. Measurements of carbon disulfide
    concentrations were made during the last 5 years of exposure on
    workers exposed to 10 mg/m3 for 10-15 years. No significant changes
    in the work environment had reportedly occurred during the entire
    exposure period. The workers showed neurological, cardiovascular and
    gynaecological disorders. (Petrov, 1969; Vasiljeva, 1973; Martynova et
    al., 1976). Animals exposed to 100 and 10 mg/m3, respectively, showed
    several adverse effects while only those exposed to 1 mg/m3 were free
    from symptoms.

         The Federal Republic of Germany has adopted a level of 30 mg/m3
    "because at 60 mg/m3 level the liver oxygenesis was inhibited and
    between 30-60 mg/m3 of longstanding exposure, coronary heart
    diseases, hypertension, psychological and neurophysiological
    disturbances can occur" (Freundt, 1975).

         In the USA, NIOSH (1977) has recommended a standard of 3 mg/m3
    (1 ppm) as a 10-h TWA concentration during a 40-h working week. A
    level of 30 mg/m3 (10 ppm) for a 15-minute sampling period is
    recommended to avoid acute toxicity. NIOSH based its choice of levels
    on the probability of excess coronary deaths, and applied a safety
    factor of 10 to the lowest concentration thought to be associated with
    such cardiovascular disorders.

         It should be stressed that the background concentration does not
    reflect personal exposure, which may be considerably higher.
    Therefore, the use of a personal sampler is recommended for the
    assessment of actual uptake of carbon disulfide by individual workers,
    accompanied by the use of the iodine-azide test. As already suggested,
    it may well be that such experience will create a need for expressing
    maximum permissible concentrations in terms of personal exposure
    instead of background exposure.

    Annex II. Table 1  Maximum permissible concentrations in
                       various countries. If not otherwise stated,
                       the figures represent TWAs.

                                                               

    Country                                 ppm         mg/3
                                                               

    Czechoslovakia (1963)                               30
    Egypt (1974)                                        30
    Finland (1972)                                      30
    German Democratic Republic (1971)                   50
    Germany, Federal Republic of (1975)     10          30
    Hungary                                             20
    Japan (1974)                            10          30
    Poland (1976)                                       25
    Sweden (1975)                           10          30
    Switzerland (1971)                      10          30
    United Kingdom                          10          30
    USA (1973)                              20          60
                                            100 (MAC)   300 (MAC)
    USSR (1976)                                           1 (MAC)
    Yugoslavia (1971)                       15           50 (MAC)
                                                               


See Also:
        Carbon disulfide (CHEMINFO)
        Carbon disulfide (ICSC)
        Carbon disulfide (PIM 102)