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.
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.
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).
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).
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 comprisi