TOXICOLOGICAL PROFILE FOR

CARBON DlSULFlDE

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service

Agency for Toxic Substances and Disease Registry

August 1996
CARBON DISULFIDE ii

DISCLAIMER

The use of company or product name(s) is for identification only and does not imply endorsement by

the Agency for Toxic Substances and Disease Registry.
CARBON DISULFIDE iii

UPDATE STATEMENT

A Toxicological Profile for Carbon Disulfide was released in September 1992. This edition supersedes

any previously released draft or final profile.

Toxicological profiles are revised and republished as necessary, but no less than once every three

years. For information regarding the update status of previously released profiles, contact ATSDR at:

Agency for Toxic Substances and Disease Registry

Division of Toxicology/Toxicology Information Branch

1600 Clifton Road NE, E-29

Atlanta, Georgia 30333


vi

*Legislative Background 

The toxicological profiles are developed in response to the Superfund Amendments and

Reauthorization Act (SARA) of 1986 (Public Law 99-499) which amended the Comprehensive

Environmental Response, Compensation, and Liability Act of 1980 (CERCLA or Superfund). This

public law directed ATSDR to prepare toxicological profiles for hazardous substances most commonly

found at facilities on the CERCLA National Priorities List and that pose the most significant potential

threat to human health, as determined by ATSDR and the EPA. The availability of the revised priority

list of 275 hazardous substances was announced in the Federal Register on April 29,1996 (61 FR

18744). For prior versions of the list of substances, see Federal Register notices dated April 17,1987

(52 FR 12866); October 20, 1988 (53 FR 41280); October 26,1989 (54 FR 43619); October 17,1990

(55 FR 42067); October 17, 1991 (56 FR 52166); October 28,1992 (57 FR 48801); and February

28,1994 (59 FR 9486). Section 104(I)(3) of CERCLA, as amended, directs the Administrator of

ATSDR to prepare a toxicological profile for each substance on the list.
CARBON DISULFIDE vii

CONTRIBUTORS

CHEMICAL MANAGER(S)/AUTHOR(S):

Henry Abadin, MSPH

ATSDR, Division of Toxicology, Atlanta, GA

John J. Liccione, Ph.D.

Sciences International, Inc., Alexandria, VA

THE PROFILE HAS UNDERGONE THE FOLLOWING ATSDR INTERNAL REVIEWS:

1. Green Border Review. Green Border review assures the consistency with ATSDR policy.

2. Health Effects Review. The Health Effects Review Committee examines the health effects

chapter of each profile for consistency and accuracy in interpreting health effects and

classifying end points.

3. Minimal Risk Level Review. The Minimal Risk Level Workgroup considers issues relevant to

substance-specific minimal risk levels (MRLs), reviews the health effects database of each

profile, and makes recommendations for derivation of MRLs.

CARBON DISULFIDE ix

PEER REVIEW

A peer review panel was assembled for carbon disulfide. The panel consisted of the following

members:

1. Dr. Henry Peters, Professor of Neurology, University of Wisconsin, Madison, WI

2. Dr. Shane Que Hee, Professor of Environmental Health Sciences, UCLA School of Public

Health, Los Angeles, CA

3. Dr. Robert Rubin, Professor of Toxicology, Environmental Health Sciences, Johns Hopkins

School of Hygiene and Public Health, Baltimore, MD

These experts collectively have knowledge of carbon disulfide’s physical and chemical properties,

toxicokinetics, key health end points, mechanisms of action, human and animal exposure, and

quantification of risk to humans. All reviewers were selected in conformity with the conditions for

peer review specified in Section 104(i)(l3) of the Comprehensive Environmental Response,

Compensation, and Liability Act, as amended.

Scientists from the Agency for Toxic Substances and Disease Registry (ATSDR) have reviewed the

peer reviewers’ comments and determined which comments will be included in the profile. A listing

of the peer reviewers’ comments not incorporated in the profile, with a brief explanation of the

rationale for their exclusion, exists as part of the administrative record for this compound. A list of

databases reviewed and a list of unpublished documents cited are also included in the administrative

record.

The citation of the peer review panel should not be understood to imply its approval of the profile’s

final content. The responsibility for the content of this profile lies with the ATSDR.








CARBON DISULFIDE 1

1. PUBLIC HEALTH STATEMENT

This public health statement tells you about carbon disulfide and the effects of exposure.

The Environmental Protection Agency (EPA) identifies the most serious hazardous waste sites

in the nation. These sites make up the National Priorities List (NPL) and are the sites

targeted for long-term federal cleanup. Carbon disulfide has been found in at least 200 of the

1,430 current or former NPL sites. However, it’s unknown how many NPL sites have been

evaluated for this substance. As more sites are evaluated, the sites with carbon disulfide may

increase. This information is important because exposure to this substance may harm you and

because these sites may be sources of exposure.

When a substance is released from a large area, such as an industrial plant, or from a

container, such as a drum or bottle, it enters the environment. This release does not always

lead to exposure. You can be exposed to a substance only when you come into contact with

it. You may be exposed by breathing, eating, or drinking the substances or by skin contact.

If you are exposed to carbon disulfide, many factors determine whether you’ll be harmed.

These factors include the dose (how much), the duration (how long), and how you come in

contact with it. You must also consider the other chemicals you’re exposed to and your age,

sex, diet, family traits, life-style, and state of health.

1.1 WHAT IS CARBON DISULFIDE?

Pure carbon disulfide is a colorless liquid with a pleasant odor that smells sweet, The impure

carbon disulfide that is usually used in most industrial processes, however, is a yellowish

liquid with an unpleasant odor like that of rotting radishes. Carbon disulfide evaporates at

room temperature, and the vapor is more than twice as heavy as air. Carbon disulfide easily

explodes in air and also catches fire very easily.
CARBON DISULFIDE 2

1. PUBLIC HEALTH STATEMENT

In nature, small amounts of carbon disulfide are found in gases released to the earth’s surface,

for example, in volcanic eruptions or over marshes. Microorganisms in the soil can also

produce gas containing carbon disulfide. Commercial carbon disulfide is made by combining

carbon and sulfur at very high temperatures. Several industries use carbon disulfide as a raw

material to make such things as rayon, cellophane, and carbon tetrachloride. Currently, the

largest user of this chemical is the viscose rayon industry. Carbon disulfide is also used to

dissolve rubber to produce tires and as a raw material to make some pesticides. See

Chapters 3, 4, and 5 for more information on the chemical and physical properties, use, and

environmental fate of carbon disulfide.

1.2 WHAT HAPPENS TO CARBON DlSULFlDE WHEN IT ENTERS THE

ENVIRONMENT?

Carbon disulfide evaporates rapidly when released to the environment. The amount of carbon

disulfide released into the air through natural processes is difficult to judge because it is in

such small amounts in nature. This also makes it hard to monitor carbon disulfide and to

explain how it behaves when it comes into contact with other compounds. Most carbon

disulfide in the air and in surface water is from manufacturing and processing activities.

However, it is found naturally in coastal and ocean waters. Carbon disulfide has also been

found in the groundwater and soil at some EPA research sites around the country, but the

number of research sites that have carbon disulfide is small.

Once released to the environment, carbon disulfide moves quickly to the air. Once in the air,

carbon disulfide stays close to the ground because it is heavier than the surrounding air. It is

estimated that carbon disulfide will break down into simpler components after approximately

12 days. Carbon disulfide moves through soils fairly quickly. Carbon disulfide accidentally

released to soils normally evaporates rapidly. However, since carbon disulfide does not bind

tightly to soils, the amount that does not evaporate can easily move down through the soil

into groundwater. Since it is very mobile, it is not likely to stay in the soil long enough to be

broken down. It does not remain very long in water either because it evaporates within

minutes. However, if dissolved in water, it is relatively stable and is not easily broken down.
CARBON DlSULFlDE 3

1. PUBLIC HEALTH STATEMENT

It is estimated that carbon disulfide is not taken up in significant amounts by the organisms

living in water.

1.3 HOW MIGHT I BE EXPOSED TO CARBON DISULFIDE?

Carbon disulfide can enter your body if you breath air, drink water, or eat foods that contain

it. You can also be exposed by skin contact with soil, water, or other substances that contain

it. Oceans are a major natural source. The amount of carbon disulfide found in the air from

natural sources such as volcanoes is so low that good measurements are not available from

many areas. One measurement shows that carbon disulfide produced by marshes contributes

less than 8% of the sulfur in the upper atmosphere.

Small amounts of carbon disulfide can enter the air by evaporation and as a by-product of

several manufacturing processes. It is not clear how long carbon disulfide stays in the air.

Estimates range from 1 to 10 weeks. The people most often exposed to carbon disulfide are

workers in plants that use carbon disulfide in their manufacturing processes. The main way

they are exposed is through the air, and secondarily the skin. Carbon disulfide has also been

found in small amounts in some drinking water in the United States. Chapter 5 contains

more information on how you might be exposed to carbon disulfide.

1.4 HOW CAN CARBON DISULFIDE ENTER AND LEAVE MY BODY?

Most people are exposed to carbon disulfide by breathing air that contains it. Carbon

disulfide easily and rapidly enters your bloodstream through the lungs. Carbon disulfide can

also enter your body through your skin, or by eating or drinking foods that are contaminated

with the chemical. About l0-30% of carbon disulfide that the body absorbs leaves through

the lungs; less than 1% leaves in the urine. The rest of the absorbed carbon disulfide

(70-90%) is changed in the body and leaves the body in the urine in the form of other

chemicals. Small amounts of carbon disulfide also leave the body in sweat and saliva. For

more information, see Chapter 2.
CARBON DISULFIDE 4

1. PUBLIC HEALTH STATEMENT

1.5 HOW CAN CARBON DISULFIDE AFFECT MY HEALTH?

At very high levels (10,000 parts of carbon disulfide per million parts [ppm] of air), carbon

disulfide may be life threatening because of its effects on the nervous system. Studies in

animals show that high levels of carbon disulfide can damage the heart. People who breathed

carbon disulfide near an accident involving a railroad car showed changes in breathing and

some chest pains. Among workers who breathed about 8 ppm, some developed very slight

changes in their nerves. Some workers who breathed more than 20 ppm during working

hours for at least 6 months had headaches, tiredness, and trouble sleeping. However, the

workers may have been exposed to other chemicals besides carbon disulfide. The current

standard for exposure in the workplace is 20 ppm over an 8-hour day and a 5-day work week.

Studies in animals indicate that carbon disulfide can affect the normal functions of the brain,

liver, and heart. However, the amount of carbon disulfide in the air to which animals in these

studies were exposed was much higher than the amounts in the air that the general public

usually breathes. The brains, livers, and hearts of the animals were affected only after

breathing air that contained carbon disulfide for days, months, or years. After pregnant rats

breathed 225 ppm carbon disulfide in the air, some of the newborn rats died or had birth

defects.

There is no information on health effects in people who eat food or drink water contaminated

with carbon disulfide. Animals fed food that contained carbon disulfide developed liver and

heart disease, and some showed abnormal behavior. These amounts, however, were very

much higher than those that occur in drinking water supplies. When pregnant animals

received large doses of carbon disulfide in their diet, some of the newborns died or had birth

defects.

Skin contact with spilt carbon disulfide can lead to burns at the contact site. In studies that

examined the harmful effects of skin contact with carbon disulfide, workers in a rayon plant

who handled fibers made with carbon disulfide for more than 14 days developed blisters on

their fingers. Rabbits developed blisters and ulcers on the treated areas of their ears.
CARBON DlSULFlDE 5

1. PUBLIC HEALTH STATEMENT

1.6 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN

EXPOSED TO CARBON DISULFIDE?

Carbon disulfide itself can be measured in breath, urine, and blood. It breaks down in the

body into other chemical substances called metabolites. These substances can be found and

measured in the urine. After carbon disulfide enters your body, these substances reach higher

levels than normally found. One chemical test using urine can be done to tell whether the

levels of these breakdown substances from carbon disulfide are higher than normal. This test

requires special equipment and is not routinely available in a doctor’s office. The test is not

specific for carbon disulfide exposure because other chemicals can also produce these

metabolites. Therefore, it cannot be used to find out exactly how much carbon disulfide you

were exposed to or to predict whether you’ll be harmed. Also, the test can only be used if

you have breathed in at least 16 ppm; this test can be used for determining longer term

exposure to carbon disulfide. A second test based on a specific metabolite is more sensitive

and specific. It also requires special equipment and cannot tell you exactly how much carbon

disulfide you were exposed to or predict whether you’ll be harmed. Carbon disulfide leaves

the body quickly in the breath and in the urine. See chapters 2 and 6 for more information

on testing for carbon disulfide.

1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO

PROTECT HUMAN HEALTH?

The federal government has set regulations to protect individuals from the possible health

effects of eating, drinking, or breathing carbon disulfide. The EPA suggested that taking into

your body each day an amount equal to 0.1 mg (milligram) of carbon disulfide per kg

(kilogram) of your body weight is not likely to cause any significant (noncancer) harmful

health effects.

The Occupational Safety and Health Administration (OSHA) regulates levels of carbon

disulfide in the workplace (see Table 7-l). OSHA requires that workroom air contain no
CARBON DISULFIDE 6

1. PUBLIC HEALTH STATEMENT

more than an average of 20 ppm of carbon disulfide over an 8-hour working shift for

5 consecutive days in a work week.

The National Institute for Occupational Safety and Health (NIOSH) recommends that the

average workroom air levels of carbon disulfide not exceed 1 ppm over a l0-hour period.

For more information on rules and standards for carbon disulfide, see Chapter 7.

1.8 WHERE CAN I GET MORE INFORMATION?

If you have any more questions or concerns, please contact your community or state health or

environmental quality department or

Agency for Toxic Substances and Disease Registry

Division of Toxicology

1600 Clifton Road NE, Mailstop E-29

Atlanta, Georgia 30333

(404) 639-6000

This agency can also provide you with the location of the occupational and environmental

health clinics. These clinics specialize in the recognition, evaluation, and treatment of illness

resulting from exposure to hazardous substances.
CARBON DISULFIDE 7

2. HEALTH EFFECTS

2.1 INTRODUCTION

The primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and

other interested individuals and groups with an overall perspective on the toxicology of carbon

disulfide. It contains descriptions and evaluations of toxicological studies and epidemiological

investigations and provides conclusions, where possible, on the relevance of toxicity and toxicokinetic

data to public health.

A glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile.

2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE

To help public health professionals and others address the needs of persons living or working near

hazardous waste sites, the information in this section is organized first by route of exposure -

inhalation, oral, and dermal; and then by health effect - death, systemic, immunological, neurological,

reproductive, developmental, genotoxic, and carcinogenic effects. These data are discussed in terms of

three exposure periods - acute (14 days or less), intermediate (15-364 days), and chronic (365 days

or more).

Levels of significant exposure for each route and duration are presented in tables and illustrated in

figures. The points in the figures showing no-observed-adverse-effect levels (NOAELs) or lowest

observed- adverse-effect levels (LOAELs) reflect the actual doses (levels of exposure) used in the

studies. LOAELs have been classified into “less serious” or “serious” effects. “Serious” effects are

those that evoke failure in a biological system and can lead to morbidity or mortality (e.g., acute

respiratory distress or death). “Less serious” effects are those that are not expected to cause significant

dysfunction or death, or those whose significance to the organism is not entirely clear. ATSDR

acknowledges that a considerable amount of judgment may be required in establishing whether an end

point should be classified as a NOAEL, “less serious” LOAEL, or “serious” LOAEL, and that in some

cases, there will be insufficient data to decide whether the effect is indicative of significant

dysfunction. However, the Agency has established guidelines and policies that are used to classify
CARBON DISULFIDE 8

2. HEALTH EFFECTS

these end points. ATSDR believes that there is sufficient merit in this approach to warrant an attempt

at distinguishing between “less serious” and “serious” effects. The distinction between “less serious”

effects and “serious” effects is considered to be important because it helps the users of the profiles to

identify levels of exposure at which major health effects start to appear. LOAELs or NOAELs should

also help in determining whether or not the effects vary with dose and/or duration, and place into

perspective the possible significance of these effects to human health.

The significance of the exposure levels shown in the Levels of Significant Exposure (LSE) tables and

figures may differ depending on the user’s perspective. Public health officials and others concerned

with appropriate actions to take at hazardous waste sites may want information on levels of exposure

associated with more subtle effects in humans or animals or exposure levels below which no adverse

effects have been observed. Estimates of levels posing minimal risk to humans (Minimal Risk Levels

or MRLs) may be of interest to health professionals and citizens alike.

Estimates of exposure levels posing minimal risk to humans (Minimal Risk Levels or MRLs) have

been made for carbon disulfide. An MRL is defined as an estimate of daily human exposure to a

substance that is likely to be without an appreciable risk of adverse effects (noncarcinogenic) over a

specified duration of exposure. MRLs are derived when reliable and sufficient data exist to identify

the target organ(s) of effect or the most sensitive health effect(s) for a specific duration within a given

route of exposure. MRLs are based on noncancerous health effects only and do not consider

carcinogenic effects. MRLs can be derived for acute, intermediate, and chronic duration exposures for

inhalation and oral routes. Appropriate methodology does not exist to develop MRLs for dermal

exposure.

Although methods have been established to derive these levels (Barnes and Dourson 1988; EPA

1989b), uncertainties are associated with these techniques. Furthermore, ATSDR acknowledges

additional uncertainties inherent in the application of the procedures to derive less than lifetime MRLs.

As an example, acute inhalation MRLs may not be protective for health effects that are delayed in

development or are acquired following repeated acute insults, such as hypersensitivity reactions,

asthma, or chronic bronchitis. As these kinds of health effects data become available and methods to

assess levels of significant human exposure improve, these MRLs will be revised.
CARBON DISULFIDE 9

2. HEALTH EFFECTS

A User’s Guide has been provided at the end of this profile (see Appendix A). This guide should aid

in the interpretation of the tables and figures for Levels of Significant Exposure and the MRLs.

2.2.1 Inhalation Exposure

Carbon disulfide can exist in air as vapor. Table 2-l and Figure 2-l summarize the available

quantitative information on the health effects that have been observed in humans and animals

following inhalation exposure to carbon disulfide. All exposure levels are expressed as parts per

million (ppm). In many workplace exposures, exposure could be by inhalation and skin exposure,

rather than inhalation exposure alone.

2.2.1.1 Death

Several epidemiology studies have reported increased mortality among workers in viscose rayon plants

who were occupationally exposed to carbon disulfide as well as other chemicals (Hernberg et al. 1970,

1973; Tolonen et al. 1975, 1979). Deaths have also been reported in a community in India following

an accidental release of large amounts of carbon disulfide, hydrogen sulfide, and sulfuric acid from a

viscose rayon plant (Kamat 1994). However, no definitive or consistent conclusions can be drawn

from these studies because of concomitant exposure to other chemicals, uncertainty about exposure

concentrations, and the likelihood of multiple routes of exposure.

In a 10-year (1975-1985) epidemiological study of 251 workers exposed to carbon disulfide and

124 controls in two viscose rayon factories in Czechoslovakia, increases in total and cardiovascular

mortality were noted in spinners exposed to high levels of carbon disulfide (Balcarova and Halik

1991). Although associated levels of exposure were not quantified for this particular group, the study

authors estimate that exposures ranged from less than 9.6 to 48 ppm. However, insufficient data were

provided to fully support their conclusions. An approximately 15% increase in deaths resulting from

circulatory disease was observed among Dutch viscose rayon workers exposed to carbon disulfide

concentrations which were described as “at least 7 ppm, and possibly higher” (Swaen et al. 1994).

The increased risk of dying from circulatory disease was greatest 20-30 years after the start of the

exposure.
CARBON DISULFIDE 10

2. HEALTH EFFECTS

The approximate LC50 for a 60-minute exposure in male mice was 220 ppm (Gibson and Roberts

1972). Inhalation exposure of pregnant rats to 642 ppm during gestation produced 33% mortality

among dams; exposure to 225 ppm produced 35% mortality among pups (Lehotsky et al. 1985). Four

of 22 mice died following inhalation exposure to 800 ppm for 6 hours a day, 5 days a week, for

90 days (Toxigenics 1983c). The reliable LC50 values for male mice and the LOAEL value for female

rats for the acute-duration category are recorded in Table 2-l and plotted in Figure 2-l.

2.2.1.2 Systemic Effects

No studies were located regarding musculoskeletal and dermal effects in humans or animals after

inhalation exposure to carbon disulfide. Information on respiratory, cardiovascular, gastrointestinal,

hematological, hepatic, renal, endocrine, ocular, body weight, and other systemic effects after

inhalation exposure is presented below. The highest NOAEL and all LOAEL values from each

reliable study for these systemic effects in each species and each duration category are recorded in

Table 2-l and plotted in Figure 2-l.

Respiratory Effects. Following an accident involving a railroad car, 27 individuals were exposed

via inhalation to an unspecified concentration of carbon disulfide. Subtle and transient changes in

pulmonary function were manifested as reduced vital capacity and decreased partial pressure of arterial

oxygen (Spyker et al. 1982). Dyspnea was reported in 77 of the 123 persons following an accidental

release of large amounts of carbon disulfide, hydrogen sulfide, and sulfuric acid from a viscose rayon

plant in India (Kamat 1994). Exposure concentrations were not stated.

White male Wistar rats exposed to 803 ppm carbon disulfide for 18 hours showed reduced cardiac and

respiratory rates and severe narcosis (Tarkowski and Sobczak 1971). However, this study used only

six or seven animals and only one dose was tested.

Cardiovascular Effects. In humans, vascular atherosclerotic changes are a primary effect following

long-term exposure to carbon disulfide. This is supported by epidemiological studies that have

established a relationship between occupational exposure to carbon disulfide and increased mortality

due to coronary heart disease (Hernberg et al. 1970, 1971, 1973; MacMahon and Monson 1988; Tiller

et al. 1968; Tolonen et al. 1979) and circulatory disease deaths (Swaen et al. 1994). Milder

manifestations such as angina have also been documented (Hernberg et al. 1971; Tolonen et al. 1979).










CARBON DISULFIDE 21

2. HEALTH EFFECTS

However, since reliable data on exposure levels were not available, it is impossible to establish a doseresponse relationship or a NOAEL. In addition, coronary heart disease has a multicausal origin that is

in part related to the saturated fat intake of the population and is also influenced by a large number of

other risk factors such as smoking, other dietary habits, diabetes, and physical inactivity. A

combination of two or more risk factors greatly increases the incidence of coronary heart disease, and

therefore carbon disulfide may be a cofactor in the presence of other risk factors (WHO 1979).

Another limitation with occupational studies reported from the viscose rayon industry is concurrent

exposure to other chemicals such as hydrogen sulfide (Hernberg et al. 1970; Rubin and Arieff 1945;

Swaen et al. 1994; Tolonen et al. 1979).

A retrospective mortality study revealed that 223 viscose rayon process workers employed for more

than 10 years and exposed to carbon disulfide at concentrations in excess of 20 ppm had a statistically

significant increase (2.5-fold) in deaths due to coronary heart disease from 1933 to 1962, compared to

174 nonprocess workers from the same factory (Tiller et al. 1968). Over the 30-year study period,

42% of all deaths in rayon process workers were attributed to coronary heart disease; the proportion

was 24% for other rayon workers and 17% for other local males used as controls. The excess

mortality was more pronounced in the 1940s and declined towards 1960, indicating a strong

dependence on the intensity of exposure, which had decreased during this interval. The same study

demonstrated that the death rate from coronary heart disease was proportionally higher among workers

engaged in the viscose spinning process than in other workers. However, nonexposed workers also

had a significantly higher death rate than expected for coronary heart disease, as did controls not

employed in the viscose industry. These factors limit the value of this study. Other limitations

include an inappropriately selected control group, failure to control for other coronary heart disease

risk factors such as smoking, dietary habits, physical inactivity, and obesity, and failure to monitor

blood pressure and blood lipid levels. In addition, there may have been concomitant exposures to

other chemicals in these industrial environments.

A prospective mortality study at a Finnish plant during the period of 1967-1977 revealed a similar

excess of deaths (2.5-fold) due to coronary heart disease (Tolonen et al. 1979). Two cohorts were

followed over a 10-year period, 1967-1977; 343 viscose rayon workers exposed to carbon disulfide

were individually matched with workers from the local paper mill. There was no significant difference

between the exposed and control groups with regard to smoking habits, physical activity, obesity, or

drug treatment. Carbon disulfide concentrations in workplace air were 10-30 ppm during the 1960s
CARBON DISULFIDE 22

2. HEALTH EFFECTS

20-60 ppm during the 1950s and higher in earlier time periods. The incidence of mortality due to

coronary heart disease was 29/343 in the exposed group versus 11/343 in the control group. Periodic

health surveys during the study revealed an increased incidence of angina and increased blood pressure

compared to a well-matched control group (Tolonen et al. 1979). The incidence of deaths from

coronary heart disease appeared to be much greater during the first 5 years as reported in interim

results of the same cohorts, but the numbers were too small to draw any conclusions (Hernberg et al.

1970, 1973).

Increased mortality from cardiovascular causes was noted in a 1975-1985 epidemiological study of

251 workers exposed to carbon disulfide compared to 124 nonexposed workers in two viscose rayon

factories in Czechoslovakia (Balcarova and Halik 1991). The workers (spinners) were exposed to

“high” levels of carbon disulfide with estimated concentrations ranging from less than 9.6 to 48 ppm.

An increased incidence of myocardial infarction was also noted in the highly exposed group compared

to controls. However, this study should be interpreted with caution since scanty data were provided

regarding methods employed.

In a study conducted on Egyptian workers employed in a viscose rayon factory, Kamal et al. (1991)

found a significantly higher prevalence of pathological changes revealed by electrocardiogram (ECG).

The study was conducted on 253 workers exposed to 20-45 ppm of carbon disulfide for 4-29 years;

the control group consisted of 99 workers. No association was found between the duration of

exposure and ECG activity; this finding indicates that the duration of exposure to carbon disulfide may

not be a major risk factor unless there are other predisposing factors. The study was limited, however,

because the exposure concentrations documented in factory records may not have been representative

of the actual exposures.

Among men who had been exposed to carbon disulfide for 5 or more years between 1942 and 1967,

the incidence of angina was 25% compared to 13% in unexposed controls, and a significant increase in

blood pressure was seen (Hernberg et al. 1971, 1976; Tolonen et al. 1975). Nonfatal first cardiac

infarctions were more frequent in the exposed group (11) than in the control group (4). The relative

risk of a fatal myocardial infarction was 4.8 times greater among those exposed to carbon disulfide; 16

of 343 men died of coronary heart disease within the 5-year period compared to 3 of 343 men in the

control group (p<0.007) (Hernberg et al. 1973; Tolonen et al. 1975). In a subsequent study, the

original relative risk estimates were adjusted for potential confounding effects of hypertension and
CARBON DISULFIDE 23

2. HEALTH EFFECTS

aging. After these adjustments, carbon disulfide exposure yielded a relative risk of 2.3 for coronary

disease mortality (Nurminen et al. 1982). Thus, although the prognosis for exposed workers was

better with improved occupational hygiene and with a reduction in the length of exposure over a

lifetime, there was apparently some increased risk attributable to carbon disulfide exposure in this

cohort. However, there were no adjustments for possible concomitant exposures to other chemicals.

A follow-up study of 343 Finnish viscose rayon workers was performed to examine the incidence of

cardiovascular mortality from 1967 to 1982 (Nurminen and Hernberg 1985). Exposure to carbon

disulfide varied greatly (approximately 22 ppm to <l0 ppm), with a decrease in exposures after 1972.

Within the first 5 years of follow-up (1967-1972), there was a 4.7-fold increase in ischemic and heart

disease mortality compared with a cohort of paper mill workers. In the period of 1972-1974, the

relative risk ratio was 3.2. After all workers with high coronary risk factors were removed from

exposure (19% of the cohort was exposed in 1977 compared to 53% in 1972), the risk of

cardiovascular death was reduced to a ratio of 1.0 in the years 1974-1982. This study indicates that

the cardiotoxic effects of carbon disulfide may be reversible with removal of individuals from the toxic

environment. Caution must be used in interpreting these data because of the increase in the incidence

of cardiovascular events in the aging cohort population and the possibility that carbon disulfide

accelerates death in high-risk individuals.

In a study of Japanese viscose rayon workers, no effects were noted on blood pressure or on the

incidence of angina. The exposed group comprised 420 rayon filament workers; 390 controls were

obtained from a local cuprammonium rayon factory (Sugimoto et al. 1978). Mean carbon disulfide air

levels were below 20 ppm at the time of the study (about 1975); these levels had been higher

(15-30 ppm) during the 1950s. These observations suggest that ethnic variation or other demographic

factors (e.g., dietary habits) may affect the response to carbon disulfide. Cardiovascular effects on 50

viscose rayon workers occupationally exposed to an average range of 3.2-9.6 ppm carbon disulfide for

3-12 years were compared to a pair-matched control group from unexposed departments of the plant

(Cirla and Graziano 1981). On ophthalmoscopy, two control and two exposed workers suffered minor

vascular changes. Both systolic and diastolic mean blood pressures were higher in the control group.

Differences were not statistically significant (p≥0.10). The use of a questionnaire, confirmed by

electrocardiography, determined one case of arrhythmia and one case of coronary heart disease in the

exposed group, with no cases reported for the control group. The one case of coronary heart disease

suggests there is some cardiac effect of carbon disulfide, but no general conclusions can be reached by
CARBON DISULFIDE 24

2. HEALTH EFFECTS

this study. The results further suggest that occupational exposure below 9.6 ppm (maximum exposure

concentration) for up to 12 years does not cause recognizable health damage. This interpretation must

be viewed with caution because the maximum exposure duration to carbon disulfide was only

12 years, with most workers between 6 and 9 years at risk. In addition, workers were exposed to

mean average concentrations of 3.2-8 ppm carbon disulfide. If carbon disulfide exerts effects through

an arteriosclerotic process, this duration of exposure may not have been adequate to observe

cardiovascular effects. Also, the study does not include the turnover rate due to death or attrition

among workers, some of which could be attributable to cardiovascular effects.

In another study, the effects of carbon disulfide on the cardiovascular system of 1,498 rayon workers

were evaluated in comparison to 481 acetate workers (Lieben et al. 1974). An electrocardiogram,

blood pressure level, total cholesterol level, and occupational exposure history were obtained for each

worker. The only statistically significant finding was a higher average blood pressure level (140/87) in

workers in the rayon plants than in workers in the acetate plants (135/83). However, blood pressure

readings did not differ significantly among workers exposed to high, medium, and low concentrations

of carbon disulfide, which suggests the lack of a dose response. Although no data were presented,

there could have been confounding exposures to other chemicals. Increased retinal arterial pressure

but not brachial arterial pressure was observed in viscose rayon workers exposed to carbon disulfide at

average concentrations of 64-161 ppm with peaks of 289 ppm for l-9 years (Maugeri et al. 1967). A

correlation between effects and duration of exposure was not detected.

Physical examinations were completed both before and after 114 workers were exposed to carbon

disulfide for 5 years (Chrostek-Maj and Czeczotko 1995a). Cardiovascular effects, as assessed by

blood pressure and electrocardiograms, were not observed. Exposure concentrations were stated as a

mean of 0-21 ppm and a median of 0-l.1 ppm. Carbon disulfide metabolites in the urine ranged from

0 to 950 mg/L. Cardiovascular effects, as assessed by blood pressure, blood coagulation, and

measurement of serum creatine kinase activity, were not observed in 247 workers exposed to carbon

disulfide at a median concentration of 4 ppm for a median duration of 4 years (Drexler et al. 1995b).

As described in Section 2.7, an interaction between carbon disulfide exposure and consumption of an

atherogenic diet may lead to enhanced cardiotoxicity in rats. Rats administered carbon disulfide at

16 ppm and greater for up to 6 months exhibited concentration-related structural and functional

changes (distention of the lumen, attenuation of myocardial vessels, irregular thickening of the aorta
CARBON DISULFIDE 25

2. HEALTH EFFECTS

wall, as well as microscopic histological changes). Although an increase in the enzyme activity

(fructose-1,6-phosphatase, glutamate dehydrogenase, and glucose-6-phosphate dehydrogenase) was

reported at the lowest concentration (3.2 ppm), the statistical significance of this finding was not

reported. Also, no structural changes were seen at 3.2 ppm. However, when rats exposed to the same

concentration of carbon disulfide were administered an atherogenic diet, there was an increase in

mortality, a decrease in albumin and increase in globulin fractions in the serum, and serious metabolic

and structural changes in the myocardium and the aorta (Antov et al. 1985).

Rats chronically administered 321.1 ppm carbon disulfide (5 hours a day, 6 days a week, for

15 months) did not develop any gross or histological lesions in the aorta; however, lipid droplets were

occasionally noted on histological examination of the coronary arteries (Wronska-Nofer et al. 1980).

In this same study, rats simultaneously fed an atherogenic diet had more advanced lipid infiltrates of

the coronary arteries, which suggests that carbon disulfide may have an accelerating effect on

atherosclerotic changes induced by dietary hypercholesterolemia. Thus, carbon disulfide may have

promoted the development of atherosclerosis and coronary heart disease via altered cholesterol

metabolism within the arterial wall.

Male Wistar rats exposed to 803 ppm for 18 hours showed reduced cardiac and respiratory rates and

severe narcosis (Tarkowski and Sobczak 1971). However, this study used only six or seven animals

and only one dose was tested.

Several studies have shown that carbon disulfide causes vascular changes in various organs of

experimentally exposed animals. Acute inhalation (2 days) of 1,285 ppm in phenobarbitone-pretreated

rats resulted in myocardial lesions characterized by necrosis, interstitial edema, and cellular infiltrate

(Chandra et al. 1972). This effect was not observed in rats treated with carbon disulfide alone.

Gastrointestinal Effects. Nausea and vomiting were reported in approximately 50% of

123 persons following an accidental release of carbon disulfide in India (Kamat 1994).

Gastrointestinal symptoms are also common among heavily exposed workers with carbon disulfide

poisoning. In one study, 28% of the workers in a viscose rayon plant had a prevalence of symptoms

(Vigliani 1954), and in another, viscose workers (n=l00) exposed to 1.9-26.4 ppm carbon disulfide in

combination with 1.0-4.0 ppm hydrogen sulfide for 3 months to 17 years complained of stomach

distress and impaired appetite (Rubin and Arieff 1945). Significant associations with nausea,
CARBON DISULFIDE 26

2. HEALTH EFFECTS

vomiting, and flatulence were also found in 119 carbon disulfide-exposed workers in a cross-sectional

study by Vanhoorne et al. (1992b). Workers were exposed to l-36 ppm for an average of 4.2 years.

These studies, however, are of limited value because of fluctuating exposure concentrations,

concomitant exposure to other chemicals, and the fact that the reported symptoms are nonspecific and

may have several etiologic agents.

No studies were located regarding gastrointestinal effects in animals after inhalation exposure to

carbon disulfide.

Hematological Effects. Relative to 18 unexposed persons, fibrolytic activity was decreased in

57 workers exposed to carbon disulfide at 59-169 ppm for 2-8 years (Visconti et al. 1967). Serum

plasmin concentrations decreased with increasing exposure duration. Red blood cell and white blood

cell counts were not significantly different from preemployment values in 114 workers exposed to

carbon disulfide at 0-21 ppm for 5 years (Chrostek-Maj and Czeczotko 1995a).

In animals, there is limited information that hematological effects occur following inhalation exposure.

Brieger (1949) studied the bone marrow of four rabbits acutely exposed (6 hours/day for 12 days) to

1,100 ppm carbon disulfide and found no hematological effects. In the same study, longer exposure

(6 hours/day for 48 days) to 300 ppm resulted in significantly increased pseudo-eosinophilic cells with

a corresponding reduction in lymphocytes. It can be concluded that carbon disulfide increases the

relative number of cells in the granulocytic series in the bone marrow. In another study, eight dogs

exposed to 400 ppm carbon disulfide for 8 hours a day, 5 days a week, for 11 weeks did not exhibit

adverse hematological effects or adverse alterations in blood chemistry except for a slight decrease in

the serum albumin level after 2 weeks (Lewey et al. 1941). Significant depression in erythrocyte

counts, total hemoglobin, and hematocrit were noted in mice exposed to 800 ppm, 6 hours daily,

5 days a week, for 90 days (Toxigenics 1983c). These studies suggest that hematologic effects are not

consistent across species. Furthermore, these effects are likely to be dose- and duration-dependent.

These changes do not correlate with clinical changes in the animals.

Hepatic Effects. Male volunteers exposed for 6 hours to graded concentrations (10-80 ppm) of

carbon disulfide showed inhibition of oxidative demethylation of orally administered amidopyrine

(Mack et al. 1974). In another study, Vanhoorne et al. (1992b) reported significantly increased liver

size and γ-glutamyltransferase (GGT) activity in 119 carbon disulfide exposed workers compared to
CARBON DISULFIDE 27

2. HEALTH EFFECTS

79 controls. Workers had been exposed to l-36 ppm for a mean of 42 years. However, since

adequate exposure data were not presented, this study should be interpreted with caution.

There is some evidence for increased serum cholesterol levels in workers exposed for prolonged

periods to carbon disulfide levels in the range of 20-60 ppm, but most of these studies did not use an

adequately matched control group (UK/HSE 1981). This study also measured total cholesterol levels

and did not differentiate between high- and low-density cholesterol. Therefore, no interpretation is

possible. An examination of total lipids, total and free cholesterol, and triglycerides in serum was

conducted in workers with chronic exposure to carbon disulfide in a viscose rayon factory in

Yugoslavia with time-weighted average (TWA) exposures of 4 ppm (n=58) or 18.5 ppm (n=102) over

17 years. Levels were compared to a nonexposed group of 41 workers (Krstev et al. 1992). Although

there was a lack of dose response, i.e., total lipid and triglyceride levels were similar regardless of

exposure, these levels were higher in exposed than in nonexposed workers. Again, no definitive

conclusion can be established. In another study, workers chronically exposed to carbon disulfide in a

viscose factory were classified by exposure duration of less than (n=17) or greater than (n=17)

20 years (El-Sobkey et al. 1979). Thirteen workers served as controls, and carbon disulfide

concentrations ranged from 0.008 to 0.02 ppm for exposed workers. Exposed workers had

significantly lower exposure duration-related mean values of thyroxine and higher mean values of free,

esterified, and total cholesterol than controls. The study authors suggested that depression of serum

thyroxine may be a key manifestation in hypercholesterolemia among carbon disulfide-exposed

workers. The small sample size, lack of information on other exposures, and poorly characterized

exposure concentrations preclude establishing conclusions from this study.

A significant positive trend for low-density lipoprotein cholesterol (LDL-Ch), total cholesterol, and

diastolic blood pressure in workers exposed to carbon disulfide was observed in a cross-sectional study

by Egeland et al. (1992). The Egeland study used existing data (Fajen et al. 1981) on 165 carbon

disulfide-exposed workers and 245 unexposed controls recruited in 1979. The persons using

medications to control ischemic heart disease and hypertension, as well as those using corticosteroid or

thyroid medications, were excluded. Affected workers had been exposed for at least 1 year in a

viscose rayon factory to a median 8-hour TWA of 7.6 ppm. The increases observed in total

cholesterol were attributed to increases in LDL-Ch since there was no apparent effect on high-density

lipoprotein cholesterol (HDL-Ch) ; triglyceride and fasting glucose levels were not associated with

carbon disulfide exposure. Although these findings of an increased risk of arteriosclerotic heart
CARBON DISULFIDE 28

2. HEALTH EFFECTS

disease have been attributed to increased LDL-Ch, the correlation between carbon disulfide exposure

and arteriosclerotic heart disease is not definitive in this study because of possible selection bias,

cumulative exposure uncertainties, lack of control for coronary disease risk factors such as diet and

exercise, and a limited statistical power to detect small changes in LDL-Ch.

Increased levels of LDL-Ch and apolipoprotein B as well as increased systolic and diastolic blood

pressure indicative of increased coronary risk were noted in 115 carbon disulfide-exposed workers in a

Belgian viscose rayon factory when compared to a control group of 76 workers (Vanhoorne et al.

1992a). Although these biochemical changes associated with cardiovascular disease were noted, no

significant increases in prevalence of angina, myocardial infarction, or ischemia, as indicated by ECG

changes, were found. In addition, elevated levels of apolipoprotein Al, which is a protective factor for

coronary risk were also noted in exposed workers; this too may be related to the toxic effects of

carbon disulfide exposure. Although the length of exposure was not specified, the authors noted that

conditions in the plant had not changed since 1932 and that concentrations ranged from 1 to 36 ppm

depending on job type. This study should be interpreted with caution since simultaneous exposure to

low levels of H2S also occurred. In addition, there may have been selection bias. Only 46% of those

eligible for the referent group participated while referents with health complaints may not have

participated, resulting in an underestimation of risk. Relative to preemployment values, increased

triglycerides and β-lipoproteins were observed in workers exposed to 0-21 ppm carbon disulfide for

5 years (Chrostek-Maj and Czeczotko 1995a). A similar effect was not observed in 62 unexposed

workers 5 years after a preemployment physical examination.

Compared to age-matched controls, an increase in total cholesterol, HDL-Ch, and LDL-Ch was

observed in women 40-49 years of age and 50-59 years of age (Stanosz et al. 1994b). The women

were exposed to carbon disulfide at 5-7 ppm for 0.5 to greater than 20 years. Only HDL cholesterol

and LDL cholesterol were increased when the values were examined by duration of carbon disulfide

exposure. Rather than being a hepatic effect, the investigators suggest that the effect may be on

hormone production by the ovaries resulting in altered lipid metabolism.

No effects on serum cholesterol levels were noted in workers chronically exposed to l0-30 ppm

carbon disulfide (Hernberg et al. 1971), and several studies failed to observe increased serum

cholesterol levels in workers exposed to carbon disulfide at concentrations below 20 ppm. In an

occupational study, 35 workers chronically exposed to carbon disulfide concentrations ranging from
CARBON DISULFIDE 29

2. HEALTH EFFECTS

6.4 to 12.8 ppm for 5-20 years exhibited a statistically significant reduction in blood cholesterol

levels; a nonsignificant reduction in total lipid levels was also observed. This study is of limited value

because of the small sample size and the likelihood of concurrent exposure to other chemicals

(Sidorowicz et al. 1980). Another study of 70 men exposed to carbon disulfide in a viscose plant who

were matched to unexposed men working in a different division of the plant found no statistically

significant differences in blood lipid profiles (total cholesterol, HDL-Ch, and triglycerides) (Franco et

al. 1982). Carbon disulfide concentrations were less than 11.2 ppm from 1972 to 1979. Workers

(n=420) in a rayon filament factory chronically exposed to carbon disulfide (unspecified

concentrations) for 4-25 years also exhibited no difference in total serum cholesterol, triglycerides, and

β-lipoprotein in comparison to controls (n=390) (Sugimoto et al. 1978).

Only transient effects on liver metabolism have been observed in animals following inhalation

exposure to carbon disulfide. Acute inhalation (8 hours) of 20 ppm carbon disulfide produced a

reversible inhibition in oxidative drug metabolism by female rat liver microsomes and an increase in

total hepatic lipid content (Freundt et al. 1974a). Rats exposed to much higher concentrations

(642 ppm) of carbon disulfide for 4 hours exhibited no histological evidence of liver damage (Magos

and Butler 1972; Magos et al. 1973). However, hepatotoxicity characterized by hydropic degeneration

in parenchymal cells of the centrilobular zone was observed in rats pretreated with phenobarbitone to

induce the liver mixed-function oxidase system and subsequently exposed to 642 ppm for 4 hours

(Magos and Butler 1972; Magos et al. 1973). Starvation further potentiated the phenobarbitoneinduced liver lesions in rats subsequently treated with carbon disulfide.

In mice, intermediate-duration inhalation exposures at a concentration of 482 ppm for up to 23 days

(4 hours a day, 5 days a week) have resulted in a marked reduction in cytochrome P-450 and

cytochrome c-reductase content after 2-3 days. The level returned to normal by the 23rd day of

treatment. A significant decrease in uridine diphosphate-glucuronyl (UDP-glucuronyl) transferase was

also noted, as well as a significant increase in lipid peroxidation (Jarvisalo et al. 1977a). Rabbits

exposed to 300 ppm for 30 minutes a day for 120 days failed to develop any histopathologic

alterations of the liver (Tsuyoshi 1959). However, because of the small sample size (n=3), the

conclusions are preliminary.

The effect of carbon disulfide on lipid metabolism in the rat has been extensively studied (WronskaNofer 1972, 1973; Wronska-Nofer et al. 1978, 1980). Serum cholesterol, phospholipids, and
CARBON DISULFIDE 30

2. HEALTH EFFECTS

triglyceride levels were significantly elevated after exposure to 161-176.6 ppm carbon disulfide for

5 hours a day, 6 days a week, for 2 months or more (Wronska-Nofer 1972, 1973). A small but

significant (p<0.05) increase was also noted in rats exposed to 74 ppm for 5 hours a day, 6 days a

week, for 8 months (Wronska-Nofer 1973). Rats maintained on a Murigran chow ad libitum diet and

exposed to 321 ppm carbon disulfide 5 hours a day, 6 days a week, for 6 months showed an increase

in the rate of cholesterol influx from serum into the aorta wall. Those rats exposed under the same

conditions for 8 months showed a slightly enhanced rate of aortic cholesterol synthesis (WronskaNofer and Parke 1978). Rats maintained on an atherogenic diet (2% cholesterol, 0.15% thiouracil) and

exposed to 321 ppm carbon disulfide for 5 hours a day, 6 days a week, for 6 months had markedly

increased serum and aortic cholesterol levels. These results suggest that carbon disulfide may increase

arteriosclerotic changes resulting from diet-induced hypercholesterolemia (Wronska-Nofer et al.

1980).

Total serum cholesterol and fatty acids became elevated, but cholesterol esters decreased, in dogs

administered 400 ppm carbon disulfide and simultaneously fed high-fat diets (Lewey et al. 1941).

These data suggest that carbon disulfide, in conjunction with a high-fat diet, may lead to increases in

cholesterol levels above those expected from high-fat diets alone. Rabbits (n=ll) exposed to higher

concentrations of carbon disulfide (750 ppm) for 6 hours a day for 5 months exhibited a transient

elevation in total serum cholesterol which was associated with weight loss (Cohen et al. 1959).

Thus, carbon disulfide does affect liver enzymes, particularly those related to lipid metabolism. The

increases in serum cholesterol that are sometimes seen following carbon disulfide exposure may be a

result of increased hepatic cholesterol synthesis.

Renal Effects. In a study with viscose rayon workers, there was a slight but statistically significant

increase in the mean plasma creatinine concentration compared with the control group (Hernberg et al.

1971). However, the study authors concluded that all values were within reference ranges. Urinalysis

did not reveal any effects on kidney function relative to preemployment values in 114 men exposed to

carbon disulfide at 0-21 ppm for 5 years (Chrostek-Maj and Czeczotko 1995a).

Inhalation exposure of mice to 800 ppm for 6 hours a day, 5 days a week, for 90 days produced

nephropathy (Toxigenics 1983c). Rabbits exposed to 300 ppm carbon disulfide for 30 minutes a day

for 120 days failed to develop any histopathological alterations of the kidney (Tsuyoshi 1959). This

study is of limited value because of the small sample size (n=3). An autopsy report of rabbits
CARBON DISULFIDE 31

2. HEALTH EFFECTS

(11 males) exposed to graded concentrations of 250-750 ppm carbon disulfide intermittently over a

period of 38 weeks revealed an increased incidence of chronic interstitial nephritis (Cohen et al. 1959).

Endocrine Effects. The available human studies provide conflicting evidence on the adverse effects

of carbon disulfide on thyroid function. However, these studies were limited by possible exposure to

other chemicals, small sample size, and lack of quantification of precise exposure concentrations.

The effects of chronic exposure to carbon disulfide on serum thyroxine and cholesterol levels were

studied in 50 workers employed in a viscose rayon factory (El-Sobkey et al. 1979). The control group

consisted of 13 workers. The carbon disulfide concentration varied from 0.0083 to 0.02 ppm and the

exposure duration from less than 20 years to greater than 20 years. An association was found between

the lower serum thyroxine levels and serum concentrations of free and esterified cholesterol in exposed

workers. According to the study authors, depression in serum thyroxine levels is related to metabolic

disturbances leading to hypercholesterolemia among carbon disulfide-exposed workers.

In a study by Lancranjan et al. (1972), 109 workers exposed to carbon disulfide for 7-31 years were

examined for thyroid function. A group of 40 workers served as controls. The exposure

concentrations varied from 19 to 29 ppm and from 72 to 96 ppm. The study authors concluded that

carbon disulfide did not induce thyroid alterations or disorders of lipid metabolism. In another study,

the effect of long-term exposure to carbon disulfide (10-36 years) was studied in 15 exposed and 16

age-matched controls (Wagar et al. 1981). The exposure levels ranged from 10 to 51 ppm. No

disturbance was noted in either thyroid function or serum prolactin values. Serum cortisol was also

unchanged.

Urinary excretion of 17-hydroxycorticosteroids (formed from precursors of adrenal origin) and

17-ketosteroids (from both adrenal and gonadal sources) was reduced in workers exposed to carbon

disulfide at 59-169 ppm for up to 8 years (Cavalleri et al. 1967). In a study that was designed to

examine the effects of carbon disulfide on the sympathetic/adrenal system, decreased diurnal urinary

excretion of adrenaline, decreased plasma dopamine, and increased serum β-hydroxylase activity were

observed in women occupationally exposed at 5-7 ppm for periods ranging from 6 months to greater

than 20 years (Stanosz et al. 1994a). Blood pressure was not significantly affected in this study,

although among exposed women, a negative correlation was observed between daily urinary excretion

of adrenaline and systolic blood pressure.
CARBON DISULFIDE 32

2. HEALTH EFFECTS

No studies were located regarding endocrine effects in animals after inhalation exposure to carbon

disulfide.

Ocular Effects. Ophthalmological changes of various types, such as increased frequency of

microaneurysms, related to the duration and intensity of exposure, have been found in Japanese

workers. Severe ocular effects characterized by dot hemorrhages or microaneurysms of the retina were

observed in Japanese workers exposed to carbon disulfide at levels between 5 and 15 ppm after 1955

and between 15 and 30 ppm earlier. The mean duration was 17 years in the first study (Sugimoto et

al. 1978; Tolonen et al. 1976) and 10.8 years in the second study (Sugimoto et al. 1976) at

concentrations averaging ≥20 ppm (high group) or <20 ppm (low group). Retinopathy, characterized

by microaneurysms, was observed in 35% (43/124) of those exposed to air concentrations above

20 ppm carbon disulfide and in 23% (29/127) of those exposed to below 20 ppm, as compared to 4%

(2/49) of the controls. These increases were statistically significant. The incidence and severity were

shown to increase with longer durations of exposure to carbon disulfide. The retinopathy was not age

related, the incidence being 37%, 29%, and 35% in exposed workers in the age groups 30-39, 40-49,

and 50-59 years, respectively (Sugimoto et al. 1976). Although other exposures were not discussed,

concurrent exposures to other chemicals may have also occurred.

A subsequent collaborative study was conducted to assess the incidence of retinopathy among groups

of workers in Finland and Japan exposed to similar levels of carbon disulfide. The comparison

showed that the differences in values obtained in the two studies were true differences and were not

caused by interobserver variation (Sugimoto et al. 1977, 1978; Tolonen et al. 1976). Retinal red dots

(microaneurysms and/or small hemorrhages) were observed in 25% (103/419) of the Japanese workers

with chronic exposure to mean atmospheric levels of carbon disulfide of 15-35 ppm during the 1950s

and below 20 ppm (5-15 ppm) since 1955, as compared to 4% (15/391) of the controls. However, no

significant increase in the incidence of retinopathy was noted in Finnish workers exposed to 5-10 ppm

carbon disulfide and to higher concentrations prior to 1970 (20-60 ppm during the 1950s and

l0-30 ppm during the 1960s): 4% (7/188) were affected compared to 3% (2/76) of the controls.

Thus, the prevalence of retinopathy among 419 Japanese workers exposed to 5-20 ppm carbon

disulfide was high, whereas the incidence among 188 Finnish workers exposed to about 5-30 ppm was

not greater than expected. The high prevalence among the Japanese workers may be explained by

biased selection of exposed workers, different actual exposures, or the fact that no attempt was made

in either study to account for the known risk factors for retinopathy (i.e., diabetes, hypertension). The
CARBON DISULFIDE 33

2. HEALTH EFFECTS

Finnish study may have selected for these findings. No data were presented regarding other possible

exposures.

In studies of Finnish workers, 100 males with the longest and most marked history of exposure and

97 unexposed males were chosen for a neuro-ophthalmological investigation (Raitta and Tolonen

1975; Raitta et al. 1974, 1981). The 100 men had been exposed for between 1 and 27 years to 10-40

ppm; they were selected from the same cohort previously described by Hernberg et al. (1970).

Corrected visual acuity, visual field, eye motility, pupillary reactions, and biomicroscopy were normal

in all eyes examined. No retinopathy was detected in either group of individuals. However, delayed

peripapillary filling of the choroid (both circumferential and segmental) occurred in 68 exposed and 38

unexposed eyes, a significant difference (p≤0.01). This was attributed to possible hemodynamic effects

of carbon disulfide exposure. In addition, the mean widths of eight retinal vessels and the smallest vein

were significantly greater in the exposed group, again attributed by the study authors to hemodynamic

alterations with exposure. The study was limited by the difficulty in characterizing exposure levels

because of the possibility that individual exposure varied widely and erratically over periods of time.

However, a follow-up study validated the hypothesis that the delayed peripapillary filling of the

choroid was related to the cardiovascular effects of carbon disulfide (Raitta and Tolonen 1975). In

this follow-up, 38 male viscose rayon workers exposed to carbon disulfide were compared to 40

unexposed workers (previously examined neuro-ophthalmologically). Measurements were taken by

oculosphygmography and were combined with individual electrocardiograms to statistically analyze

the characteristics of the ocular pulse wave. Results showed that the exposed group of workers had a

significantly lower pulse wave than that of the unexposed group, suggesting an increased rigidity of

the ocular vascular bed in the viscose rayon workers. This study provided further evidence that carbon

disulfide was not retinopathic in this Finnish cohort and in addition suggested a possible mechanism

for the ocular effects of carbon disulfide.

To determine the effect of carbon disulfide exposure on retinal vasculature, American subjects from a

viscose rayon plant (156 exposed, 233 unexposed) underwent pupillary dilation (with a short-acting

mydriatic), direct ophthalmoscopy, and retinal photography with monochromatic light (NIOSH

1984a). Photographs were read by an ophthalmologist and rated as normal, as having definite or

uncertain microaneurysms, or as having definite or uncertain hemorrhages. Subjects were categorized

by job and characterized as having definitely low (DL<3 ppm), moderate (M=3-7.1 ppm), or definitely

high exposure (DH>7.1 ppm). Retinal microaneurysms and hemorrhages were more prevalent in the
CARBON DISULFIDE 34

2. HEALTH EFFECTS

combined exposed groups than in the comparison group (p≤0.04). There was a concentration-related

increase in the incidence of both definite and uncertain microaneurysms with exposure to carbon

disulfide. No such trend was apparent for hemorrhages, nor for definite aneurysms alone. The

combined exposed groups had almost 20% retinal microaneurysms (both definite and uncertain)

compared to 7.5% for the comparison groups (significant, p≤0.01). The combined exposed groups had

10.5% retinal hemorrhages (both definite and uncertain) compared to 3% for the comparison group

(significant, p≤0.01). The difficulties in characterizing dose levels and measuring the number of

aneurysms by photography limit interpretation of the findings. Evidence regarding the occurrence of

retinopathies due to carbon disulfide exposure is not uncomplicated. It appears that there may be a

group of individuals, both Eastern and Western, who are genetically predisposed to respond with

retinopathy to low levels of carbon disulfide exposure (NIOSH 1984a; Sugimoto et al. 1976, 1977).

Conflicting evidence shows no retinopathy with exposure to slightly higher levels of carbon disulfide

in the Finnish population (Hernberg et al. 1970; Raitta and Tolonen 1975; Raitta et al. 1974; Sugimoto

1977; Tolonen 1975; Tolonen et al. 1976). The differences in response by various populations have

not been resolved.

Thirty workers in a viscose rayon plant were divided into two groups based on carbon disulfide

exposure concentrations. The control group was exposed to average concentrations of 3.2 ppm, while

the exposed workers experienced average levels of 16-32 ppm. Pigmentary changes and

microvascular retinal lesions were observed in both groups (DeLaey et al. 1980; DeRouck et al. 1986).

The study authors concluded that carbon disulfide affects several ocular structures and functions at low

exposure levels. However, this study is limited by a small sample population, probable concomitant

exposure to other chemicals, and an inappropriately chosen control group that was also exposed to

carbon disulfide. In another study, viscose workers (n=l00) intermittently exposed to 1.9-26.4 ppm

carbon disulfide in combination with 1.0-4.0 ppm hydrogen sulfide for 3 months to 17 years

complained of burning of the eyes (Rubin and Arieff 1945). This study is of limited value because of

fluctuating exposure concentrations, concomitant exposure to hydrogen sulfide and other chemicals,

and lack of a control group.

Adverse ocular effects in workers of a viscose silk plant exposed 6 hours a day, 5 days a week, for

0.5-30 years to less than 3.2 ppm carbon disulfide were reported by Szymankova (1968).

Disturbances were manifested as vascular or inflammatory degenerative changes in the retinas of 12
CARBON DISULFIDE 35

2. HEALTH EFFECTS

out of 75 (16%) of the exposed workers, which disappeared in 11 workers following cessation of

carbon disulfide exposure.

Four female monkeys exposed to 256 ppm for 6 hours a day, 5 days a week, for 5-13 weeks suffered

permanent visual impairment with degeneration of retinal ganglion cells compared to one control

(Merigan et al. 1988). Visual acuity thresholds in two macaque female monkeys were severely

disrupted after 5 weeks of intermittent exposure (6 hours a day, 5 days a week) to 256 ppm carbon

disulfide. One monkey showed some recovery at 16 weeks postexposure; the other showed no

improvement (Merigan et al. 1985). The observed effects were secondary to the effects on the optic

nerve.

Body Weight Effects. Significant associations with anorexia were found in a cross-sectional study

of 119 workers exposed to l-36 ppm carbon disulfide over a mean of 4.2 years (Vanhoorne et al.

1992b). This study, however, did not provide adequate exposure data. No information was located

regarding effects on body weight in humans after inhalation exposure to carbon disulfide.

Female Wistar rats exposed to 800 ppm for 15 weeks (5 days a week, 6 hours a day) showed a 10%

decrease in body weight gain (Hirata et al. 1992b). Male Long-Evans rats showed a 6-8% decrease at

lower concentrations (350-600 ppm) following inhalation exposure for 10 weeks (Tepe and Zenick

1984). During a 14-day exposure (10 hours/day) to carbon disulfide at 600 ppm, male rats lost 14%

of their body weight (Wilmarth et al. 1993). This concentration also resulted in a narcotic-like stupor

in the exposed rats. Contrary to these findings, male Long-Evans rats that were exposed to 500 ppm

for 5 or 12 weeks (5 days a week, 6 hours a day) showed no significant changes in body weight gain

(Clerici and Fechter 1991). Female Long-Evans rats exposed to 800 ppm for 11 weeks (7 days a

week, 7 hours a day) had a 15% decrease in body weight gain; this effect was not seen at 400 ppm

(Rebert and Becker 1986). Inhalation exposure of Fischer 344 and Sprague-Dawley rats at 800 ppm

for 90 days (5 days a week, 6 hours a day) caused a 16-30% decrease in body weight gain in both

sexes (Toxigenics 1983a, 1983b). The percent of decrease in body weight gain depended on the strain

of rat used (Toxigenics 1983a, 1983b). Inhalation exposure of Wistar rats to 546 ppm for 8 months or

to 482 ppm for up to 14 months produced decreases in body weight (Szendikowski et al. 1974;

Wronska-Nofer 1973).
CARBON DISULFIDE 36

2. HEALTH EFFECTS

Other Systemic Effects. Workers exposed for less than 5 years to TWA concentrations of

4.8-8 ppm had significantly elevated plasma sodium and chloride ions and decreased erythrocyte

potassium and calcium (Pines 1982). However, the large variance in the electrolyte measurements

among workers, the concomitant exposure to other chemicals, the fluctuating exposure concentrations,

and the lack of a dose response for blood electrolyte alterations limit the value of this study.

Animal studies include a necropsy report on 10 male rabbits exposed to graded concentrations of

250-750 ppm carbon disulfide intermittently for 38 weeks that revealed increased adrenal weight,

hyperplasia of adrenal cortex, and mild hemosiderosis of the spleen (Cohen et al. 1959). No

information was given as to whether the controls underwent a sham exposure process, thereby

controlling for the stress of the exposure procedure.

2.2.1.3 Immunological and Lymphoreticular Effects

The only study located that specifically addressed a possible immunological effect of carbon disulfide

exposure in humans reported data that indicated that the β-lipoprotein isolated from carbon disulfideexposed workers (presumably exposed via inhalation) is antigenically identical to lipoproteins isolated

from healthy nonexposed controls (Bobnis et al. 1976). The authors concluded that these findings

suggested no immunologic component involved in the increase of arteriosclerotic lesions found in

carbon disulfide-exposed workers. There are no further data to either support or refute this

conclusion.

No studies were located regarding immunological or lymphoreticular effects after carbon disulfide

exposure in either humans or animals.

2.2.1.4 Neurological Effects

The primary target of carbon disulfide appears to be the nervous system. Neurophysiological and

behavioral effects as well as pathomorphology of peripheral nervous system structures have been

reported in humans as well as animals. Acute exposure to high concentrations of carbon disulfide can

result in fainting and loss of consciousness. These effects were observed in 36-39% of 123 persons

exposed to carbon disulfide following an accidental release of carbon disulfide, hydrogen sulfide, and

sulfuric acid from a viscose rayon factory in India (Kamat 1994).
CARBON DISULFIDE 37

2. HEALTH EFFECTS

Most information available on neurotoxic effects of carbon disulfide in humans comes from

occupational epidemiology studies. These exposures are considered to occur via inhalation, although

some dermal exposures could have conceivably occurred, especially under conditions that may have

prevailed 40-50 years ago. Separating possible effects of concomitant exposures to other chemicals

can also present a problem. An examination of 118 male workers in a viscose rayon plant exposed for

a median length of 15 years to carbon disulfide at an estimated average concentration of between 10

and 20 ppm revealed that the carbon disulfide-exposed workers had reduced maximal motor

conduction velocity of the median, ulnar, deep peroneal, and posterior tibia1 nerves when compared to

the controls (workers in a paper mill) (Seppalainen and Tolonen 1974). Individuals working in the

plant before 1960 were exposed to higher levels (20-40 ppm) of carbon disulfide than were those

working after this time. Furthermore, follow-up examination of these workers indicated that removal

from the exposure environment did not lead to improvement of the nerve conduction velocity.

However, it was noted that when individuals were removed from carbon disulfide exposure for l0-15

years, there was an equal division of people with either normal or decreased conduction velocities

compared to a greater percentage of decreased velocities in individuals absent for 0-4 years. The

authors of this study had earlier reported on neurophysiological findings in 36 workers exposed to high

levels of carbon disulfide and described diminished nerve conduction velocities indicating

polyneuropathy in many subjects (Seppalainen et al. 1972). Polyneuritis was reported to be present in

almost all workers occupationally exposed to carbon disulfide for an average of 40 months at

unspecified concentrations (Lancranjan et al. 1972). Overt polyneuropathy was reported in 9 of 17

male workers exposed to 150-300 ppm carbon disulfide for greater than 2 years, while 19 workers

exposed to 15-150 ppm also had some symptoms of polyneuropathy (Chu et al. 1995). Nerve

conduction velocities were significantly different in subjects with overt polyneuropathy when

compared to subjects with subclinical effects and in subjects with subclinical effects when compared to

unexposed controls.

Three groups of grain workers in three different work facilities (grain inspectors, malt laboratory

workers, and grain elevator workers) showed various neurological effects. Their symptoms included

distal sensory shading indicated by decreased sensitivity to pinprick and light touch, intention tremors,

resting tremors, and nerve conduction abnormalities. The authors of this study concluded that the

similarities of these symptoms to those reported in viscose rayon workers implicate carbon disulfide.

The 21 subjects in this study were, however, self-selected, no controls were used, and no

measurements of actual exposure to carbon disulfide were made (Peters et al. 1988). All individuals

reported being able to smell the fumigant mixtures of carbon disulfide and carbon tetrachloride, and it
CARBON DISULFIDE 38

2. HEALTH EFFECTS

is suggested that at this point safe levels had been exceeded. Possible contributions to effects from the

other components of the pesticide were not considered. It has been suggested that the symptoms of

the grain workers exposed to the fumigant mixtures of carbon disulfide and carbon tetrachloride

resemble those of patients with idiopathic Parkinson’s disease (Matthews et al. 1990). Clinically,

Peters et al. (1982) described loss of associated movements, cogwheeling, and atypical tremor in the

grain workers resembling early Parkinsonism.

Clinical neurological examination of 16 men formerly exposed to carbon disulfide for at least 10 years

revealed abnormalities in 15. Cerebral computerized tomography (CT-scans) showed signs of atrophy

in 13, and neuropsychological examination indicated brain organic changes in 13. The authors of this

study believed that long-term exposure to carbon disulfide involved a risk of developing toxic

encephalopathy (Aaserud et al. 1988). Exposures were assumed to be between 9.6 and 19 ppm, with

occasional higher exposures. There was no quantitation of individual exposures, however, and no

adjustment was made to account for other possible occupational exposure or for lifestyle factors.

CT-scans also revealed evidence of brain atrophy in 12 of 20 workers exposed to carbon disulfide at

0-21 ppm for 5 years (Chrostek-Maj and Czeczotko 1995b). The changes were observed most

frequently in the frontal lobe. CT-scans were only completed in the 20 individuals with the worst

psychiatric effects. Exactly what was being measured in the psychiatric examinations was not clear.

In this study, psychiatric exams were completed before and 5 years after the start of exposure. In the

exposed group of 114 men, the prevalence of “pseudoneurotic” symptoms increased from 8.4% to

43%. A similar increase was not observed among 62 unexposed control workers. Peters et al. (1988)

noted that magnetic resonance imaging findings in 2 out of the 3 grain storage workers were indicative

of central demyelination.

Regional cerebral blood flow was examined using Doppler ultrasound in 15 workers exposed to

3.2-28.9 ppm carbon disulfide for a mean of 20 years (Aaserud et al. 1992). Studies were performed

4 years after exposure ended. Asymmetrical blood flow patterns were observed in 8/14 workers, all of

whom had encephalopathies consistent with carbon disulfide exposure. However, when the results

were corrected to adjust for a possible influence of pCO2, the values did not differ between the

exposed workers and referents. No clear conclusions about this study can be made because of the

small number of exposed workers, lack of a current exposure group, possible selection bias, and age

variation between cohort and referents.
CARBON DISULFIDE 39

2. HEALTH EFFECTS

A study was conducted on 81 patients who had worked in environments containing toxic chemicals,

who exhibited chronic carbon disulfide poisoning, and who showed evidence of polyneuropathy

(Vasilescu 1976). The patients showed decreased conduction velocity in sensory nerves. These

decreases were greater than those seen in the motor nerve velocities and, in some patients, occurred

before any clinical signs. No measurements of actual exposure were given, however, and no estimates

were made on the duration of occupational exposures or the chemicals that may have contributed to

the total exposure history of the patients. Carbon disulfide was one of the major contaminants.

Workers exposed to carbon disulfide (n=145) were evaluated for its effects on the peripheral nervous

system and compared to a group of nonexposed artificial fiber plant workers (n=212) located on the

same premises (Johnson et al. 1983). The mean exposure period was 12.1 ± 6.9 years (mean ± SD),

and individuals were divided into three groups based on previous exposure histories, job descriptions,

and current carbon disulfide levels established on the basis of 8-hour personal monitors. The median

carbon disulfide level for the comparison group was 0.2 ppm, while the median carbon disulfide levels

of exposed individuals were 1, 4.1, and 7.6 ppm. The mean exposure concentration of all groups

considered together was 7.3 ± 17.2 ppm (mean f SD) (23 mg/m3), ranging from 0.6 to 16 ppm

(1.9-50 mg/m3). Carbon disulfide levels showed variability during breakdown periods at the plant

which occurred “infrequently” but exposed some workers to brief periods of high carbon disulfide

concentrations. Surface electrodes were used to measure maximum motor conduction velocity (MCV)

in the ulnar and peroneal nerves and sensory nerve conduction velocity (SCV) in the sural nerve.

There was a dose-related reduction in motor nerve conduction velocities in the calves and ankles,

which was statistically significant in the high-concentration exposure group and in the average

exposure group. However, the reductions were within the range of normal values. The study authors

considered this to indicate minimal neurotoxicity. A chronic-duration MRL of 0.3 ppm was

established for this effect, using 7.6 ppm as the LOAEL. In addition, reductions in the peroneal nerve

conduction velocity appeared to be related to the workers’ cumulative exposure to carbon disulfide.

This study reported health-related effects at average levels of exposure much less than those usually

reported for occupational cohort studies. However, potential coexposure of these viscose rayon

workers to hydrogen sulfide, tin oxide, zinc oxide and sulfate, sodium hydroxide, sulfuric acid, and

lead may account for a portion of the toxicity response.

Mental performance and personality disorders were examined in 17 long-term workers from each of

two rayon factories, one group with a long history of relatively high exposures to carbon disulfide
CARBON DISULFIDE 40

2. HEALTH EFFECTS

(mean concentration of carbon disulfide measured after 1971 was 57.8 ppm) and the other with lower

exposures (mean concentration of carbon disulfide measured after 1971 was 19.3 ppm). Twenty-one

test variables were used: 3 intelligence tests, 6 personality tests, and 12 ability measurements. The

workers from the factory with the highest exposure measurements showed more anxiety, introversion,

and depression than the other workers. They also did significantly worse on tests designed to measure

number facility, sustained attention, speediness, and carefulness. There were, however, no estimates of

individual exposure and no control for concomitant exposure to other chemicals (Foa et al. 1976).

Lack of attention and reduced perceptive ability were observed in viscose rayon workers exposed to

carbon disulfide at 0.6-2.6 ppm with peaks of 11.2 ppm (Cassitto et al. 1993). The investigators

suggest the effects may be a result of transient peak concentrations of carbon disulfide rather than the

low concentrations. Other studies have indicated that grain storage workers had intense exposures

interspersed often with periods of more minimal contact with anti-weevil chemicals (Matthews et al.

1990; Peters et al. 1982, 1986a, 1986b, 1988).

Behavioral examinations (psychological tests, psychomotor tests, and cognitive-perceptual tests) of

131 workers in a rayon plant who were exposed to carbon disulfide were compared to those of

167 workers who worked in textile plants that manufactured other synthetic fibers. Exposure and

companion (control) groups and exposure levels are the same as those described for the Johnson et al.

(1983) study. The workers completed a checklist of symptoms characteristic of various

neurobehavioral syndromes. The results showed no behavioral changes of any major significance.

The rayon workers did report symptoms of neurobehavioral ailments, however. Workers were

classified individually according to job title and the past and present exposure levels for individuals in

that job title. The exposures measured in the plant were generally below 20 ppm, suggesting that

these levels may be too low to identify behavioral changes (Putz-Anderson et al. 1983).

A study of neuropsychological variables in carbon disulfide-exposed workers investigated 120 workers

selected on the basis of age not exceeding 50 years and an absence of family or personal history of

nervous disorders. The test battery consisted of three intelligence tests, three personality

questionnaires, a test of memory involving measures of perception, recognition, and free recall, and

two performance measures. Workers were grouped according to exposure categories (none; low, about

20 ppm; medium, between 20 and 38 ppm; and high, greater than 38 ppm). The no-exposure and

low-exposure categories were combined for analysis. Differences in the groups’ measurements were

statistically analyzed and revealed decreased intelligence scores, performance, and memory and
CARBON DISULFIDE 41

2. HEALTH EFFECTS

increased fatigue and depression in the workers with higher exposures. These changes were dose

related, although the exposure variable was categorical and not quantitative (Cassitto et al. 1978; Cirla

et al. 1972). Neurological effects in 50 viscose rayon workers occupationally exposed to an average

concentration ranging from 3.2 to 9.6 ppm carbon disulfide for 3-12 years were compared to a pairmatched control group from unexposed departments of the plant (Cirla and Graziano 1981). There

were no significant differences in the exposed and control groups for three considered parameters:

maximum and minimum conduction velocity and residual latency on the peroneal nerve.

Psychological examinations of 25 pairs showed no apparent differences between the exposed and

control groups. Electromyography and clinical diagnosis revealed only one exposed worker with

minimal neuropathy. Furthermore, four exposed and two unexposed workers were clinically diagnosed

with the nontoxic syndrome and radiculopathy, and no cases of polyneuropathy were found in either

group. Clinical diagnosis of central impairment was found in two exposed workers and no unexposed

workers with psychoorganic syndrome. The number of neuropathy or psychoorganic cases was not

significant enough to associate exposure to carbon disulfide with adverse neurological effects.

Furthermore, the absence of significant differences in peripheral nerve motor conduction velocity and

psychological parameters lends particular weight to the conclusion that occupational exposure below

9.6 ppm (maximum exposure concentration) for up to 12 years does not cause recognizable adverse

neurological health effects.

In a cross-sectional study of the chronic effect of carbon disulfide exposure on the central nervous

system, researchers measured the brain stem auditory evoked potential (BAEP) in Japanese spinning

workers from a viscose rayon factory (Hirata et al. 1992a). The workers were divided into three

groups depending upon length of exposure: 34 current workers exposed for more than 240 months,

24 current workers exposed for 24-84 months, and 16 former workers exposed for more than

120 months. The 39 unexposed controls were workers in a nylon filament factory. The TWA

exposures ranged from 3.3 to 8.2 ppm (mean 4.76 ppm). The latencies of the three main components

of BAEP increased compared to those in the control group. The significantly higher interpeak

latencies in workers exposed to carbon disulfide for more than 240 months suggest that chronic

exposure to carbon disulfide involves the auditory ascending tract in the brain stem. Despite long

exposure, BAEP parameters in workers exposed to more than 120 months were not significantly higher

than those of the control group.
CARBON DISULFIDE 42

2. HEALTH EFFECTS

Neuropsychological and neuropathological examinations were performed on 16 viscose rayon workers

in Norway exposed to 3.2-28.9 ppm for an average of 20 years (Aaserud et al. 1990). Workers were

also exposed to hydrogen sulfide (80 mg/m3

) while working. The clinical tests performed included

electroencephalograms (EEG), electromyograms (EMG), computerized axial tomography (CAT)

scans, and motor and sensory neurography. Workers complained of dyspnea, tiredness, nausea,

decreased memory, and irritability. Major neurological deficits occurred in 6/16 workers, while minor

deficits occurred in 9/16. Pathological changes in EEG patterns were noted in two workers while six

showed pathological changes in EMG. Decreased nerve impulse conduction and motor, sensory, and

mixed motor/sensory neuropathies were demonstrated. Cerebral or cerebellar atrophy was noted in

13/16 workers, and neurophysiological examinations showed psychomotor retardation and

coordination difficulties. Study deficiencies were the lack of a control group and confounding factors

in the subjects, including alcohol abuse.

The neurotoxic effects after 10 years or more of long-term, low-level occupational exposure to carbon

disulfide in workers at a viscose rayon plant were examined by assessing markers of the peripheral and

autonomic nervous system (Ruijten et al. 1990, 1993). Reinvestigation of 44 of 45 exposed and 31 of

37 matched control workers revealed changes in the motor nerve conduction velocity (Ruijten et al.

1993). The exposure concentration in the two studies varied from 1 to 30 ppm. For peripheral nerves,

a decrease in the conduction velocity in both fast and slow motor nerve fibers (peroneal nerve) was

observed in exposed workers. Sensory conduction velocities were reduced and the refractory period of

the sural nerve was increased. The effects on the sural nerve were pronounced. A small decrease in

conduction velocities in the absence of symptoms of neuropathy and decreased response amplitudes

suggest a mild presymptomatic nerve impairment.

The relationship between electric impulse transmission and visual stimuli was examined in a group of

21 patients with chronic carbon disulfide exposure in a rayon production plant for 20-36 years and

control groups of 25 or 36 healthy unexposed males (Sikora et al. 1990). A significant correlation was

observed in latency and amplitude of response. The correlations suggest cerebral dysfunction of the

visual pathway and diminished ability to transform visual information to motor reaction at the level of

the cortical association center. The study was limited by the lack of quantification of exposure levels

and the variability in responses in the exposed group.
CARBON DISULFIDE 43

2. HEALTH EFFECTS

Finger tremor accompanying voluntary movement was studied in 19 control subjects and 19 grain

workers exposed to carbon disulfide-based fumigants for 13.5 years (Chapman et al. 1991).

Comparison was made between finger tremor detected using computerized techniques and

Parkinsonian tremor detected visually on neurological examination. The measurement of amplitude

and frequency provided a more accurate diagnosis than the visual observation. The distribution of

tremor frequency power in the grain workers was reminiscent of tremor in idiopathic Parkinson’s

disease. These findings suggest that the measurement of subtle tremor frequency changes may provide

an early indication of chronic carbon disulfide poisoning. However, the study was limited by the lack

of exposure concentrations and the use of only symptomatic cases.

Animal studies on the neurotoxicity of carbon disulfide have usually been done in rats and provide

histopathologic and neurochemical data that support a neurotoxic effect for carbon disulfide. In

general, the doses used in these animal studies are considerably higher than the occupational exposures

seen in epidemiological studies.

In a study that examined effects in rats (Wistar) and mice (H strain) exposed to carbon disulfide for

4 hours, rats appeared to be more sensitive than mice (Frantik et al. 1994). The concentration that

resulted in a 30% inhibition of electrically evoked seizure discharge was 1,370 ppm in male rats and

2,600 ppm in female mice.

Short-term exposures to inhaled carbon disulfide in rats have shown consistent results with respect to

brain chemistry changes and sensory and motor nerve conduction alterations. Rats exposed for

4 hours a day for 10 days at 642 ppm showed decreased noradrenaline, increased dopamine, and

elevated tyrosine in the brain (Magos and Jarvis 1970). The authors proposed that changes in tyrosine,

dopamine, and noradrenalin may be caused by a feedback mechanism in which the increase in

dopamine prevents a conversion of tyrosine to dopamine. No relationship to clinical signs or

behavioral effects was noted. Further work at the same exposure level indicates that the noradrenaline

concentration remains significantly decreased for at least 20 hours after a l-hour exposure, but the

dopamine levels return to normal (Magos et al. 1974). Female rats exposed to 777.1 ppm for 12 hours

showed swollen brain mitochondria and elevated brain adenosine triphosphate (ATP) levels compared

to controls (Tarkowski et al. 1980). However, no histopathological changes were noted in brain tissue.

Under the same experimental conditions, rats exposed to 257 ppm for 5 hours a day, 5 days a week,
CARBON DISULFIDE 44

2. HEALTH EFFECTS

for 10 months showed biochemical changes that involved uncoupling of oxidative phosphorylation

(Tarkowski et al. 1980).

Mice exposed to 0, 120, 580, 2,200, or 3,700 ppm carbon disulfide for 1 hour showed no behavioral

changes at 120 ppm but did at 580 ppm and higher (Liang et al. 1983). The same study investigated

an intermediate-duration exposure as well. Mice were exposed to 0, 260, 580, or 840 ppm carbon

disulfide for 4 hours a day, 5 days a week, for approximately 30 days. No changes were observed at

260 ppm, but concentration-related decreased responses to operant behavior were observed at 580 ppm

and at 840 ppm. The study is limited because there is no indication of the number of animals used.

For the 30-day exposure study, there was no truly unexposed control, since some of the mice from the

acute phase were used. The same mice were used for all doses in the intermediate phase, with

l0-14 days between each dose exposure. It is therefore unclear whether the effects noted were due to

the dose or were a cumulative effect of previous doses.

Male Wistar rats were exposed to 578 ppm carbon disulfide for 10 months. Also reported in the same

paper were results from an 18-hour exposure to 803 ppm. The rats developed different signs of

poisoning depending upon the type of exposure: the l0-month exposure caused loss of motor

equilibrium, muscular weakness, and hind-limb paresis, and the acute dosing caused severe narcosis,

reduced cardiac and respiratory rate, straightening of hind limbs, and lower body temperature.

However, brain mitochondria in both groups of animals exhibited the same types of disturbances in

oxidative phosphorylation-uncoupling of oxidative phosphorylation, decreased phosphorus-oxygen

(P:O) ratio, and a lower ATP-inorganic phosphorus (ATP-Pi) exchange rate (Tarkowski and Sobczak

1971). Although this study used only six or seven animals and one dose, the results were consistent

and do not conflict with other information regarding the effects of carbon disulfide on metabolism.

A narcotic-like stupor was observed during carbon disulfide exposure of rats at 600 ppm 10 hours a

day for 14 days (Wilmarth et al. 1993). By the end of the study, mild ataxia and moderate hind-limb

splay were also observed. Neurobehavioral effects were observed in rats exposed to 642.2 ppm of

carbon disulfide for 4 hours a day, 5 days a week, for 6 weeks. No changes were seen after 3 weeks

of exposure, but hind-limb extensor responses and motor coordination were impaired after 6 weeks of

exposure. Recovery had occurred by 3 weeks after cessation of exposure. The carbon

disulfide-exposed rats were stimulated less than the air-ventilated controls by 3 mg/kg of

d-amphetamine, suggesting that repeated exposure to carbon disulfide affects the availability of brain
CARBON DISULFIDE 45

2. HEALTH EFFECTS

noradrenaline for release. This effect also disappeared by 3 weeks after exposure (Tilson et al. 1979).

These results are consistent with those of Magos and Jarvis (1970) and Magos et al. (1974) (discussed

above) in which noradrenaline was shown to be decreased in the brains of acutely exposed rats.

Motor capacity (static endurance and dynamic performance at forced motor activity) was studied in a

total of 96 albino rats that were repeatedly exposed to 0 (42 males/group), 48, 385, or 770 ppm carbon

disulfide via inhalation (18 males/group) (Frantik 1970). Acute toxicity was measured 0-60 minutes

after termination of exposure, and chronic toxicity was measured 48-72 hours postexposure. After

initial exposure to the 770-ppm dose there were reductions in spontaneous motor activity (60%),

conditioned avoidance, and motor performance. Effects persisted for 24 hours but disappeared

completely 3 days postexposure and failed to reappear after repeated experiments. Symptoms of motor

impairment were observed after a variable latent period and were related to exposure concentration

(385-ppm dose, 18 weeks; 770-ppm dose, 8 weeks). On the average, motor capacity (maximum speed

and endurance at dynamic performance) was reduced by 40-50% at the 385-ppm dose and by more

than 80% at the 770-ppm dose. Motor function recovered during the first 8 weeks. The study is

limited by the lack of quantitative measurement of nervous system impairment.

Neuromuscular and sensory effects were evaluated in Long Evans rats exposed to 500 ppm (6 hours a

day for 5 or 12 weeks) using an acoustic startle test (Clerici and Fechter 1991). Neuromuscular

integrity was shown to be compromised based on auditory startle reflex amplitude; animals showed a

70% recovery 4 weeks postexposure. No clinical signs of neurotoxicity or changes in hearing function

or acoustic tone thresholds were noted. Use of a single exposure concentration precluded assessment

of dose response.

The chronic effect of carbon disulfide exposure on the central nervous system was examined by

auditory brainstem responses (ABR) in female JCl Wistar rats (Hirata et al. 1992b). Rats were

exposed by inhalation to 200 or 800 ppm, 6 hours a day, 5 days a week, for 15 weeks. Auditory

responses were measured before exposure, every 3 weeks during exposure, and in weeks 2 and 6 after

exposure. The delayed latencies of ABR were observed at 800 ppm suggesting a conduction

dysfunction. The transient delay of ABR responses at 200 ppm indicated only slight conduction

dysfunction. Rats recovered 2-6 weeks after carbon disulfide exposure.
CARBON DISULFIDE 46

2. HEALTH EFFECTS

Neuropathology has been investigated in several studies of carbon disulfide exposure in rats. The

results are consistent with regard to effect but not with regard to the dose required to produce the

effect. Axonal swellings, demyelination at axonal enlargements, swelling of nerve terminals at

neuromuscular junctions, muscle atrophy and degeneration, damage of the terminal axons, myelin

indentation, fiber breakdown, and distended mitochondria have been reported (Jirmanova and Lukas

1984; Juntenen et al. 1977; Szendzikowski et al. 1974). These experiments used only one dose, which

varied between 482 and 770.7 ppm, and a control group; therefore, no dose response can be

established using only these data. A study by Rebert and Becker (1986) attempted to establish a

temporal dose-response relationship for peripheral nerve conduction activity. Their work with rats

showed that visual-evoked potentials and conduction time in peripheral nerves and in brainstem

auditory pathways were longer in animals exposed to 800 ppm, 7 hours a day, 7 days a week than in

those exposed to 400 ppm for the same duration (11 weeks). The potentials in the groups exposed to

lower levels were longer than in the controls, although the differences were not statistically significant.

Four female monkeys exposed to 256 ppm for 6 hours a day, 5 days a week, for 5-13 weeks suffered

permanent visual impairment with degeneration of retinal ganglion cells (Merigan et al. 1988). Visual

acuity thresholds in two macaque female monkeys were severely disrupted after 5 weeks of

intermittent exposure (6 hours a day, 5 days a week) to 256 ppm carbon disulfide. One monkey

showed some recovery at 16 weeks postexposure; the other showed no improvement (Merigan et al.

1985).

Neurological effects such as hind-limb motor difficulties, reduced nerve conduction velocity, and

degeneration of nerve fibers were seen in rats exposed to 700 ppm of carbon disulfide for 5 hours a

day, 5 days a week, for 12 weeks (Colombi et al. 1981). These pathologies continued to 3 weeks

postexposure but were slightly improved 6 weeks after carbon disulfide exposure. The improvement

continued up to the 18th week of recovery, suggesting that the process may be reversible. This study

was limited by the use of a single carbon disulfide dose. In another study, paralysis of hind limbs was

observed in Wistar rats exposed to 546 ppm for 8 months (5 hours a day, 6 days a week); this effect

was not seen at 321 ppm (Wronska-Nofer 1973).

Morphological changes in the peripheral nerve and the spinal cord were studied in rats and mice

exposed to 50, 300, or 800 ppm carbon disulfide, 6 hours a day, 5 days a week, for 90 days (Gottfried

et al. 1985; Toxigenics 1983a, 1983b, 1983c). Rats exposed to 50 ppm showed no changes in any

parameters; rats exposed to 300 ppm showed only occasional swelling of axons in dorsal corticospinal
CARBON DISULFIDE 47

2. HEALTH EFFECTS

fibers of the lumbar spinal cord; and rats exposed to 800 ppm showed extensive neurofilamentous

axonal swelling in the spinal cord. Neurofilamentous axonal swelling was particularly seen in the

distal portion of long fiber tracts, including prominent swellings in the dorsal ascending sensory fibers,

whereas it was only intermittently seen in the dorsal corticospinal fibers. In addition, extensive

peripheral nerve changes were seen at the level of the posterior tibia1 nerve. The sciatic nerve showed

no appreciable loss and only occasional axonal swelling. Ultrastructurally, the axonal swellings

contained abundant disorganized neurofilaments, decreased microtubules, and thin or absent myelin.

Brain and body weight were decreased in proportion to the concentration, with the decrease in brain

weight statistically significant in the 800-ppm group.

The highest NOAEL values and all reliable LOAEL values for neurological effects are recorded in

Table 2-1 and plotted in Figure 2-l.

2.2.1.5 Reproductive Effects

Data on reproductive effects of carbon disulfide in humans come from studies of occupational cohorts

that are exposed primarily via inhalation to carbon disulfide in the workplace. These studies are

limited by generally poor exposure measurements, concomitant exposures to other chemicals, and

occasionally the lack of appropriate control groups. Nonetheless, the data provide some evidence that

carbon disulfide may act on the reproductive system.

In some studies, effects in females included an increased incidence of spontaneous abortion at levels as

low as about 2 ppm (6-7 mg/m3

) (Heinrichs 1983; Wang and Zhao 1987). Other epidemiological

studies have not corroborated these reports, however. In a community study of spontaneous abortion,

occupation, and air pollution, the study authors found no relationship between carbon disulfide

concentrations and miscarriage rates (Hemminki and Niemi 1982). Another study reported that women

exposed to 0.5-4.7 ppm (1.7-14.8 mg/m3

) had significantly more menstrual disorders than nonexposed

women; however, there was no increase in the rate of spontaneous abortion, stillbirth, premature

delivery, or congenital malformation (Zhou et al. 1988). Increased rates of menstrual disorders and

toxemia of pregnancy were also reported in workers exposed to 12-18 ppm carbon disulfide (Cai and

Bao 1981). However, concomitant exposures to other chemicals were not considered.
CARBON DISULFIDE 48

2. HEALTH EFFECTS

Researchers examined 15 men exposed in a viscose plant to unspecified concentrations of carbon

disulfide and hydrogen sulfide for 10-36 years and compared them with 16 age-matched controls

(Wagar et al. 1981). The carbon disulfide concentrations at the viscose plant were below 10 ppm just

prior to the study, but the levels had been higher previously. Serum follicle-stimulating hormone

(FSH) and luteinizing hormone (LH) were significantly increased in the exposed workers. The study

authors concluded that this was a sign of primary gonadal insufficiency. However, no changes were

seen in serum testosterone or thyroid functions. Exposures were not well characterized, only a small

number of workers were examined, and semen analysis was not performed; these limitations preclude

developing conclusions from this study. In a National Institute for Occupational Safety and Health

(NIOSH) study of 434 American workers, semen quality was evaluated in 86 exposed and 89

unexposed workers (Meyer 1981). The duration of carbon disulfide exposure ranged from 12 months

to 257 months. Statistical analysis of sperm count, ejaculation volume, and morphology patterns

showed no statistically significant difference between the exposed and unexposed groups. Exposures

were not well characterized and were designated as definitely high (DH=18 workers), moderate (M=27

workers), definitely low (DL=22 workers), and difficult to quantify or other (O=19 workers). A

further limitation was the possibility that the poor rate of worker participation (50%) in the semen

sampling could have affected the results. In another workplace study, men (n=116) exposed to carbon

disulfide at 0.3-9.6 ppm or >9.6 ppm complained of decreased libido and impotence more frequently

than 79 unexposed controls (Vanhoorne et al. 1994). Reproductive histories did not reveal any effects

on fertility. Examination of semen from 43 exposed workers and 35 controls did not show any

adverse effects.

A review of some reports from the USSR and other Eastern Bloc countries indicates that, although

these studies may be deficient in design and reporting of data, there is enough evidence to warrant

concern about the effects of carbon disulfide on the female reproductive system. Reported adverse

effects included menstrual disturbances, endocrine alterations, and increased incidence of miscarriage

(Zielhuis et al. 1984).

Effects in males occupationally exposed to carbon disulfide have included teratospermia, decreased

sperm motility, hypospermia, and decreased libido (Lancranjan 1972). Studies have stressed the

importance of assessing the statistical power of a test for comparing sperm count or morphology

(Wyrobek 1983) and the need for more clearly defining the link between changes in morphology and

altered fertility (Schrag and Dixon 1985). The relationship between paternal exposure to carbon
CARBON DISULFIDE 49

2. HEALTH EFFECTS

disulfide and pregnancy was studied in 540 workers and their wives (NIOSH 1983). Patterns of fetal

loss, number of births, and time between live births were examined by comparing pregnancies

conceived after paternal exposure to carbon disulfide to pregnancies occurring in an unexposed

population. Several statistical analyses showed no relationship between carbon disulfide exposure and

fertility measures.

Evidence in animals supports the effect of carbon disulfide on the reproductive system. Male LongEvans rats exposed to 600 ppm carbon disulfide 5 or 6 hours a day, 5 days a week, for 10 weeks

showed significant alterations in copulatory behavior and a decrease in ejaculated sperm counts by the

4th and 7th weeks of exposure, respectively. Caudal epididymal sperm counts were not depressed and

testes appeared histologically normal. The plasma testosterone levels were significantly reduced.

Exposed rats had significantly reduced weight gains during the experiment (Tepe and Zenick 1984;

Zenick et al. 1984).

The NOAEL and LOAEL values for reproductive effects in animals are recorded in Table 2-l and

plotted in Figure 2- 1.

2.2.1.6 Developmental Effects

Developmental effects of carbon disulfide have been reported in several animal studies. Inhalation

exposure of pregnant rats did not produce congenital malformations at levels of 3.2 and 0.01 ppm.

However, administration of 3.2 ppm was also associated with viability impairments and retardation of

morphological and sensory development, and 0.1 ppm was associated with behavioral changes

(Tabacova and Balabaeva 1980b). To study the reproductive toxicity and teratogenicity of carbon

disulfide, other inhalation exposure studies of pregnant Wistar or Sprague-Dawley rats and New

Zealand white rabbits exposed to 20 or 40 ppm carbon disulfide were conducted (Hardin et al. 1981;

NIOSH 1980). Results showed an absence of maternal toxicity, fetal toxicity, and teratogenicity.

These studies were limited by the absence of information regarding exposure conditions and the

presentation of results as a summary of 10 tested chemicals with little experimental detail.

A developmental study was conducted using New Zealand White rabbits, which are more sensitive

than rats to the effects of carbon disulfide (PA1 1991). In this study, rabbits (24/group) were exposed

by inhalation to 0, 60, 100, 300, 600, or 1,200 ppm, 6 hours a day, on gestation days 6-18. Animals
CARBON DISULFIDE 50

2. HEALTH EFFECTS

were evaluated on day 29. Maternal toxicity was observed as reduced body weight gain and adverse

clinical signs (ataxia, lowered food consumption, wheezing) in the 1,200-ppm group, with some

sporadic hematologic alterations at 600 ppm (for example, decreased hematocrit on gestation day 19).

These effects were not seen in an initial range-finding study in which rabbits were exposed to 1,000

ppm carbon disulfide. Embryotoxic effects (reduced mean fetal body weight) and post-implantation

loss were seen in the 600- and 1,200-ppm exposure groups. Teratogenic effects (increased cumulative

skeletal and visceral malformations) were also seen at 1,200 ppm carbon disulfide. In this study the

NOAEL for developmental effects was 300 ppm and the NOAEL for maternal toxicity was 600 ppm

because of the lack of biological significance in the hematologic findings at this exposure

concentration.

In another developmental study, B6C3Fl mice and Fischer and Sprague-Dawley rats were exposed to

0, 49, 297, or 798 ppm carbon disulfide 6 hours a day, 5 days a week, for 90 days (Toxigenics 1983a,

1983b, 1983c). Examination of the mice and rats that received the highest dose revealed maternal

toxicity but no developmental toxicity.

Based on data from mice exposed for 10 minutes to 750 ppm 14C-labelled carbon disulfide, carbon

disulfide and its metabolites pass the placenta at all stages of gestation and localize selectively in

tissues reported to be target organs for the effects of this chemical (brain, blood, liver, and eye)

(Danielsson et al. 1984). This finding provides evidence that carbon disulfide or its metabolites may

exert effects directly on the embryo.

Maternal reproduction and fetal parameters were evaluated for groups of 20-23 pregnant SpragueDawley rats exposed to 0, 100, 200, 400, and 800 ppm carbon disulfide, 6 hours a day, during days

6-20 of gestation (Saillenfait et al. 1989). Maternal toxicity for the animals exposed to 400 or

800 ppm was evidenced by the significant decrease in maternal body weight gain (19% and 31%

decrease) of the exposed rats compared to the controls (p≤0.01). When gravid uterine weight was

subtracted from the dam’s body weight gain, the maternal weight was significantly reduced by 56%

and 144% versus the controls. Exposure to 400 or 800 ppm carbon disulfide resulted in a significant

reduction of fetal body weights for both sexes; the respective weight reduction from control for males

was 7% and 14% (p≤0.0l), and for females was 6% and 20% (p≤0.01). Clubfoot was the only

external malformation occurring at higher frequency than in the controls; however, the one fetus

affected in one litter at 400 ppm and the seven fetuses affected in five litters at 800 ppm were not
CARBON DISULFIDE 51

2. HEALTH EFFECTS

sufficient for statistical significance. Incidence of unossified stemebrae was significantly increased in

groups exposed to 800 ppm (p≥0.0l), but no other soft tissue anomalies or major skeletal anomalies

were present in any treated groups.

Behavioral and neurotoxic effects in the offspring of rats exposed via inhalation have been reported.

Perinatal mortality was shown to be dose related to prenatal carbon disulfide exposure levels (225 and

642 ppm) in rats (Lehotzky et al. 1985). Exposure to 642 ppm carbon disulfide throughout pregnancy

for 2 hours daily produced no malformations of fetuses in rats or mice but did increase the death rates

of the embryos at all stages of intrauterine development (Yaroslavski 1969).

In a developmental study in which only the dams of both F0 and F1 generations were dosed during

gestation, the F1 offspring of albino rats were exposed for 8 hours daily throughout pregnancy to 64.2,

32.1, 3.2, or 0.01 ppm carbon disulfide and were postnatally exposed to the same exposure

concentrations for the same duration (Tabacova et al. 1983). Both the F1 and F2 generations showed a

marked increase in malformations and behavioral and learning changes at the highest concentration,

but the F2 generation also showed the same effects at the two lower concentrations. Maternal toxicity

and teratogenic effects were observed in offspring of dams of all generations exposed to 32 or 64 ppm

carbon disulfide. The two lower exposure levels, although nonteratogenic, provoked functional and

behavioral disturbances of varying degree. The study authors suggested that carbon disulfide causes

preconditioning to increased effects in the next generation. There are, however, no other data that

support a conditioning effect of carbon disulfide. This study is limited by the lack of information on

chemical exposure (including chemical purity, atmosphere verification, or analytical techniques) on the

control animals, and on the methods used to select F1 and F2 generations. In addition, there was in

excess of a 300-fold difference in concentration below the lowest treatment level (0.01 ppm) and the

next higher level (3.2 ppm); there was not a clear dose response; there was no information on mode of

control exposure; there was a lack of concurrent controls (separate control animals were used for

higher and lower exposure animals); animal diet and housing conditions were not specified; and there

was a lack of information regarding the significance of the increased behavioral effects measured in

exposed animals (reduced exploratory activity and “increased emotional activity”). Finally, the low

effect levels found in this study were not substantiated in subsequent inhalation studies by Saillenfait

et al. (1989) and PAI (1991). However, the design of the Tabacova et al. (1983) study was

significantly different from both the Saillenfait et al. (1989) and PAI (1991) studies. The lack of
CARBON DISULFIDE 52

2. HEALTH EFFECTS

substantiation of the Tabacova et al. (1983) study may be due to differences in the designs of the

Saillenfait et al. (1989) and PAI (1991) studies.

All reliable LOAEL values for developmental effects are recorded in Table 2-l and plotted in

Figure 2-1.

2.2.1.7 Genotoxic Effects

No studies were located regarding genotoxic effects in humans after inhalation exposure to carbon

disulfide.

Carbon disulfide failed to produce significant chromosomal aberrations in the bone marrow of rats

inhaling 20 and 40 ppm for either acute or intermediate periods (NIOSH 1980).

Other genotoxicity studies are discussed in Section 2.5.

2.2.1.8 Cancer

There is no definitive evidence for an increased cancer potential from carbon disulfide in humans.

The number of deaths due to neoplasms was compared in a cohort of rayon plant workers versus paper

mill workers, and no significant differences in mortality were found between the years 1967 and 1982

(Nurminen and Hernberg 1985). Thus, there appears to be no association between occupational

exposure to carbon disulfide and cancer in this study. (This information was reported incidentally in

another study examining cardiovascular mortality, described in Section 2.2.1.2.) On the other hand,

data supporting an increased odds ratio for lymphocytic leukemia in rubber workers exposed to several

different kinds of solvents including carbon disulfide have been reported (Arp et al. 1983). Categories

of exposure were based on process descriptions for the person’s job classification and not on ambient

air measurements. Jobs incorporating benzene use were specifically excluded. The odds ratio was

not, however, statistically significant at p<0.05. Data did indicate a statistically significant (p<0.00l)

odds ratio for exposure to carbon disulfide and development of lymphocytic leukemia when researchers

carefully analyzed specific exposures in the group to solvents other than benzene (carbon disulfide, toluene,

xylene, naphtha, ethanol, acetone, hexane, phenol, trichloroethylene, trichloroethane, and 13 others). This

odds ratio was higher than that detected for benzene, which was not statistically
CARBON DISULFIDE 53

2. HEALTH EFFECTS

significant (Checkoway et al. 1984). Deaths from lymphatic leukemia in this same cohort were also

shown to be associated with exposure to carbon disulfide (Wilcosky et al. 1984). There are several

potential confounding factors in these analyses. All three reports are based on nested case-control

studies from the same cohort of rubber workers. The small number of cases for each particular type

of cancer examined and the large number of solvents used in the analysis indicate a need for cautious

interpretation. Many of the solvents were used in mixtures so that identifying a single causal agent is

not possible. Confounding factors from nonoccupational or other occupational exposures were not

taken into account. In addition, the system designed to estimate historical exposures may have had

weaknesses, specifically that the designation of “permitted to use” may not indicate actual use.

No studies were located regarding cancer in animals after inhalation exposure to carbon disulfide.

2.2.2 Oral Exposure

Humans are not likely to be exposed to significant quantities of carbon disulfide in food or water.

Most information on the effects of oral exposure to carbon disulfide is derived from studies in animals.

These studies are summarized in Table 2-2 and Figure 2-2, and the findings are discussed below. All

doses are expressed as mg/kg/day.

2.2.2.1 Death

First-hand reports of death from oral exposure to carbon disulfide are very rare. Three case reports

cited in Gosselin et al. (1984) indicate that half an ounce (concentration not specified) caused death

following ingestion.

In mice, Gibson and Roberts (1972) determined the median oral lethal dose (LD50) over a 24-hour

period to be 3,020 mg carbon disulfide/kg. In Wistar rats, a single dose of carbon disulfide

administered by gavage at doses up to 632 mg/kg did not cause death, nor were deaths noted in the

rats after a 4-week (5 days a week) administration of 253 mg/kg/day carbon disulfide, also by gavage

(Hoffmann and Klapperstück 1990). No deaths were noted after a 4-week (5 days a week)

administration of 253 mg/kg/day carbon disulfide by gavage to Wistar rats (Hoffmann and Muller

1990).
CARBON DISULFIDE 54

2. HEALTH EFFECTS

2.2.2.2 Systemic Effects

The systemic toxicity of carbon disulfide after oral exposure is manifested primarily in the liver,

mainly as enzymatic disruptions. Animal data show that hepatic toxicity is potentiated by pretreatment

with agents that induce hepatic microsomal enzymes. Cardiovascular effects have also been reported,

although these data are limited.

No studies were located regarding respiratory, gastrointestinal, renal, dermal, or ocular effects in

humans or animals after oral exposure to carbon disulfide. Information on cardiovascular,

hematological, musculoskeletal, hepatic, and body weight effects is presented below. The highest

NOAELs and a reliable LOAEL for hepatic and cardiac effects in mice and rats, respectively, for the

acute-duration category are recorded in Table 2-2 and plotted in Figure 2-2.

Cardiovascular Effects. No studies were located regarding cardiovascular effects in humans after

oral exposure to carbon disulfide.

Anesthetized male Wistar rats acutely exposed to 632 mg carbon disulfide/kg (0.5 mL/kg) had a

significantly reduced occurrence of some cardiac arrhythmias after coronary occlusion by surgical

ligation when compared to controls (Hoffman 1987). In addition, the heart rate measured before the

procedure was significantly lower in exposed rats than in the controls (Hoffman 1987).

Exposure of anesthetized male rats at a lower gavage dose (253 mg/kg/day) daily for 4 weeks

produced a decrease in left ventricular systolic pressure and changes in an electrocardiograph

(Hoffmann and Klapperstück 1990). When coronary ligation was performed 1 hour after exposure,

these animals showed an earlier appearance of cardiac arrhythmias, delay in acotroitine-induced

arrhythmia, and decreased survival. No exposure-related effects occurred at a lower dose level

(126 mg/kg). This study also examined the effects of a single gavage administration of carbon

disulfide on ECG parameters in anesthetized rats. Changes in ECG were noted at 373 and 506 mg/kg;

dose response was noted in QTc. Heart rate was decreased at 632 mg/kg. No significant changes in

contractile force of the left ventricle were noted.

In conscious male Wistar rats administered 506 mg/kg carbon disulfide once by gavage, blood pressure

was decreased (p≤0.001) 5 hours after treatment, but this change was reversible in another 5 hours




CARBON DISULFIDE 59

2. HEALTH EFFECTS

(Hoffmann and Klapperstück 1990). The NOAEL was 253 mg/kg. In subacute experiments, no

effects on blood pressure or heart rate were observed in rats after receiving carbon disulfide at 126 or

253 mg/kg/day for 4 weeks; however, the study authors did not examine the effects on these

parameters at 506 mg/kg/day.

Hematological Effects. No studies were located regarding hematological effects in humans after

oral exposure to carbon disulfide.

In a study by Pilarska et al. (1973), rats administered 25 mg carbon disulfide/kg/day for 60 days

developed normochromic and normocytic anemia, eosinopenia, and an increase in reticulocyte cell

numbers. No changes in leukocyte or platelet numbers were observed, however. No other studies

were found on the hematological effects in animals after oral exposure to carbon disulfide.

Musculoskeletal Effects. No studies were located regarding musculoskeletal effects in humans

after oral exposure to carbon disulfide.

In rats treated by gavage with carbon disulfide in olive oil at 12.5 mg/kg/day for 1, 2, or 4 weeks, a

decreased response of the ancoccygeus muscle to noradrenaline was observed relative to vehicletreated controls (Gandhi and Venkatakrishna-Bhatt 1993). The response of the muscle to

noradrenaline was tested in vitro in a muscle bath. The reduction in sensitivity to noradrenaline

increased with increasing duration of exposure. The investigators suggested that the mechanism of

decreased noradrenaline responsiveness may be a result of a block of calcium influx, a delay of the

calcium efflux, an inhibition of the uptake of calcium, a decreased sensitivity to calcium by the

muscle, or a combination of these mechanisms.

Hepatic Effects. No studies were located regarding hepatic effects in humans after oral exposure to

carbon disulfide.

In animals, oral exposure to carbon disulfide does not appear to cause significant liver toxicity,

although the data are limited. Male mice orally exposed to 3-300 mg/kg/day (1-14 days) have shown

rapid, reversible, dose-related suppression of hepatic microsomal enzymes (Masuda and Yasoshima

1988; Masuda et al. 1986). An acute-duration MRL of 0.01 mg/kg/day was derived based on dosedependent decreases in the activities of liver microsomal drug-metabolizing enzymes in mice (Masuda
CARBON DISULFIDE 60

2. HEALTH EFFECTS

et al. 1986). The LOAEL for this effect was 3 mg/kg/day. The following enzyme activities were

decreased: hydroxylation of aniline, O-dealkylation of p-nitroanisole, 7-ethoxycoumarin and

7-ethoxyresorufin, N-demethylation of N,N-dimethylaniline, NADPH-cytochrome P-450 reductase

activity, and P-450-associated peroxidase activity. In addition, a decrease in cytochrome P-450

content and total heme content was observed. The inhibition of enzyme activities was reversible.

There were no effects on the activities of NADH-ferricyanide reductase, NADPH-cytochrome c

reductase, flavin-containing monoxygenase, UDP-glucuronyltransferase, glucose-6-phosphatase, heme

oxygenase, and glutathione S-transferase. Also, the content of cytochrome b5 was not altered. In rats

and mice, single oral doses of 1,263 mg/kg/day have caused necrotic lesions, suppression of

microsomal enzymes, fat accumulation, and increased liver weight. These effects are significantly

enhanced by pretreatment with a microsomal enzyme inducer such as phenobarbitone (Bond and

DeMatteis 1969; Bond et al. 1969; El-Masry et al. 1976; Freundt et al. 1974a). These studies are

limited by the use of an unspecified or small number of animals and, in the case of Bond et al. (1969),

by the lack of quantitative analysis.

In sheep pretreated with DDT, a dose of 63.2 mg carbon disulfide/kg/day was reported to cause

hepatic lesions accompanied by microsomal enzyme suppression and increases in total liver water and

electrolytes (Wilkie et al. 1985). This study is of limited value because of its lack of controls to

eliminate or account for possible synergistic effects of carbon disulfide and DDT.

Body Weight Effects. No studies were located regarding body weight effects in humans after oral

exposure to carbon disulfide.

In a study by Hoffmann and Klapperstuck (1990), male Wistar rats that had been administered

253 mg/kg/day carbon disulfide for 4 weeks by gavage showed a 10% decrease in body weight

compared to the controls. In a developmental toxicity study, gestational exposure to 25 mg/kg/day for

10 days produced a 19% decrease in the maternal body weight gain of female New Zealand rabbits

(Jones-Price et al. 1984b).

2.2.2.3 Immunological and Lymphoreticular Effects

No studies were located regarding immunological and lymphoreticular effects in humans or animals

after oral exposure to carbon disulfide.
CARBON DISULFIDE 61

2. HEALTH EFFECTS

2.2.2.4 Neurological Effects

No studies were located regarding neurological effects in humans after oral exposure to carbon

disulfide.

Compared to untreated rats, significant decreases in noradrenaline in the midbrain, hypothalamus, and

medulla oblongata were observed in rats 2 hours after they received a single gavage dose of 300 mg

carbon disulfide/kg body weight (Kanada et al. 1994). 3,4-Dihydroxyphenylalanine was significantly

increased in the midbrain, as was dopamine in the medulla oblongata. In the hippocampus, no change

in acetylcholine was observed. Clinical signs were not reported in this study. Hind-limb paralysis was

noted in New Zealand rabbits and outbred rats administered 25 and 400 mg/kg/day, respectively, for

l0-14 days during gestation (Jones-Price et al. 1984a, 1984b).

2.2.2.5 Reproductive Effects

No studies were located regarding reproductive effects in humans or animals after oral exposure to

carbon disulfide.

2.2.2.6 Developmental Effects

No studies were located regarding developmental effects in humans after oral exposure to carbon

disulfide.

Administration of carbon disulfide by oral gavage at doses up to 150 mg/kg/day to New Zealand white

rabbits (gestational days 9-19) and 600 mg/kg/day to albino rats (gestational days 6-15) resulted in

signs of maternal toxicity, such as transient hind-limb paralysis and loss of body weight over the

period of gestation (Jones-Price et al. 1984a, 1984b). In rabbits, there were statistically significant,

dose-related increases in the number of resorptions: mean values of 12, 43, 42, and 61 resorption at 0,

25, 75, and 150 mg/kg/day, respectively. Also, dead fetuses were found: 13%, 33%, 43%, and 62%

dead/litter for each respective dose group (p<0.00l). Average fetal body weight was decreased

significantly in each dose group: 45.5, 45.2, 41.6, 39.5 g/litter for each dose group, respectively. In

rabbits, there was a significant increase in the number of malformed fetuses in 150-mg/kg/day (highdose) animals; however, there was no characteristic pattern of carbon disulfide-related malformations.
CARBON DISULFIDE 62

2. HEALTH EFFECTS

Males were affected to a greater extent than females. The teratogenic effect of carbon disulfide

appears to be more severe in males at the 150-mg/kg/day dose than in females (when separated by

dose, p<0.036 for males and p<0.481 for females), whereas the percentage of live fetuses and the

average fetal body weight are not sex-dependent. In contrast, rats exhibited only decreased average

fetal weight at doses greater than 200 mg/kg/day (moderate dose). No increase in resorption, fetal

deaths, or malformations was found in carbon disulfide-treated rats.

The highest NOAEL and a reliable LOAEL for developmental effects in rats and rabbits are recorded

in Table 2-2 and are plotted in Figure 2-2.

2.2.2.7 Genotoxic Effects

No studies were located regarding genotoxic effects in humans or animals after oral exposure to

carbon disulfide.

Genotoxicity studies are discussed in Section 2.5.

2.2.2.8 Cancer

No studies were located regarding cancer in humans or animals after oral exposure to carbon disulfide.

2.2.3 Dermal Exposure

2.2.3.1 Death

No studies were located regarding death in humans or animals after dermal exposure to carbon

disulfide.

2.2.3.2 Systemic Effects

No studies were located regarding respiratory, cardiovascular, gastrointestinal, hematological,

musculoskeletal, hepatic, renal, or ocular effects in humans or animals following dermal exposure to

carbon disulfide.
CARBON DISULFIDE 63

2. HEALTH EFFECTS

Dermal Effects. Dermal contact with carbon disulfide is important in the occupational setting

(Dutkiewicz and Baranowska 1967). Viscose rayon workers have been reported to develop serious

blisters that progressed to hemorrhagic blisters covered by a thin membrane. These blisters appeared

on the fingers in spite of wearing rubber gloves (Hueper 1936).

The implication of carbon disulfide as the causative agent is supported by experiments in rabbits

whose ears were dermally exposed to carbon disulfide. Blisters similar to those found in the rayon

workers developed on the animals’ ears despite protective covering (Hueper 1936).

No studies were located regarding the following health effects in humans or animals after dermal

exposure to carbon disulfide:

2.2.3.3 Immunological and Lymphoreticular Effects

2.2.3.4 Neurological Effects

2.2.3.5 Reproductive Effects

2.2.3.6 Developmental Effects

2.2.3.7 Genotoxic Effects

Genotoxicity studies are discussed in Section 2.5.

2.2.3.8 Cancer

No studies were located regarding cancer in humans or animals after dermal exposure to carbon

disulfide.

2.3 TOXICOKINETICS

The available data from human and animal studies indicate that carbon disulfide is extensively and

rapidly absorbed via inhalation, oral, and dermal routes. Absorbed carbon disulfide is distributed

throughout the body. Because of its lipophilic nature, its distribution is greatest in organs such as the

brain and liver where it is metabolized to thiocarbamates. Carbon disulfide is metabolized by

cytochrome P-450 to an unstable oxygen intermediate which either spontaneously degrades to atomic

sulfur and carbonyl sulfide or hydrolyzes to form atomic sulfur and monothiocarbonate. Carbonyl
CARBON DISULFIDE 64

2. HEALTH EFFECTS

sulfide is converted to monothiocarbonate by carbonic anhydrase. Monothiocarbonate degrades to

generate carbonyl sulfide or forms carbon dioxide and hydrogen sulfide. Unlike in animals, oxidation

of sulfur to inorganic sulfate does not contribute significantly to the metabolism of carbon disulfide in

humans. Despite the differences in the metabolism of carbon disulfide between animals and humans,

dithiocarbamates are the common metabolites formed in these species after reaction with amino acids.

These metabolites contribute in part to the neurotoxic effects of carbon disulfide.

The kidneys are the primary route of excretion of carbon disulfide metabolites. Conjugation of carbon

disulfide or carbonyl sulfide with endogenous glutathione results in formation of thiozolidine-2-thione4-carboxylic acid and 2-oxythiazolidine-4-carboxylic acid, respectively, which are excreted in the

urine. The unmetabolized carbon disulfide is excreted unchanged in the breath, and small amounts

(<l%) have been detected in the urine.

2.3.1 Absorption

2.3.1.1 Inhalation Exposure

Studies conducted on human subjects reported rapid and extensive absorption of inhaled carbon

disulfide. Rapid absorption was demonstrated in a study conducted on volunteers exposed to

17-51 ppm for l-4 hours (Teisinger and Soucek 1949). The amounts of carbon disulfide retained in

the body and excreted by the lungs and kidneys were determined by measuring the carbon disulfide in

inspired and expired air, blood, and urine during and after completion of the experiment until it

disappeared from the urine and blood. About 80% of the inhaled carbon disulfide was retained during

the first 15 minutes of exposure which decreased to about 40% after 45 minutes and remained at that

level for the rest of the exposure period. The degree of retention did not depend on the exposure

concentration. Only 5% of the retained carbon disulfide at the end of the exposure period was

subsequently eliminated in the exhaled air. About 0.06% of the retained carbon disulfide was excreted

unchanged in the urine and was detectable 24 hours after exposure. In another retention study

involving exposure to vapor for an unspecified period (Soucek 1957), about 10-30% of the retained

carbon disulfide was exhaled, and less than 1% was excreted in urine as carbon disulfide. The

concentration of inhaled carbon disulfide was not reported. About 70-90% was metabolized.
CARBON DISULFIDE 65

2. HEALTH EFFECTS

Studies in animals indicate that carbon disulfide is rapidly absorbed following inhalation exposure.

Absorption of carbon disulfide was studied by evaluating pulmonary and urinary excretion of carbon

disulfide during and after exposure. Studies in rabbits indicate that an equilibrium concentration of

carbon disulfide is reached after inhalation exposure to 20-150 ppm for 1.5-2.0 hours (Toyama and

Kusano 1953). About 70-80% of the inhaled carbon disulfide was absorbed. After termination of

exposure, 15-30% of the absorbed carbon disulfide was excreted through the lungs and less than 0.1%

by the kidneys. In dogs exposed to 25-60 ppm carbon disulfide, equilibrium concentrations in blood

were attained after 0.5-2.0 hours (McKee et al. 1943). Desaturation of blood carbon disulfide was

almost complete within the first 30-60 minutes after exposure. Approximately 8-13% of the retained

carbon disulfide was exhaled, less than 0.5% was excreted in the urine, and none was excreted in the

feces. Excretion in the urine occurred within 2 hours of exposure. Freundt et al. (1975) observed that

an equilibrium concentration of carbon disulfide in blood was attained after exposure of rats to

400 ppm carbon disulfide for 1 hour. Equilibrium was reached in liver and blood between 1 and

8 hours after exposure. Elimination of free carbon disulfide from these tissues was rapid, with an

estimated half-life in the blood of 35 minutes and in the liver of approximately 1 hour.

The data presented above indicate that carbon disulfide is absorbed by humans and animals following

inhalation exposure and reaches equilibrium rapidly (0.5-8 hours) across a wide range of doses and

exposure durations.

2.3.1.2 Oral Exposure

No studies were located regarding absorption of carbon disulfide following oral exposure of humans.

In rats, intragastric administration of 10 mg/kg 14C-carbon disulfide resulted in exhalation of 63% of

the dose within 4 hours as unchanged carbon disulfide (DeMatteis and Seawright 1973). It is evident

from these results that a large fraction of orally administered carbon disulfide is absorbed by rats.

2.3.1.3 Dermal Exposure

Dermal exposure of humans to aqueous solutions of carbon disulfide resulted in significant absorption

through the skin. A series of experiments were performed to investigate the rate of absorption of

carbon disulfide by immersion of the hand in aqueous solutions of increasing concentrations

(0.33-1.67 g/L) for 1 hour (Dutkiewicz and Baranowska 1967). Absorption was calculated indirectly
CARBON DISULFIDE 66

2. HEALTH EFFECTS

by determining carbon disulfide elimination by the lung or directly by measuring carbon disulfide

concentration in the solutions before and after immersion of the hand. Rates of absorption of carbon

disulfide, determined from analysis of the solutions, ranged from 0.232 to 0.789 mg/cm2

/hour and were

about 10 times higher than rates calculated from lung excretion of carbon disulfide. In the former

case, 25% of the absorbed dose was exhaled in the desaturation period; in the latter, only 3% was

eliminated in the expired air. These findings suggest that carbon disulfide excretion varies with the

route of absorption. This study provided only brief details of the experimental procedure, and

therefore factors other than absorption through the skin (e.g., evaporation) may have accounted for the

reduced carbon disulfide concentration noted at the end of the experimental period. Nevertheless,

these results suggest that rapid absorption of carbon disulfide can occur in humans through skin.

Occupational exposure of persons with pathological skin conditions has also been noted to increase the

dermal absorption of carbon disulfide (Drexler et al. 1995a).

The limited information available on skin absorption in animals indicates that carbon disulfide is

appreciably absorbed. Exposure of rabbit skin to high concentrations of the vapor (800 ppm and

above) for 1 hour resulted in detectable amounts of carbon disulfide in the breath (Cohen et al. 1958).

A linear relationship was noted between the dermal exposure concentration and the amount of carbon

disulfide exhaled. No detectable carbon disulfide was found in the breath of rabbits exposed to

150 ppm vapor by skin contact for 6 hours (Cohen et al. 1958).

2.3.2 Distribution

2.3.2.1 Inhalation Exposure

Absorbed carbon disulfide is taken up by the blood (McKee et al. 1943) and is distributed throughout

the body (Brieger 1967). Because of the lipophilic nature of carbon disulfide, distribution is greatest

to lipid-rich tissues and organs such as the brain and liver where it is metabolized to dithiocarbamate

(Santodonato et al. 1985). Milk from nursing mothers occupationally exposed to carbon disulfide was

found to contain an average of 12.3 μg carbon disulfide/l00 mL (Cai and Bao 1981). Exposure

concentrations of carbon disulfide ranged from 9.3 to 21.1 ppm for a 6.5-hour period. Exposure to

7.4-40 ppm for a shorter duration (2-4 hours) resulted in a lower average milk concentration of

6.8 μg/l00 mL.
CARBON DISULFIDE 67

2. HEALTH EFFECTS

The distribution of carbon disulfide following inhalation exposure has been studied in rabbits and rats

(Toyama and Kusano 1953). In rabbits, blood equilibrium concentrations of carbon disulfide were

reached after exposure to 20-150 ppm for 1.5-2.0 hours. In rats exposed to 60-350 ppm carbon

disulfide, distribution was primarily to the brain, kidney, and liver. In contrast to rabbits, blood

equilibrium concentrations for various carbon disulfide exposures in rats were not determined.

Although carbon disulfide was rapidly eliminated from rat tissues during the first 6-8 hours after

exposure, low concentrations of carbon disulfide were still detected in the tissues 20 hours after

exposure. A separate study reported that equilibrium concentrations of carbon disulfide in blood were

attained in dogs after 0.5-2.0 hours of exposure to 25-60 ppm carbon disulfide (McKee et al. 1943).

Desaturation was largely complete within the first 30-60 minutes after inhalation exposure.

Anesthetized male Sprague-Dawley rats exposed to 640 ppm carbon disulfide had an exponential

increase in carbon disulfide in the blood which reached an apparently steady state after 90 minutes of

exposure. After discontinuation of exposure, the blood concentration decreased rapidly, with

elimination half-lives reported to be 6 and 85 minutes for the fast and slow components, respectively.

In all tissues except fat, the carbon disulfide concentration approached steady state within 4-5 hours of

exposure. Loss of free carbon disulfide was rapid from all tissues except the liver and kidneys, which

retained 25% and 29%, respectively, at 8 hours postexposure (McKenna and DiStefano 1977a).

Inhalation exposure of pregnant mice to carbon disulfide during gestation resulted in rapid absorption

and distribution of carbon disulfide and its metabolites in embryonic and fetal tissues within 1 hour

(Danielsson et al. 1984). Pregnant mice were exposed via inhalation to 25 microcuries (μCi) 35S- or

14C-carbon disulfide for 10 minutes on day 9, 14, or 17 of gestation. The levels of 35S-labelled

metabolites in the embryonic neuroepithelium were higher in the fetal brain than in the maternal brain

during early gestation (day 9). The concentrations in the fetal brain, eyes, and skeleton exceeded that

of other fetal organs during mid-gestation (day 14). In late gestation (day 17), the levels in the fetal

and maternal brain were relatively low, but high uptake of radioactivity was seen in the placenta, fetal

blood, liver, and eyes. During early gestation, the distribution of 14C-labelled metabolites was similar

to that of 35S-labelled metabolites with an immediate higher uptake in the embryo (including

neuroepithelium) than in the maternal serum. On days 14 and 17 of gestation, radioactivity was

present in the ventricle of the fetal brain. High levels were detected in the fetal liver and blood at late

gestation (day 17). In contrast to 35S-labelled metabolites, 14C-labelled metabolites were retained

longer (up to 24 hours) in the fetal brain and liver. High concentrations of 14C-labelled metabolites

were also seen in the fetal urinary tract. Thus, the distribution pattern varied with the age of the
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conceptus and also with the radiolabel of carbon disulfide. These results indicate that carbon disulfide

and its metabolites pass through the placenta at all stages of gestation and localize selectively in

various tissues of the body.

2.3.2.2 Oral Exposure

No studies were located regarding distribution of carbon disulfide in humans or animals following oral

exposure.

2.3.2.3 Dermal Exposure

No studies were located regarding distribution of carbon disulfide in humans or animals following

dermal exposure.

2.3.2.4 Other Routes of Exposure

The distribution of free carbon disulfide and bound carbon disulfide liberated by acid hydrolysis was

investigated in the tissues of white rats after a large, single subcutaneous dose (approximately

361 mg/kg) of carbon disulfide (Bartonicek 1957, 1959). Results of these studies indicate that

following absorption, free carbon disulfide is rapidly removed from the blood and tissues. Negligible

blood levels were present 11 hours after the dose was administered (Bartonicek 1957, 1959). Initially,

free carbon disulfide accumulated in the blood, adrenals, and brain, but levels in the organs rapidly

decreased, and only very small amounts were present after 10-16 hours.

A similar rapid reduction of free carbon disulfide levels in the blood was noted when radiolabelled

35S-carbon disulfide was administered parenterally to guinea pigs (Strittmatter et al. 1950). About

20-50% of intracardially injected 35S-carbon disulfide was retained; the amount of material retained

depended on the concentration of dose administered. The largest amount of radiolabel appeared in the

liver (0.43 μg) and the least amount in the brain (0.05 μg) at 1.5 hours following injection. Only 10%

of the labelled compound remained in the tissues after 48 hours. Urinary and fecal excretion was not

reported. In guinea pigs exposed to carbon disulfide vapors (13.6-25.7 ppm), the brain and blood

contained more 35S-label relative to the liver. Forty-eight hours later, 30-50% of 35S-label remained in

the tissues such as blood, liver, brain, kidney, and skin. The urinalyses revealed that urinary 35S-label
CARBON DISULFIDE 69

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was about 30% of the retained sulfur, with about 85% or 90% of it appearing in the first 24-hour

output, the larger part of the metabolized material in the urine being excreted as inorganic sulfate. The

feces contained about 5-15% metabolized 35S-label, the amount of which increased with the increasing

dose of carbon disulfide.

Only metabolites of carbon disulfide were found 3 hours after a dose of 14C- or 35S-labeled carbon

disulfide was intraperitoneally administered (Snyderwine and Hunter 1987). Distribution varied with

the age of the rat and the radiolabel injected. Following intraperitoneal administration of 14C-carbon

disulfide, 4-9% of the dose was metabolized to carbon dioxide depending on age. Significantly more

carbon disulfide was metabolized to carbon dioxide by 30- and 40-day-old rats than by 1-20-day-old

rats. The biotransformation products of carbon disulfide which were covalently bound remained in

tissues from rats of all ages. Twenty-four hours after dosing with 35S-labeled carbon disulfide, up to

13 times more labeled metabolites were covalently bound in organs from l-day-old rats than in similar

organs from 40-day-old rats.

The data presented above indicate that the absorbed carbon disulfide is rapidly distributed via blood to

other tissues irrespective of the route of exposure.

2.3.3 Metabolism

Limited information is available on the biotransformation of carbon disulfide in humans, and the

metabolic products of carbon disulfide are not completely known. In animals and humans the

proposed metabolic pathways involved in the metabolism of carbon disulfide (Beauchamp et al. 1983)

are depicted in Figure 2-3, reactions i-x. Reaction i has been demonstrated in in vivo animal studies

and in in vitro assays. Reactions ii-v are proven by in vitro studies, while products of reactions vi-ix

are the results of proposed metabolic pathways of carbon disulfide in animals and humans. Carbon

disulfide is metabolized by cytochrome P-450 to an unstable oxygen intermediate (reaction i). The

intermediate may either spontaneously degrade to atomic sulfur and carbonyl sulfide (reaction ii) or

hydrolyze to form atomic sulfur and monothiocarbonate (reaction iii). The atomic sulfur generated in

these reactions may either covalently bind to macromolecules (reaction iv) or be oxidized to products

such as sulfate (reaction v). The carbonyl sulfide formed in reaction ii may be converted to

monothiocarbonate by carbonic anhydrase (reaction viii). Monothiocarbonate may further

spontaneously degrade in reaction ix, regenerating carbonyl sulfide or forming carbon dioxide and

CARBON DISULFIDE 71

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sulfide bisulfide ion (HS) (reaction vii). The HS- formed in reaction vii can subsequently be oxidized

to sulfate or other nonvolatile metabolites (reaction vi).

Dithiocarbamates are the products of the reaction of carbon disulfide with amino acids (Brieger 1967).

In vitro studies demonstrated that carbon disulfide readily combines with the amino acids in human

blood, the half-life of this reaction being approximately 6.5 hours (Soucek 1957). Thiocarbamide has

been found in the urine of exposed workers (Pergal et al. 1972b). After inhalation exposure of male

subjects, up to 90% of the retained carbon disulfide was metabolized while the remainder was

eliminated unchanged by various routes (McKee et al. 1943). High levels of thiocarbamide and trace

amounts of 2-thio-5-thiazolidinone were identified by chromatographic analysis of the urine of

workers exposed to carbon disulfide by inhalation (Pergal et al. 1972a, 1972b). Van Doorn et al.

(1981a, 1981b) reported conjugation of carbon disulfide or carbonyl sulfide with endogenous

glutathione to yield thiazolidine-2-thione-4-carboxylic acid and 2-oxythiazolidine-4-carboxylic acid,

respectively. High concentrations (approximately 320 mM) of thiazolidine-2-thione-4-carboxylic acid

(TTCA) were detected in the urine of women exposed to approximately 32 ppm (100 mg/m3) carbon

disulfide through inhalation (refer to Figure 2-3).

In contrast to the results obtained in animals, oxidation to inorganic sulfate does not appear to

contribute significantly to the metabolism of carbon disulfide in humans. A marked increase in

inorganic sulfate excretion in the urine was noted in a case study of a young worker with signs of

carbon disulfide poisoning because of exposure to high levels of the vapor; no increase was noted in

the amount of inorganic sulfate excreted in the urine (Djerassi and Lumbroso 1968). However, exact

dose, mode of exposure, and duration were not presented in the study.

Carbon disulfide is oxidized by the liver mixed-function oxidase (MFO) system to carbonyl sulfide,

which then undergoes further desulfurization, releasing elemental sulfur. This reaction has been shown

to occur in vitro (Dalvi et al. 1974; DeMatteis 1974). In vivo studies in rats using 14C-labelled carbon

disulfide demonstrated that significant amounts (80%) of 14CO2, are exhaled after exposure to carbon

disulfide. Following intraperitoneal administration of approximately 100 mg carbon disulfide/kg, about

5% of the total dose was excreted in the breath as carbon dioxide. This amount was increased to 13%

in animals pretreated with phenobarbital to induce liver microsomal enzymes (DeMatteis and

Seawright 1973). Snyderwine and Hunter (1987) found that 4-9% of an intraperitoneally administered

dose of 14C-carbon disulfide was excreted as 14CO2 in expired air, with 30- and 40-day-old rats
CARBON DISULFIDE 72

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excreting more (9% versus 4%) 14CO2, than 1-20-day-old rats. This was attributed to the increased

hepatic MFO of carbon disulfide to carbon dioxide in 30-40-day-old rats.

The metabolic formation of carbonyl sulfide from carbon disulfide was confirmed in an in vivo study

(Dalvi and Neal 1978). After intraperitoneal injection of 14C-carbon disulfide in nonpretreated rats,

carbonyl sulfide was excreted by the lung in greater quantities than carbon dioxide. Pretreatment with

phenobarbital, however, resulted in a greater amount of excretion of carbon dioxide than carbonyl

sulfide. In both experiments, excretion of 14C-carbonyl sulfide and carbon dioxide accounted for

14-43% of the total administered radioactivity, with about twice as much carbon dioxide. These

results indicate that phenobarbital treatment caused induction of cytochrome P-450 which catalyzed

the conversion of carbon disulfide to carbonyl sulfide faster in pretreated rats than in rats not pretreated

with phenobarbital. The role of the cytochrome P-450 monooxygenase system in catalyzing carbonyl

sulfide formation was also confirmed by in vitro studies (Dalvi et al. 1974, 1975). The rate of

carbonyl sulfide formation was NADPH-dependent and increased with microsomes obtained from

phenobarbital-treated rats.

In a study designed to examine the effect of P-450 induction on the metabolism of carbon disulfide to

TTCA, rats were treated with nothing, ethanol, phenobarbital, 3-methylcholanthrene, or phenobarbital

and ethanol before being exposed to carbon disulfide at 50 ppm for 6 hours (Kivisto et al. 1995).

After 7 days the pretreatment regimens were repeated in the same rats, and the rats were again

exposed to carbon disulfide at 500 ppm for 6 hours. None of the inducers had any effect on urinary

excretion of TTCA. About 7.6% and 2.3% of the dose was excreted as TTCA at 50 and 500 ppm,

respectively, suggesting saturation. However, the investigators speculated that saturation may not have

occurred because the physical activity level of the rats was reduced at 500 ppm suggesting that carbon

disulfide uptake at 500 ppm may also have been reduced because of the lowered respiratory rate.

They also note that the saturation observed in rats is not likely to occur in humans at the prevailing

occupational exposure concentrations. Saturation of TTCA production was observed in an oral study

in rats (Kivisto et al. 1995). In rats treated with a single gavage dose of 1, 10, 30, or 100 mg/kg,

4.6%, 2.4%, 1.7%, and 0.8%, respectively, of the dose was excreted in the urine as TTCA.

The effect of P-450 induction or glutathione depletion on carbon disulfide metabolism to TTCA in rats

following oral exposure has also been studied (Kivisto et al. 1995). The rats were pretreated with

nothing, acetone, phenobarbital, 3-methylcholanthrene, or three inhibitors of glutathione production,
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namely phorone, diethylmaleate, or buthionine sulfoximine, before being given a single gavage dose of

carbon disulfide at 26-34 mg/kg. Phenobarbital decreased the output of TTCA by 21% during the

first 12 hours of the urine collection. None of the other P-450 inducers had any effects on TTCA

excretion, and the investigators suggested that the effect of phenobarbital may have been a result of

cytochrome P-450 aggregation. Buthionine sulfoximine, an inhibitor of glutathione production,

reduced the total output of TTCA by about 40%. Phorone and diethylmaleate pretreatment, which

transiently reduce glutathione, decreased TTCA excretion.

2.3.4 Excretion

2.3.4.1 Inhalation Exposure

Following inhalation exposure, the primary route of excretion of unmetabolized carbon disulfide in

humans is exhalation. In one study it was estimated that 6-10% of the carbon disulfide that was taken

up was excreted by the lungs (McKee et al. 1943). In a study conducted on humans, carbon disulfide

levels in the exhaled breath decreased rapidly on cessation of exposure (Soucek 1957). The excretion

by the lung accounted for 10-30% of the absorbed carbon disulfide. Less than 1% was excreted

unchanged in the urine. The remaining 70-90% of the dose was metabolized. The details regarding

carbon disulfide exposure levels were not available. A correlation was established between carbon

disulfide exposure of rayon workers and urinary excretion of a metabolite or metabolites that catalyzed

the reaction of iodine with sodium azide (Djuric 1967). This test indicated exposures to carbon

disulfide above 16 ppm but failed to identify specific urinary metabolites. The failure to detect carbon

disulfide exposure below 16 ppm may be because of interference with the reaction by dietary sulfur

containing compounds.

In dogs exposed to 25-60 ppm carbon disulfide for 0.5-2.0 hours, approximately 8-13% of the carbon

disulfide that was taken up was exhaled; less than 0.5% was excreted in the urine (McKee et al. 1943).

Experimental details and control information are limited in this study. Inhalation exposure of rabbits

to 20-150 ppm carbon disulfide for 1.5-2 hours resulted in excretion of 15-30% of the absorbed

carbon disulfide via the lung and less than 0.1% by the kidney after termination of exposure (Toyama

and Kusano 1953).
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In guinea pigs, carbon disulfide metabolites are excreted as inorganic sulfur compounds in the urine

(Strittmatter et al. 1950). Inhalation exposure to 14 ppm 35S-carbon disulfide for 8 hours or to 26 ppm

35S-carbon disulfide for 40 hours resulted in excretion of the administered dose mainly in the urine

(63%) and expired air (30%) within 48 hours of exposure. The metabolized material was excreted in

the urine predominantly in the form of inorganic sulfur compounds; some organosulfur derivatives

were also present. Most of the unmetabolized carbon disulfide was excreted in the expired air.

The studies discussed above indicate that the lungs are the primary route of excretion of unmetabolized

carbon disulfide in humans and animals exposed by inhalation, whereas the kidneys are the primary

route of excretion of carbon disulfide metabolites.

2.3.4.2 Oral Exposure

No studies were located regarding excretion of carbon disulfide in humans after oral exposure.

Rats administered 10 mg 14C-carbon disulfide/kg by gavage excreted 63% of the dose as unchanged

carbon disulfide in the breath (DeMatteis and Seawright 1973).

2.3.4.3 Dermal Exposure

Following dermal exposure of humans to aqueous solutions of carbon disulfide of increasing

concentrations (0.33-1.67 g/L) for 1 hour, only 3% of the absorbed carbon disulfide was eliminated by

the lungs (Dutkiewicz and Baranowska 1967). For details and study limitations, see Section 2.3.1.3.

Exposure of rabbit skin to high concentrations of carbon disulfide vapor (800 ppm and above) for

1 hour resulted in detectable amounts of carbon disulfide in the breath of animals (Cohen et al. 1958).

A linear relationship was noted between the exposure concentration and the amount of carbon disulfide

in the exhaled breath.

2.3.4.4 Other Routes of Exposure

Appreciable amounts of absorbed carbon disulfide are excreted unchanged in breath regardless of the

route of exposure (refer to Sections 2.3.4.1, 2.3.4.2, and 2.3.4.3). Small amounts of carbon disulfide
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are excreted in the sweat and saliva of exposed individuals. In mice injected intraperitoneally with

30-42 μg of 35S-carbon disulfide, about 13-23% of the radiolabel was excreted via the lung

(Strittmatter et al. 1950). Rats receiving 10 mg 14C-carbon disulfide/kg by intraperitoneal injection

excreted about 70% of the dosed material as unchanged carbon disulfide in the breath (DeMatteis and

Seawright 1973). Rats receiving 19 mg/kg 14C-carbon disulfide intraperitoneally excreted 58-83% free

carbon disulfide in expired air in the 3 hours following dosing (Snyderwine and Hunter 1987).

Younger rats expired significantly more free carbon disulfide than older rats. In another study (Dalvi

and Neal 1978), intraperitoneal administration of 14C-carbon disulfide to rats resulted in excretion of

carbonyl sulfide by the lungs in greater quantities than carbon dioxide. Pretreatment of rats with

phenobarbital, however, resulted in a greater amount of excretion of carbon dioxide than carbon

disulfide. In both experiments, excretion of 14C-carbonyl sulfide and carbon dioxide accounted for

14-43% of the total administered radioactivity, with about twice as much carbon dioxide.

2.4 MECHANISMS OF ACTION

Despite the apparent differences between animals and humans in the metabolism of carbon disulfide,

dithiocarbamates are the common metabolites formed. These may in part account for the neurotoxic

effects of carbon disulfide. Formation of dithiocarbamates has been demonstrated in both in vitro and

in vivo studies in these species. Metabolism studies in animals clearly indicate that carbon disulfide is

metabolized by two distinctly different pathways (see Figure 2-3): it can form dithiocarbamates and

glutathione conjugates, or it can be catalyzed by the monooxygenase system to generate reactive

sulfur. However, the relative contributions of each of these metabolic pathways to the development of

the acute and chronic toxicity of carbon disulfide remain to be determined. Both metabolic pathways

suggest several potential mechanisms of toxicity. Formation of dithiocarbamates may in part account

for peripheral neurotoxicity. Furthermore, the nonenzymatic reaction of carbon disulfide with free

amino groups suggests a potential interaction with biological macromolecules such as proteins and

nucleic acids. In contrast, the formation or generation of reactive sulfur may inhibit the microsomal

monooxygenase system and disturb the metabolism of other endogenous and exogenous compounds.

In the paragraphs that follow, the two metabolic pathways are discussed in detail. The relative

importance of these two pathways is also discussed.
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Carbon disulfide combines readily with the amine groups of amino acids to produce dithiocarbamates,

which are water-soluble metabolites. Such reactions have been demonstrated with free amino groups

in serum in vivo (Cohen et al. 1958). The formation of acid-labile carbon disulfide, readily destroyed

at low pH, was also consistent with significant in vivo formation of dithiocarbamate metabolites

(McKenna and DiStefano 1977a; Snyderwine and Hunter 1987). Following absorption of inhaled

carbon disulfide by the lung, free carbon disulfide is distributed to various tissues where it is either

eliminated, primarily by the lung, or further metabolized to acid-labile carbon disulfide metabolites.

The formation of acid-labile carbon disulfide metabolites may continue to increase at steady-state

concentrations of carbon disulfide as long as free carbon disulfide is available to the tissue and amine

substrates are available. This was demonstrated in rats exposed to 640 ppm carbon disulfide for

8 hours in which acid-labile carbon disulfide metabolites continued to accumulate in several tissues

after steady-state levels of carbon disulfide were reached (McKenna and DiStefano 1977a).

The formation of the carbon disulfide metabolite, dithiocarbamate, may explain the mechanism of

carbon disulfide-induced neurotoxic effects. For example, McKenna and DiStefano (1977b) found a

decrease in the activity of copper-requiring enzyme, dopamine-β-hydroxylase, in response to increased

inhalation exposure to carbon disulfide (0.1-2.0 mg/L for 8 hours). The effect of carbon disulfide was

attributed to the formation of dithiocarbamates, which complex with copper, since in vitro inhibition of

purified dopamine-β-hydroxylase by carbon disulfide was dependent on preincubation with amines

capable of dithiocarbamate formation (McKenna and DiStefano 1977b). The inhibition of dopamineβ-hydroxylase decreased progressively with increasing Cu++ concentration, and equimolar

concentrations of Cu++ and inhibitor were without effect, suggesting that the inhibition occurred

through the binding of enzymic copper.

An alternative mechanism proposed to explain the neurotoxic effect of carbon disulfide is the

formation of a dithiocarbamate derivative of pyridoxamine, a form of vitamin B6, with carbon disulfide

(Vasak and Kopecky 1967). Investigators postulated that transaminases and amine oxidases would be

inhibited because these enzymes require the pyridoxamine phosphate form of vitamin B6, as a cofactor.

In subsequent in vivo studies, evidence of altered tryptophan metabolism (consistent with an inhibition

of B6-requiring enzymes) appeared to support this hypothesis (Abramova 1966). Furthermore,

supplementation of the diet with vitamin B6, delayed some of the neurotoxic effects of carbon disulfide

(Teisinger 1974). However, continued research could not detect any change in the tissue content of

vitamin B6 in rats after chronic exposure to carbon disulfide (Okayama et al. 1988), and in a later
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study the authors suggested that the abnormalities in tryptophan metabolism caused by exposure to

carbon disulfide were not related to vitamin B6 deficiency (Okayama et al. 1988). In this instance,

they studied the activities of enzymes in the kynurenine pathway in rats chronically exposed to carbon

disulfide. Increased activities of L-tryptophan-2,3-dioxygenase, kynurenine-3-hydroxylase, and

kynureninase in the high-concentration group (800 ppm) were found; this may indicate activation of

the kynurenine pathway upon carbon disulfide exposure rather than vitamin B6 deficiency (Okayama et

al. 1988).

The effects of carbon disulfide on the microsomal drug metabolizing system were demonstrated in rats

by Freundt et al. (1975). Exposure of rats by inhalation to low concentrations of carbon disulfide

(20-400 ppm for 8 hours) inhibited microsomal drug metabolism. This was reflected by increased

hexobarbital sleep times. Pretreatment of rats with SKF-525A, an inhibitor of cytochrome

P-450-mediated metabolism, reduced the liver damage from carbon disulfide in phenobarbitalpretreated animals (Bond and DeMatteis 1969).

Valentine et al. (1993) have shown that the initial dithiocarbamate protein adduct decomposes to

isothiocyanate derivatives which then react with protein nucleophiles resulting in crosslinking. The

crosslinking of protein in the nerve axons to cause their ultimate degeneration is correlated with the

crosslinking of spectrin, a blood cell membrane protein. This suggests that the latter can be used as a

biomarker of adverse effect of nerve damage.

Acute intraperitoneal injections of 504 mg/kg carbon disulfide for 3 consecutive days in male rats

caused a significant decrease in aminopeptidase activity in the thalamus and cerebellum of the brain

(de Grandarias et al. 1992). The role of aminopeptidase activity in carbon disulfide neurotoxicity was

postulated.

It has been postulated that carbon disulfide cardiotoxicity may be mediated by disruption of the energy

supply in the heart (Klapperstuck et al 1991). The mechanism for carbon disulfide acceleration of

arteriosclerotic plaque formation involves direct injury to the vessel epithelium and changes in lipid

metabolism.

It has been postulated that the reduced thyroid activity in workers exposed to carbon disulfide may be

related to a central involvement of catecholamine metabolism (Cavalleri et al. 1978).
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2.5 RELEVANCE TO PUBLIC HEALTH

There are substantial data available on which to base conclusions regarding the potential health effects

of carbon disulfide exposure in residents near hazardous waste sites and occupationally exposed

individuals. The principal adverse health effects noted in humans exposed via inhalation are

neurotoxic and cardiovascular effects (Aaserud et al. 1988, 1990; Egeland et al. 1992; Hernberg et al.

1971; Hirata et al. 1992a; Lancranjan 1972; Ruijten et al. 1990, 1993; Sikora et al. 1990; Tolonen et

al. 1979; Vanhoorne et al. 1992a). Most of the human data are derived from occupational studies.

Although these are somewhat limited by the difficulties in estimating the exact dose for individuals

and by the fact that most industrial environments have multiple types of exposures, these data are

consistent with effects noted in experimental animal studies. In addition, the toxicokinetic studies and

the derivations of mechanisms of action are consistent with these observations. Specific health effects

are discussed in greater detail below.

Minimal Risk Levels for Carbon Disulfide

A User’s Guide has been provided at the end of the profile (see Appendix A) to aid in the

interpretation of MRLs.

Inhalation

• An MRL of 0.3 ppm was derived for chronic exposure to carbon disulfide. This MRL was

derived based on peripheral neuropathy (reduced motor nerve conduction velocity) in humans

after prolonged occupational exposure to carbon disulfide. A LOAEL of 7.6 ppm was

established for this effect. Although a dose response was achieved, the effect was considered

minimal since the reductions in motor nerve condition velocity were within a range of clinically

normal values. This concentration was divided by an uncertainty factor of 30 (3 for use of a

LOAEL, 10 for human variability) to yield the calculated MRL of 0.3 ppm.

No acute-duration or intermediate-duration inhalation MRLs were derived since potential MRL values

would not have been as protective of human health as the chronic-duration MRL. In addition, there is

greater confidence in the chronic-duration MRL since it is based on human data.
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Oral

• An MRL of 0.01 mg/kg/day was derived for acute exposure to carbon disulfide. This MRL was

derived based on the inhibition of enzyme activities, specifically decreases in the activities of

several hepatic microsomal cytochrome P-450-dependent drug-metabolizing enzymes and

cytochrome P-450 content. A LOAEL of 3 mg/kg/day was established for this effect. Also, the

effect was minimal since the inhibition of enzyme activities was selective and reversible. This

dose was divided by an uncertainty factor of 300 (3 for use of a minimal LOAEL, 10 for

extrapolation from animals to humans, and 10 for interhuman variability) to yield the calculated

MRL of 0.01 mg/kg/day.

No intermediate- or chronic-duration oral MRLs were derived because of a lack of reliable LOAELs

and a lack of definite target organs.

Death. Several epidemiology studies have reported increased mortality due to cardiovascular disease

in cohorts of workers occupationally exposed to carbon disulfide (Balcarova and Halik 1991; Hernberg

et al. 1970, 1973; Swaen et al. 1994; Tolonen et al. 1975, 1979). It is not possible, however, to draw

accurate or definitive conclusions from these reports regarding the levels of exposure associated with

an effect. This is because of the wide range of exposure levels that workers experience and the

difficulty in estimating exact levels from area sampling done at different times and with different

methods. Moreover, historical exposure data are lacking in most of the studies, and occupational

studies frequently encompass concomitant exposures to other chemicals. However, decreased survival

associated with ventricular fibrillation in rats has been noted following oral exposure to carbon

disulfide (Hoffman 1987). There are no studies available that address death following dermal

exposure in humans or animals.

Systemic Effects. The systemic toxicity of carbon disulfide is manifested primarily as

cardiovascular, hepatic, and ocular effects in both humans and animals following inhalation exposure.

Respiratory Effects. Some transient respiratory effects have been noted in humans briefly exposed to

unspecified amounts of carbon disulfide (Kamat 1994; Spyker et al. 1982). Limited studies were

available that specifically address respiratory function changes in exposed animals. Decreased
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2. HEALTH EFFECTS

respiratory rate was noted in rats exposed to 803 ppm carbon disulfide for 18 hours (Tarkowski and

Sobczak 1971).

Cardiovascular Effects. Several studies of occupationally exposed individuals have documented an

increased incidence of elevated blood pressure (Egeland et al. 1992; Hernberg et al. 1971; Tolonen et

al. 1979; Vanhoorne et al. 1992a). This indicates that an elevation in blood pressure could be one

mechanism for the adverse cardiovascular effects of carbon disulfide. Concomitant occupational

exposure to hydrogen sulfide may be a confounding factor. At relatively low concentrations (median

1.1 or 4 ppm) cardiovascular effects have not been observed in humans occupationally exposed to

carbon disulfide (Chrostek-Maj and Czeczotko 1995a; Drexler et al. 1995b). A transient decrease in

blood pressure was reported in rats administered 506 mg/kg carbon disulfide once by gavage

(Hoffmann and Klapperstück 1990). ECG changes were seen at 373 and 506 mg/kg, while heart rate

decreased at 632 mg/kg. The other studies on animals attest to the adverse effects of carbon disulfide

on the cardiovascular system (Antov et al. 1985; Chandra et al. 1972; Wronska-Nofer et al. 1980).

These effects included lipid droplet infiltration in the coronary arteries, metabolic and structural

changes in the myocardium and the aorta, and myocardial lesions characterized by necrosis, interstitial

edema, and cellular infiltrate.

Gastrointestinal Effects. Gastrointestinal symptoms are commonly reported in workers exposed to

carbon disulfide (Rubin and Arieff 1945; Vanhoorne et al. 1992b; Vigliani 1954). These symptoms

are subjective, however, and cannot be identified with a specific exposure level. No animal studies

have been done that address effects on the gastrointestinal system.

Hematological Effects. Fibrolytic activity was decreased in workers exposed to carbon disulfide at

59-169 ppm for 2-8 years (Visconti et al. 1967). Red blood cell and white blood cell counts were not

significantly different from preemployment values in workers exposed to carbon disulfide for 5 years

(Chrostek-Maj and Czeczotko 1995a).

There are limited animal data concerning hematological effects after inhalation exposure. No

hematological effects were seen in rabbits acutely exposed to 1,100 ppm carbon disulfide for 12 days

(Briegor 1949). However, exposure to 300 ppm for 48 days resulted in significant increase in pseudoeosinophils. Significant decreases in erythrocyte counts, total hemoglobin, and hematocrit were noted

in mice exposed to 800 ppm for 90 days (Toxigenics 1983c). Animal studies also show an elevation
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of serum lipids following carbon disulfide exposure (Wronska-Nofer 1972, 1973; Wronska-Nofer et al.

1980). Vascular arteriosclerotic changes may be a unifying mechanism for the toxic effects caused not

only on the cardiovascular system but also in the liver and kidney (Beauchamp et al. 1983).

Musculoskeletal Effects. No studies were located regarding musculoskeletal effects in humans after

exposure to carbon disulfide by any route. In rats treated by gavage with carbon disulfide, a decreased

response of the ancoccygeus muscle to noradrenaline was observed relative to the vehicle-treated

controls (Gandhi and Venkatakrishna-Bhatt 1993). The response of the muscle to noradrenaline was

tested in vitro.

Hepatic Effects. In humans, inhalation or oral exposure to carbon disulfide causes inhibition of

microsomal enzymes and increased liver size (Mack et al. 1974; Vanhoorne et al. 1992b). Similar

changes were seen in animals without accompanying histological evidence of liver damage (Magos

and Butler 1972; Magos et al. 1973; Tsuyoshi 1959). However, hepatoxicity characterized by hydropic

degeneration in parenchymal cells of the centrilobular zone was observed in rats pretreated with

phenobarbital to induce the liver mixed-function oxidase system. Effects on lipid metabolism, for

example, increased levels of serum cholesterol, total lipids, and triglycerides, have been seen in

workers exposed by inhalation to carbon disulfide (Krstev et al. 1992; Stanosz et al 1994b; UK/HSE

1981). Serum cholesterol, phospholipids, and triglyceride levels were significantly elevated in rats

following inhalation exposure to carbon disulfide (Wronska-Nofer 1972, 1973). One postulated

mechanism involved in the toxicity of carbon disulfide is its suppressive effect on the microsomal

hepatic enzyme system (Mack et al. 1974). Many of the hepatic effects of carbon disulfide as well as

the interactions of other chemicals with carbon disulfide would then result from the loss of the

capability to detoxify other harmful chemicals.

An acute-duration oral MRL was calculated on the basis of decreases in the activities of several

hepatic microsomal cytochrome P-450-dependent drug metabolizing enzymes and cytochrome P-450

content in mice after acute exposure to 3 mg/kg/day (Masuda et al. 1986). The calculated acuteduration

oral MRL is 0.01 mg/kg/day.

Renal Effects. Although several reviews of the literature on carbon disulfide refer to renal effects in

humans, no studies were located that specifically address renal toxicity (Beauchamp et al. 1983; WHO

1986). Rabbits exposed to a wide range of levels of carbon disulfide for 38 weeks showed an
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increased incidence of chronic interstitial nephritis (Cohen et al. 1958). Nephropathy was observed in

mice exposed via inhalation at 800 ppm for 90 days (Toxigenics 1983c). Because of limited available

data, the significance of these findings in animals with regard to adverse effects in humans is not

known.

Endocrine Effects. The available data in humans provide conflicting evidence regarding the adverse

effects of carbon disulfide exposure on thyroid function (El-Sobkey et al. 1979; Lancrajan et al. 1972;

Wagar et al. 1981). Based on decreases in the urinary excretion of products of adrenal/gonadal or

adrenal/sympathetic origin, exposure of workers to carbon disulfide may affect adrenal gland function

(Cavalleri et al. 1967; Stanosz et al. 1994a). These studies also involved possible exposure to other

chemicals and did not identify the precise exposure level.

Dermal Effects. Dermal effects are limited to a report of blisters on the hands of viscose rayon

workers presumably due to carbon disulfide exposure. This is borne out by studies in rabbits in which

similar blisters could be induced by carbon disulfide exposure (Hueper 1936). This indicates that

dermal contact from either occupational exposure or from contaminated soil or water near hazardous

waste sites could cause adverse effects.

Ocular Effects. Ophthalmological changes of various types including fundus anomalies, retinal

microaneurysms, retinopathy, and burning eyes have been reported in workers occupationally exposed

to carbon disulfide (DeLaey et al. 1980; NIOSH 1984a; Raitta et al. 1974, 1975; Rubin and Arieff

1945). These findings suggest that chronic low-level occupational exposure to carbon disulfide or

exposure at hazardous waste sites could result in ophthalmological changes.

Body Weight Effects. A 14-day exposure to carbon disulfide at a concentration that resulted in a

narcotic-like stupor caused male rats to lose 14% of their body weight (Wilmarth et al. 1993).

Inhalation exposure of rats for intermediate durations has been reported to produce a dose-dependent

decrease in body weight gain. This effect varied depending upon the sex and the strain of rat used

(Clerici and Fechter 1991; Hirata et al. 1992b; Tepe and Zenick 1984; Toxigenics 1983a, 1983b).

However, the implications of these findings with regard to adverse effects in humans are unknown.

Other Systemic Effects. Workers occupationally exposed to carbon disulfide exhibited elevated

plasma sodium and chloride levels and decreased erythrocyte potassium and calcium levels (Pines
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1982). In animals, increased adrenal weight, hyperplasia of adrenal cortex, and mild hemosiderosis of

the spleen have been observed (Cohen et al. 1959). However, the value of these studies is limited by

confounding factors, lack of dose-response relationships, and limitations in study design.

Immunological and Lymphoreticular Effects. The only study available (Bobnis et al. 1976)

reported no immunological component involved in the increase of arteriosclerotic lesions found in

carbon disulfide-exposed workers.

Neurological Effects. The primary target organ for carbon disulfide toxicity is the nervous system.

In humans, behavioral changes, neurophysiological changes, and neuropathology have been

demonstrated (Aaserud et al. 1988, 1990; Chrostek-Maj and Czeczotto 1995b; Chu et al. 1995; Hirata

et al. 1992a; Lancranjan 1972; Ruijten et al. 1990, 1993; Sikora et al. 1990). Some studies have noted

that these changes were reversed following removal from exposure; other studies have indicated no

improvement. One of the major problems has been in establishing levels of exposure associated with

the onset of symptoms.

In occupational settings, exposure levels vary daily and over the course of years. Improved

technology and an awareness of the harmful effects of carbon disulfide exposure have resulted in a

marked decrease in the ambient levels in the workplace from approximately 60 ppm to about 10 ppm.

Concomitant exposures to other chemicals remain a problem. Animal data suggest serious

neurological effects from carbon disulfide exposure, but most of the studies are single-dose studies

using levels of carbon disulfide one to two orders of magnitude larger than those levels seen in

occupational settings. Because of difficulties in accurately measuring low concentrations of carbon

disulfide in environmental settings and in assessing subtle behavioral or neurological effects, it is hard

to draw conclusions about levels or durations of exposure that represent no-effect levels for

neurotoxicity in humans. The mechanism of neurotoxicity appears to involve effects on both the

axons and the myelin sheaths. In an in vitro assay, De Caprio et al. (1992) demonstrated formation of

protein-bound isothiocyanate adducts in carbon disulfide-treated peptides and protein. Based on these

findings, the study authors proposed that a direct reaction of carbon disulfide with neurofilament

lysineamino moieties was a step in the mechanism of neuropathy. Valentine et al. (1993) have shown

that the protein in degenerated axons caused by carbon disulfide exposure is greatly crosslinked.

Externally, the nerves show swellings paranodally, retraction of myelin from specific nodes, and

degeneration of the distal axon (especially long ones). The isothiocyanate adducts formed from
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dithiocarbamate adducts cause crosslinking of the nerve proteins, leading to the phenomena observed

in electron micrographs.

Valentine et al. (1995) postulated that covalent crosslinking of low molecular weight neurofilament

triplet proteins by dithiocarbamates proceeded through liberation of carbon disulfide.

A chronic-duration inhalation MRL was calculated on the basis of reduced motor nerve conduction

velocity in humans after occupational exposure to an average of 7.6 ppm carbon disulfide, for

individuals working approximately 8 hours a day, 5 days a week, for 12.1 years (the mean exposure

period) (Johnson et al. 1983). The calculated chronic-duration inhalation MRL is 0.3 ppm.

Reproductive Effects. Birth defects have been reported in newborns of women workers exposed to

carbon disulfide (Bao et al. 1991). However, no definite conclusion can be made because of the

inadequacy of available data (lack of exposure analysis and dose-response assessment) since the study

was reported only as an abstract. Decreased sperm count and decreased libido in men and menstrual

irregularities in women exposed in the workplace have been the most frequently reported effects. In

exposed women, possible disruptions of the neurohormonal-endocrine balance necessary for normal

ovarian and uterine cycles may lead to amenorrhea, abnormal menstrual cycles, and even sterility

(WHO 1979; Zielhius et al. 1984). However, community and workplace studies have not shown a

decreased fertility rate, an increase in the time between live births, or an effect on semen quality with

carbon disulfide exposure (Hemminki and Niemi 1982; Meyer 1981; NIOSH 1983; Vanhoorne et al.

1974; Zhou et al. 1988). Potential reproductive effects are supported by animal studies, primarily in

male rodents, that report decreased sperm count, abnormal coital behavior, and reduced plasma

testosterone (Tepe and Zenick 1984; Zenick et al. 1984). These effects are supported by data from

intraperitoneal exposures to rats. No effects on the testicular structures were seen at 6.25 mg/kg/day

administered for 60 days. Some disorganization of seminiferous tubules was seen at 25 mg/kg/day for

60 days, and a decrease in spermatogenesis was seen at 25 mg/kg/day for 120 days (Gondzik 1971).

Developmental Effects. Although developmental effects have been seen in the offspring of women

exposed to carbon disulfide in the workplace (Bao et al. 1991), the data are inadequate to draw any

definitive conclusion. The Bao et al. (1991) study was reported as an abstract, and there was a lack of

exposure analysis and dose-response assessment. There are reports of congenital malformations in the

offspring of rats exposed via inhalation (Tabacova and Balabaeva 1980a), but the general finding in
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the animal studies of developmental effects is one of increased embryotoxicity (Lehotzky et al. 1985;

Yaroslavskii 1969). In a preliminary study reported only in abstract form, increases in early

resorptions and decreases in viable fetuses were observed in New Zealand white rabbits exposed by

inhalation to 600 or 1,200 ppm (Gerhart et al. 1991). No effects were noted at 300 ppm.

Pharmacokinetic studies indicate that carbon disulfide and its metabolites pass the placenta at all stages

of gestation and localize in the recognized target organs for this chemical (brain, blood, liver, and

eyes) (Danielsson et al. 1984), but the levels at which these exposures could produce effects in humans

is not identifiable at this time.

Genotoxic Effects. There are some data on in vitro genotoxicity of carbon disulfide. Haworth et

al. (1983) evaluated carbon disulfide at five doses both with and without S9 activation in the

Salmonella/microsome assay. All results were negative. Other studies in Salmonella typhimurium and

Escherichia coli, both with and without activation, were also negative (Donner et al. 1981; Hedenstedt

et al. 1979). Salmonella strain TA98 was used in a host-mediated assay investigating the ability of

carbon disulfide to induce reverse mutations. Carbon disulfide was not considered to be an active

mutagen in this test; however, the results are equivocal in this regard (NIOSH 1980). A response

curve suggestive of carbon disulfide-induced unscheduled deoxyribonucleic acid (DNA) synthesis was

observed in human WI-38 cells, but the results failed to meet the criteria indicative of a positive

response (NIOSH 1980). Carbon disulfide was not considered to be an a mutagen in this test. Studies

in lymphocytes (Garry et al. 1990) demonstrated a requirement for microsomal activation in the

induction of dose-related (p≤0.05) increases in sister chromatid exchanges. This finding is consistent

with past work on the cytochrome P-450 monooxygenase system that suggests a requirement for

microsomal activation to form a highly reactive metabolite. Carbon disulfide was reported to inhibit

the mutagenic activity of 1,2-dimethylhydrazine and azoxymethane in a host-mediated assay (Moriya

et al. 1979). In this report, the authors suggested that this effect was due to carbon disulfide’s

prevention of in vivo oxidation of azomethane to azoxymethane. This would be consistent with the

known suppressive effects of this chemical on the cytochrome P-450 system. Results of carbon

disulfide on the Drosophila sex-linked recessive lethal test were also negative (Donner et al. 1981;

NIOSH 1980). Carbon disulfide failed to produce significant chromosomal aberrations in the bone

marrow of rats inhaling carbon disulfide for either acute or intermediate periods (NIOSH 1980). There

are no mutagenicity data on humans exposed occupationally to carbon disulfide, so at this time it is

difficult to predict effects of carbon disulfide at the DNA level.
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Cancer. There are no definitive data in humans or animals that indicate a carcinogenic potential for

carbon disulfide. In the absence of positive genotoxic data, increased cancer risk does not appear to

be an effect of exposure to carbon disulfide.

2.6 BIOMARKERS OF EXPOSURE AND EFFECT

Biomarkers are broadly defined as indicators signaling events in biologic systems or samples. They

have been classified as markers of exposure, markers of effect, and markers of susceptibility

(NAS/NRC 1989).

Due to a nascent understanding of the use and interpretation of biomarkers, implementation of

biomarkers as tools of exposure in the general population is very limited. A biomarker of exposure is

a xenobiotic substance or its metabolite(s), or the product of an interaction between a xenobiotic agent

and some target molecule(s) or cell(s) that is measured within a compartment of an organism

(NAS/NRC 1989). The preferred biomarkers of exposure are generally the substance itself or

substance-specific metabolites in readily obtainable body fluid(s) or excreta. However, several factors

can confound the use and interpretation of biomarkers of exposure. The body burden of a substance

may be the result of exposures from more than one source. The substance being measured may be a

metabolite of another xenobiotic substance (e.g., high urinary levels of phenol can result from

exposure to several different aromatic compounds). Depending on the properties of the substance

(e.g., biologic half-life) and environmental conditions (e.g., duration and route of exposure), the

substance and all of its metabolites may have left the body by the time samples can be taken. It may

be difficult to identify individuals exposed to hazardous substances that are commonly found in body

tissues and fluids (e.g., essential mineral nutrients such as copper, zinc, and selenium). Biomarkers of

exposure to carbon disulfide are discussed in Section 2.6.1.

Biomarkers of effect are defined as any measurable biochemical, physiologic, or other alteration within

an organism that, depending on magnitude, can be recognized as an established or potential health

impairment or disease (NAS/NRC 1989). This definition encompasses biochemical or cellular signals

of tissue dysfunction (e.g., increased liver enzyme activity or pathologic changes in female genital

epithelial cells), as well as physiologic signs of dysfunction such as increased blood pressure or

decreased lung capacity. Note that these markers are not often substance specific. They also may not
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be directly adverse, but can indicate potential health impairment (e.g., DNA adducts). Biomarkers of

effects caused by carbon disulfide are discussed in Section 2.6.2.

A biomarker of susceptibility is an indicator of an inherent or acquired limitation of an organism’s

ability to respond to the challenge of exposure to a specific xenobiotic substance. It can be an

intrinsic genetic or other characteristic or a preexisting disease that results in an increase in absorbed

dose, a decrease in the biologically effective dose, or a target tissue response. If biomarkers of

susceptibility exist, they are discussed in Section 2.8, “Populations That Are Unusually Susceptible.”

2.6.1 Biomarkers Used to Identify or Quantify Exposure to Carbon Disulfide

Levels of carbon disulfide detected in exhaled breath, blood, urine, and milk as well as various

metabolite concentrations in the urine of exposed individuals have been studied as biomarkers of

carbon disulfide exposure.

Because of its solubility in lipids and affinity for proteins, environmental carbon disulfide is quickly

absorbed in the blood and other body tissues through inhalation or cutaneous absorption. The

absorbed carbon disulfide is then eliminated through the lungs unchanged as carbonyl sulfide or as

carbon dioxide, or it is converted to water-soluble metabolites, which are excreted by the kidneys.

Metabolites of carbon disulfide found in the urine are often utilized as biomarkers of exposure.

Sulfates, for example, are nonspecific products of the metabolism of carbon disulfide and many other

compounds. Some investigators have observed an increase in total urinary sulfate levels (specifically

inorganic sulfates) in humans after exposure to 22 ppm of carbon disulfide vapor for 1.5 hours

(McKee et al. 1943) suggesting that sulfate levels may be useful as a nonspecific biomarker of

exposure, perhaps in combination with other markers. However, other researchers have made

conflicting observations. More recently, certain specific dithiocarbamates have been used in more

specific and reliable tests (discussed below) of carbon disulfide exposure.

Carbon disulfide is also found in the saliva and sweat of exposed individuals in small quantities.

These measurements have not been shown to quantitatively correlate with carbon disulfide exposure.

The concentration of carbon disulfide in the feces is very low and therefore has also not been routinely

used as a biological marker of exposure (Djuric 1967).
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Higher cholesterol levels (correlated with exposure levels), higher blood creatinine levels, marked

disturbances of the hepatic cytochrome P-450 content and of the associated microsomal

monooxygenase system, as well as the inhibition of succinic-oxidase enzyme activity, may also be

considered as nonspecific biomarkers of carbon disulfide exposure. More research, however, needs to

be done in order to determine whether a direct correlation exists between these parameters and carbon

disulfide exposure.

The following paragraphs describe reasonably specific biomarkers for carbon disulfide exposure in

humans that correlate with exposure levels to varying degrees.

Carbon disulfide levels eliminated by exhalation may yield some information about recent, short-term

exposure; however, the breath test has not been widely used for monitoring occupational exposure

because of several confounding factors. The first phase of carbon disulfide elimination by breath is

very fast. Pollutant concentrations in the breath, therefore, may reflect variable uptake during the day

but may not be a good reflection of the longer term uptake and exposure values for an entire working

day. Results from breath tests for carbon disulfide exposure are further confounded by the fact that

absorption and elimination rates of carbon disulfide by the lungs are variable among different

individuals and within the same individual because of differences in activity and metabolic rates.

Chronically exposed persons, for example, have a lower retention rate than those exposed for the first

time (Campbell et al. 1985; Djuric 1967).

Because of these confounding factors, results of breath tests for carbon disulfide exposure do not

correlate well with its environmental levels. However, one might be able to detect carbon disulfide

exposure more reliably if measurements of carbon disulfide were made during a second slower

elimination phase and if a more sensitive detection technique were used. A quadrupole mass

spectrometer makes the measurement of carbon disulfide in exhaled breath much more sensitive,

detecting exposure levels as low as 1 ppm. In an investigation by Campbell et al. (1985), the shortterm

elimination of carbon disulfide was studied measuring uptake that had taken place l-2 hours

before the test. Carbon disulfide levels in the breath were found to fluctuate, but the value of next-day

tests measuring the slower elimination phase of carbon disulfide by the breath should be explored.

Nevertheless, the use of exhaled carbon disulfide remains an equivocal biomarker of exposure.
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Blood carbon disulfide levels may also serve as a biomarker of exposure. Data from blood tests,

however, have not shown consistent correlation with carbon disulfide exposure levels in past studies.

Blood carbon disulfide concentration after exposure may be a poor indicator of actual exposure

because of rapid clearance from this tissue (Beauchamp et al. 1983; WHO 1979). A confounding

factor in using blood carbon disulfide concentration as a biomarker of exposure is the fact that two

different species of carbon disulfide exist in the blood. “Free” carbon disulfide is unbound carbon

disulfide that is still dissolved in blood plasma; “bound” or “acid-labile” carbon disulfide refers to an

appreciable amount of carbon disulfide dissolved in plasma lipids or bound to proteins in the blood.

The equilibrium between free and acid-labile carbon disulfide in blood varies inter- and

intraindividually, rendering blood carbon disulfide measurements less reliable for calculating exposure

dose. Moreover, bound carbon disulfide’s rate of release into other body systems may vary also. A

head-space gas chromatography detection technique used to measure acid-labile carbon disulfide may

bear investigation. Carbon disulfide levels are usually measured in acid-treated whole blood; however,

it is suspected that the greater percentage of carbon disulfide in the blood is bound to blood cell

membranes because of its affinity for lipids and proteins (Campbell et al. 1985). This means that the

lack of correlation of blood plasma levels of carbon disulfide with exposure data may be due to a

significant portion of the carbon disulfide not being measured at all as it is not in the plasma.

Some investigators have measured levels of carbon disulfide in urine as a biomarker of exposure, but

this is probably optimal only for measuring high exposure levels (Beauchamp et al. 1983). Good

correlation between urinary carbon disulfide levels and work exposure was not found in any studies.

The measurements of excreted or “free” carbon disulfide may have been confounded by the presence

of various thiometabolites or “bound” species. Moreover, the volatility of carbon disulfide and

individual variations in urinary flow rate and metabolism may have confounded results in these studies

(Djuric 1967).

The concentration of crosslinked red blood cell spectrin has been suggested as a marker of nerve

protein crosslinking damage that leads to slower conduction velocities and abnormal nerves due to

protein adduct formation initially with dithiocarbamates which decompose to form isothiocyanate

adducts (Valentine et al. 1993). These latter adducts can then cause the actual crosslinking of both

spectrin and nerve protein. As new red blood cells must be made to replace the damaged spectrin, the

crosslinking of this protein may serve as a longer term biomarker of carbon disulfide exposure.
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The iodine-azide test measures possible carbon disulfide exposure, based on the decolorization of

iodine in the presence of urinary carbon disulfide thiometabolites. The iodine-azide test is a means for

determining longer term carbon disulfide exposure at air concentrations of 50 mg/m3

 (around 16-20

ppm) and above (Baselt 1980; Beauchamp et al. 1983; Campbell et al. 1985; Lieben 1974; WHO

1986). However, it is not a very sensitive test for exposure at lower concentrations of concern to

OSHA. The iodine-azide test measures the catalysis of the reaction between iodine and sodium azide

by the following metabolites of carbon disulfide acting as biomarkers of exposure: thiourea, which is

the main urinary thiometabolite involved in this test, 2-thio-5-thiazolidinone, and a third unidentified

metabolite. The latter two chemicals are present in very small quantities and are not as important in

catalyzing the iodine-azide reaction (Beauchamp et al. 1983). However, even though exposure can be

detected, the utility of such measurements is limited by the lack of the correlation between exposure

and urinary carbon disulfide described in the previous paragraph; that is, level or duration of exposure

cannot be quantified.

Measuring the total concentration of urinary thio compounds (including glutathione conjugates,

mercapturic acids, and other sulfur-containing carbon disulfide metabolites) can serve as a good

marker of exposure. The level of total thio compounds correlates with carbon disulfide exposure

levels and is a more sensitive biomarker of exposure than the iodine-azide test (Beauchamp et al.

1983; Van Doorn et al. 1981a). This biomarker detects an exposure to 6 ppm carbon disulfide for

8 hours (Beauchamp et al. 1983). These compounds are not absolutely specific for carbon disulfide

exposure.

TTCA is used as an indicator to assess the degree of occupational exposure to carbon disulfide

(Thienpont et al. 1990). Although the detection limit was estimated at 0.05 mg of TTCA/g of urinary

creatinine, the study did not provide data on carbon disulfide exposure levels.

In a rayon production factory, exposure to carbon disulfide was measured by personal air sampling and

the excretion of TTCA in urine (Meuling et al. 1990). Based on the personal air-sampling, the TWA

exposure level for carbon disulfide was 12.6 mg/m3 (4 ppm). The study authors established a

calculated biological limit value of 0.77 mg TTCA/g creatinine (0.57 mmol/mol creatinine) to

correspond with 95% confidence, to a TWA air concentration lower than the threshold limit value

(TLV) of 30 mg/m3

.
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Measuring levels of one particular urinary thiometabolite of carbon disulfide may serve as an even

more sensitive and specific biomarker of exposure. TTCA, which is a product of glutathione

conjugation, is quantitatively related to carbon disulfide uptake (Beauchamp et al. 1983; Campbell et

al. 1985; Drexler et al. 1994). Carbon disulfide exposure levels of 2.5 ppm and above are detected by

this analytical method. Carbon disulfide exposure correlates well with urinary TTCA concentrations,

especially once the metabolite levels are normalized to urinary creatinine content. It appears that

TTCA levels may be used as a sensitive monitor of longer term exposure in workers (Beauchamp et

al. 1983; Campbell et al. 1985; Drexler et al. 1994). One limitation of urinary TTCA levels is that

this compound has been detected at low concentrations (range, 0.005-0.15 mg/g creatinine) in persons

not exposed to carbon disulfide (Lee et al. 1995). The source of this TTCA is thought to be from

dietary intake, especially the consumption of brassica vegetables (e.g., cabbage) (Simon et al. 1994).

Therefore, in persons who eat large amounts of these vegetables, measurements of urinary TTCA may

overestimate carbon disulfide exposure. Baseline sampling is therefore necessary to correct for

nonworkplace exposure sources.

Biological monitoring for carbon disulfide exposure was performed using the iodine-azide test and

TTCA test in urinalysis of workers with high exposure to carbon disulfide (36-46 ppm) (van Poucke

et al. 1990). Based on the findings of the study, the specificity and the sensitivity were low for the

iodine-azide test and high for the TTCA test. ACGIH (1986, 1994) has recommended a biological

exposure index of end-of-shift urinary TTCA of 5 mg/g creatinine.

Therefore, it appears that because of the limitations in the methodology for measuring carbon disulfide

in blood, breath, and urine of exposed individuals, direct measurement of this compound is not the

most sensitive test for determining the extent of exposure (Beauchamp et al. 1983; Campbell et al.

1985; Djuric 1967; McKee et al. 1943; WHO 1979). For the present, the biomarker that correlates

best with exposure is measurement of metabolites in the urine. The iodine-azide and TTCA tests can

be conducted to measure urinary levels of carbon disulfide metabolites as they have been shown to

correlate with exposure (Baselt 1980; Beauchamp et al. 1983; Campbell et al. 1985; Lieben 1974;

WHO 1986), with the TTCA test being more sensitive and specific than the iodine-azide test.

For more information concerning absorption, distribution, metabolism, and excretion of carbon

disulfide, refer to Section 2.3.
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2.6.2 Biomarkers Used to Characterize Effects Caused by Carbon Disulfide

The battery of biomarkers discussed here may be used as indicators of probable carbon disulfide

exposure. However, the physiological effects of carbon disulfide poisoning are numerous and range

from mild to severe. Their utilization as biomarkers of effect are confounded by their occurrence in

response to other epidemiological, nutritional, and environmental factors. Their significance as

biomarkers is further reduced by the fact that these effects occur with great variance in the cohort

exposed population.

The following are proposed as likely biomarkers of effect for carbon disulfide; however, more

information about their possible correlation with actual carbon disulfide exposure and their reliability

and consistency is necessary before they can be utilized to indicate level or duration of exposure or

predict potential health effects.

Several neurological parameters may be useful as more specific biomarkers of polyneuropathy from

carbon disulfide exposure. CT-scans, magnetic resonance imaging, and pneumoencephalography

(PEG) may indicate early cerebral/cerebellar atrophy in humans (Beauchamp et al. 1983; Peters et al.

1988). EMGs have detected signs of neurogenic lesions in humans, and changes in brain EEG

patterns in animals have accompanied carbon disulfide-induced central nervous system toxicity.

Moreover, neurophysiological methods may be utilized to detect decreasing nerve conduction velocity,

which is a biomarker of peripheral nervous system effects (WHO 1981).

Changes in lipid metabolism are the most obvious biomarkers of carbon disulfide’s vasculopathic

effects. Hypercholesterolemia (Toyama and Sakurai 1967) and high β-lipoproteins in the blood

(Prerovska and Drdkova 1967) have been observed by investigators following long-term occupational

carbon disulfide exposure. Elevated blood lipid concentrations following long-term carbon disulfide

exposure in humans may be an appropriate indicator of ensuing arteriosclerosis, clinical vasculopathy,

and increased risk of cardiovascular disease (El-Sobkey et al. 1979). However, the accuracy and

reliability of this parameter as a potential biomarker of exposure for carbon disulfide are in question

since many things can cause changes in lipid metabolism.

More specific blood lipid parameters, however, may prove to be useful in the future. Changes have

been observed in lipid metabolism when a cytochemical enzymological examination of leukocytes and
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platelets was carried out for over 600 exposed workers (Micu et al. 1985). Researchers found high

levels of lymphocytic lipids and low levels of granulocytic lipids. Another investigator found elevated

serum cholesterol and fatty acids and low cholesterol ester levels in an 11-week study of dogs.

However, only the experimental animal group fed a high-fat diet showed altered lipid metabolism.

The exposed groups on normal and high-carbohydrate diets had normal serum lipid content (Lewey et

al. 1941).

In exposed women, possible disruptions of the neurohormonal-endocrine balance necessary for normal

ovarian and uterine cycles may lead to amenorrhea, abnormal menstrual cycles, spontaneous abortions,

and even sterility (WHO 1979; Zielhuis et al. 1984). Serum thyroxine levels, which decrease

following carbon disulfide exposure, have also been suggested as a biomarker (Cavalleri 1975).

Higher plasma creatinine levels were observed among workers exposed to 4-18 ppm of ambient

carbon disulfide. Creatinine level in plasma may be utilized as a nonspecific biomarker of short-term

renal dysfunction (Hernberg et al. 1971). Another such biomarker of renal effects may be the blood

sugar level. Higher than normal blood sugar levels in response to carbon disulfide exposure were

observed in a chronic-duration human study (Hernberg et al. 1971) and an intermediate-duration dog

study (Lewey et al. 1941).

In studying the effects of carbon disulfide exposure on enzyme systems of carbohydrate metabolism,

McKee et al. (1943) observed that the succinic-oxidase system was inhibited. They noted a 10%

decrease in the activity of this system. Carbohydrate metabolism is crucial in proper neural function;

thus, succinic-oxidase activity may serve as an appropriate biomarker of nervous system effects

(McKee et al. 1943).

In conclusion, the following summarizes possible correlative biological markers of early carbon

disulfide poisoning: (1) electromyographical indications of neural lesions; (2) decreased

neuromuscular conduction velocity; (3) abnormal lipid metabolism as indicated by

hypercholesterolemia; (4) decreased steroid hormone levels (Lieben 1974); (5) low urinary thiamine

levels; (6) high plasma creatinine levels; and (7) lower succinic-oxidase enzyme activity (Beauchamp

et al. 1983; Hernberg et al. 1971; Lewey et al. 1941; WHO 1981). In addition, covalent crosslinking

to erythrocyte spectrin may find application as a biomarker (Valentine et al. 1993). All of these are

early indicators of central and peripheral nervous system, cardiovascular, endocrine, and reproductive
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toxicity. Also, these biological markers are not specific for carbon disulfide. One or a combination of

these markers may prove to be a useful biomarker for carbon disulfide effects. See Section 2.2 for

other effects caused by carbon disulfide.

2.7 INTERACTIONS WITH OTHER SUBSTANCES

Many of the chemical interactions with carbon disulfide appear to be related to loss of microsomal

cytochrome P-450. Carbon disulfide suppresses the hepatic cytochrome P-450 microsomal enzyme

system. Elimination of phenazone, a drug often used in the study of hepatic microsomal enzyme

activity, is significantly and reversibly inhibited in rabbits exposed to 193 ppm carbon disulfide for

5 hours a day, 6 days a week, for 6 months (Orzechowska et al. 1984). It has been proposed that the

active sulfur atoms released following carbon disulfide metabolism suppress the cytochrome P-450

enzymes, thus inhibiting detoxification of other drugs or chemicals.

The influence of carbon disulfide exposure on the cardiovascular actions of adrenaline and

noradrenaline was examined in urethane-anesthetized rats. Electrocardiographic change (T-wave

elevation) consistent with slight myocardial ischemia was noted in anesthetized rats administered

carbon disulfide (253 mg/kg/day) for 4 weeks and challenged with adrenaline or noradrenaline

(Hoffmann and Muller 1990; Klapperstück et al. 1991). Carbon disulfide-exposed rats were more

prone to ventricular arrhythmias (extrasystoles) and a prolongation of the PR interval than nontreated

animals. Thus, the hypertensive adrenergic effects of these drugs appear to be enhanced in carbon

disulfide-exposed rats. It was further shown by Klapperstück et al. (1991) that lactic dehydrogenase

M isozyme activity was increased under these condition, while total lactate dehydrogenase activity was

not, a change that has been associated with adaptation to anaerobic metabolism. Based on these

findings, the study authors postulated that carbon disulfide cardiotoxicity may be mediated by

disruption of the energy supply. Administration of up to 506 mg/kg carbon disulfide by gavage to

urethane-anesthetized Wistar rats did not cause changes in the development of cardiac arrhythmias

induced either by ischemia (coronary ligation) or by aconitine administration (Hoffmann and

Klapperstuck 1990).

The combined effect of carbon disulfide exposure and ethyl alcohol has been examined to determine if

carbon disulfide exposure results in the Antabuse syndrome, an intolerance to alcohol. The

metabolism of Antabuse, disulfuram, or tetraethylthiuram disulfide (TETD) produces carbon disulfide
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and diethylamine. The metabolites of Antabuse inhibit the enzymes necessary to metabolize ethyl

alcohol (aldehyde dehydrogenase and catalase), which results in the Antabuse syndrome due to a

buildup of aldehyde. Symptoms include a sensation of heat, a fall in blood pressure, nausea, and in

extreme cases circulatory collapse (Djuric 1971). Research by Freundt et al. (1976) on rats and

humans of the combined effects of carbon disulfide exposure and ethanol ingestion indicate that, at

low (20 ppm) and medium (400 ppm) levels of carbon disulfide exposure and blood alcohol levels of

approximately 0.75%, there is a carbon disulfrde inhibition of aldehyde dehydrogenase with an

increase in acetaldehyde concentrations in the blood. However, these increased acetaldehyde

concentrations were not considered great enough to indicate the Antabuse syndrome. The study

authors asserted that the Antabuse syndrome is not likely to occur in subjects who have blood alcohol

levels of up to 0.8% and are exposed to 10 ppm carbon disulfide.

The possible role of the ethanol-inducible isozyme of cytochrome P-450 in the metabolism of carbon

disulfide has been examined (Snyderwine et al. 1988). Rats were administered various alcohols

(methanol, ethanol, isopropanol, and isobutanol) by gavage. Eighteen hours after alcohol

administration, rats were administered carbon disulfide intraperitoneally at doses of 1, 100, or

625 mg/kg. The results showed that pretreatment of rats with these alcohols enhances the metabolism

of carbon disulfide by increasing the ethanol-inducible isoform of cytochrome P-450 with isopropanol

being most potent. Furthermore, the study authors indicate that alcohol induction of P-450-dependent

carbon disulfide metabolism per se is not sufficient to result in carbon disulfide-induced hepatic

damage although it does lead to the loss of specific cytochrome P-450 function.

The chronic effect of carbon disulfide and ethanol was examined by Opacka et al. (1984). Rats were

exposed to 257 ppm of carbon disulfide for 5 hours a day, 6 days a week, for 11 months, and 10%

ethanol (in water ad libitum for the last 3 months, control water ad libitum). Control rats were

exposed to filtered air. The behavior, memory, and learning ability of the ethanol-fed rats were

adversely affected compared to controls. Additional studies indicate biochemical alterations in the

central nervous system and increased β-glucuronidase activity; ultrastructural studies show

degeneration in the peripheral nervous system, particularly in the myelin sheath. These authors

reported that the effects from combined exposures are greater than those from each substance alone.

Wronska-Nofer et al. (1986) investigated the hepatotoxicity of combined ethanol and carbon disulfide

in the rat. Rats were chronically exposed to 482 ppm (1.5 g/m3

) of carbon disulfide 5 hours a day,

5 days a week, for 5 months and given a 10% ethanol solution as their sole source of fluids. Ethanol
CARBON DISULFIDE 96

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increased the hepatotoxicity of carbon disulfide by potentiating the effects (further depressing the

P-450 levels) of carbon disulfide on the activity of the microsomal cytochrome P-450 monooxygenases

of the liver and on the hepatic endoplasmic reticulum (development of giant mitochondria and

degranulation of the rough endoplasmic reticulum).

An occupational epidemiological study of grain workers indicates that there are neurotoxic effects

from exposure to the 80/20 carbon tetrachloride/carbon disulfide fumigant. Most of the effects

(dysfunction of the peripheral axons, auditory nerve, optic nerve, and extrapyramidal system, as well

as altered behavior and cognition) also appear in viscose rayon workers exposed to carbon disulfide.

However, a combined effect with carbon tetrachloride could not be ruled out. EPA banned the use of

80/20 carbon tetrachloride/carbon disulfide fumigants after June of 1986 because of the potential for

combined and synergistic toxic effects on the nervous system (EPA 1989a). In sheep, combined

treatment with carbon tetrachloride and carbon disulfide, whether given simultaneously or separated by

6 hours (carbon disulfide then carbon tetrachloride), is effective in controlling liver fluke (Seawright et

al. 1972). Carbon tetrachloride can be hepatotoxic in sheep; when it is administered with carbon

disulfide, however, the toxicity is significantly reduced. The mechanism by which carbon disulfide

protects against carbon tetrachloride toxicity in rats was investigated by Seawright et al. (1980).

Carbon tetrachloride requires microsomal metabolism in the liver to exert a toxic effect. Carbon

disulfide is effective in decreasing microsomal metabolic activity through the loss of cytochrome

P-450 and therefore decreases the microsomal metabolism of carbon tetrachloride.

Carbon disulfide potentiates the toxic effect of amphetamines in rats; this effect increases with duration

of exposure to carbon disulfide (Caroldi et al. 1987). Freundt et al. (1974b) have found that the effect

of sodium phenobarbital pretreatment on rat liver fat accumulation following exposure to carbon

disulfide is dependent on the dose and method of ingestion of carbon disulfide. Fat accumulation is

significant if the phenobarbital-treated rat is exposed orally to a very high dose of carbon disulfide

(1,263 mg/kg body weight); however, inhalation of 20-200 ppm of carbon disulfide (8 hours for

2-7 days) in a phenobarbital-treated rat did not produce fat accumulation in the liver. Extrapolation to

human beings is difficult, but the study authors asserted that the sensitivity of hepatic MFOs to carbon

disulfide is similar qualitatively and quantitatively in rats and humans. They suggest that it is not

hazardous for individuals without hepatic disease to take barbiturate-containing drugs and

simultaneously work in 20-200 ppm carbon disulfide (Freundt et al. 1974b).
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Carbon disulfide interacts with several organophosphorus compounds including the insecticides

malathion and parathion. Metabolism of malathion and parathion requires cytochrome P-450 and is

thus inhibited by carbon disulfide (Dalvi and Howell 1978). It is important to note that carbon

disulfide would potentiate the toxic effect of compounds that require cytochrome P-450 microsomal

metabolism for detoxification.

Oral administration of diethylthiocarbamate and carbon disulfide (separately) protects mice against

chloroform-induced kidney injury (Masuda and Nakayma 1983a). The mechanism for protection is

postulated to be the inhibition of the kidney microsomal mono-oxygenase system by the thiono-sulfur

groups of diethylthiocarbamate and carbon disulfide because chloroform requires metabolic activation

in the kidney to induce nephrotoxicity. Carbon disulfide also protects mice from 1,2-dimethylhydrazine-induced neoplasia of the large intestine (Wattenberg and Fiala 1978). 1,2-Dimethylhydrazine requires several steps of metabolic activation, including the N-oxidation of azomethane to

azoxymethane. This step is inhibited by the loss of microsomal MFO activity caused by carbon

disulfide.

In a well-conducted study by Antov et al. (1985), rats were administered carbon disulfide by inhalation

for l-6 months with or without an arteriogenic diet (consisting of cholesterol, choleic acid, and

vitamin D2), which was used to develop the sclerotic process. Concentrations of 16, 32, and 64 ppm

carbon disulfide produced significant changes in the myocardium in a dose-response relationship. The

administration of the atherogenic diet potentiated the cardiotoxicity and enhanced the sclerotic process.

Although changes in enzyme activity (statistical significance not reported) were noted, no substantial

structural changes occurred in the heart muscle or aorta at the lowest dose of carbon disulfide tested

(3.2 ppm) without the atherogenic diet. Histological changes characterized by vacuolar dystrophy and

interstitial fibrosis occurred at 16 ppm carbon disulfide and became more advanced at higher

concentrations (64 ppm). The study authors concluded that carbon disulfide has an arteriogenic effect.

Carbon disulfide was reported to inhibit the mutagenic activity of 1,2-dimethylhydrazine and

azoxymethane in a host-mediated assay (7-week-old ICR mice) (Moriya et al. 1979). These authors

suggested that this effect is due to carbon disulfide’s prevention of in vivo oxidation of azomethane to

azoxymethane.
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2.8 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE

A susceptible population will exhibit a different or enhanced response to carbon disulfide than will

most persons exposed to the same level of carbon disulfide in the environment. Reasons include

genetic make-up, developmental stage, age, health and nutritional status (including dietary habits that

may increase susceptibility, such as inconsistent diets or nutritional deficiencies), and substance

exposure history (including smoking). These parameters may result in decreased function of the

detoxification and excretory processes (mainly hepatic, renal, and respiratory) or the pre-existing

compromised function of target organs (including effects on clearance rates and any resulting endproduct metabolites). For these reasons we expect the elderly with declining organ function and the

youngest of the population with immature and developing organs will generally be more vulnerable to

toxic substances than healthy adults. Populations who are at greater risk due to their unusually high

exposure are discussed in Section 5.6, “Populations With Potentially High Exposure.”

There are studies that have investigated particular metabolic traits that may result in hypersusceptibility to carbon disulfide (Djuric et al. 1973; Stokinger and Scheel 1973). The study conducted by

Djuric et al. (1973) reported on 72 workers who had been divided into three groups: 18 exposed to

carbon disulfide at levels below the industrial air limit of 20 ppm (60 mg/m3

) (controls), 21 who had

been exposed to levels higher than 20 ppm but had shown no signs or symptoms of carbon disulfide

intoxication (resistant), and 33 who had polyneuritis or other signs of overexposure and had been

removed from exposure (susceptibles). All individuals were administered an oral dose of 0.5 g of

disulfiram (Antabuse), a compound that produces carbon disulfide when metabolized. It was assumed

that carbon disulfide and disulfiram are metabolized by the same or similar enzyme system, and

determination of diethyl dithiocarbamates (DDC) in urine after disulfiram administration was used to

evaluate the rate at which sulfur compounds are metabolized. The excretion of DDC was significantly

lowest in the susceptible group (49.70 μg/mg creatinine) when compared to both the control

(160.05 μg/mg creatinine) and resistant (90.04 μg/mg creatinine) groups. These results led to the

suggestion that the reduced ability of the symptomatic workers to metabolize this compound would

lead to hypersusceptibility to carbon disulfide and would thus be associated with the clinical signs

observed in that group. No supporting data have been located, however.

The study authors (Djuric et al. 1973) suggested that carbon disulfide exposure causes a decrease in

excretion of DDC, especially in once-poisoned workers; thus carbon disulfide exposure produced a
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disturbance in the metabolism of sulfur compounds. They also suggested that in the susceptible

worker group this decreased metabolic conversion appeared to persist even 5-10 years after exposure,

and thus carbon disulfide exposure may have led to an irreversible metabolic disturbance. These

authors did not speculate on the mechanism of actual metabolic inhibition, nor did they propose any

genetic hypothesis. One study limitation included the problematic issue of whether it is possible to

establish that a prior hypersusceptibility existed in testing workers who had been exposed for long

periods of time and whose differences in metabolism may have related to the circumstances of their

exposure rather than to a previous susceptibility.

Because it appears that one common mechanism of the cerebral, cardiovascular, and hepatic effects

may be an acceleration of the arteriosclerotic process (see Section 2.4), individuals at risk for

arteriosclerosis or those with early arteriosclerosis would probably be at increased risk for health

effects following exposure to carbon disulfide (NIOSH 1978). The mechanism for carbon disulfide

acceleration of arteriosclerotic plaque formation involves direct injury to the vessel endothelium and

changes in lipid metabolism.

Three other groups are recognized as being unusually susceptible to carbon disulfide: alcoholics

(including those treated with Antabuse), those with neuropsychic disorders, and those with vitamin B6

deficiency (Djuric et al. 1973; Lefaux 1968; Peters et al. 1982). Carbon disulfide reduces the levels of

vitamin B6, which in turn upsets carbohydrate metabolism, particularly the cerebral carbohydrates

(Lefaux 1968).

2.9 METHODS FOR REDUCING TOXIC EFFECTS

This section describes clinical practice and research concerning methods for reducing toxic effects of

exposure to carbon disulfide. However, because some of the treatments discussed may be

experimental and unproven, this section should not be used as a guide for treatment of exposures to

carbon disulfide. When specific exposures have occurred, poison control centers and medical

toxicologists should be consulted for medical advice.
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2.9.1 Reducing Peak Absorption Following Exposure

There are no specific methods available to reduce the absorption of carbon disulfide following

exposure. Activated charcoal (Stutz and Janusz 1988) and gastric lavage or induced emesis using a

saturated sodium bicarbonate solution to decrease gastric acidity and to preclude hydrogen sulfide

formation (Dreisbach and Robertson 1987) have been suggested for treatment of carbon disulfide

ingestion. However, the use of emetics is controversial (Bronstein and Currance 1988; Stutz and

Janusz 1988). If contamination occurs via the skin, thorough washing with soap and water has been

suggested. For eye contamination, flushing the eyes with copious amounts of water is the

recommended treatment (Stutz and Janusz 1988).

Urea (0.5-1.5 g/kg) administered intravenously has been recommended to inactivate free carbon

disulfide in the blood; intravenous administration of large doses of vitamin B6 has also been

recommended (HSDB 1995).

2.9.2 Reducing Body Burden

Unmetabolized carbon disulfide is exhaled unchanged in expired air (McKee et al. 1943), whereas

metabolites are excreted primarily in the urine (Soucek 1957). Therefore, increasing ventilation and

urinary output may be potential methods to facilitate mitigation of the effects of carbon disulfide.

However, such methods have not been attempted with regard to carbon disulfide within a clinical

setting. Removing the patient from the contaminated area followed by supportive care is the suggested

basic form of treatment (Bronstein and Currance 1988; Dreisbach and Robertson 1987; Ellenhorn and

Barceloux 1988; Haddad and Winchester 1990; Morgan 1982; Stutz and Janusz 1988).

Carbon disulfide is metabolized by cytochrome P-450 to an unstable oxygen intermediate which may

either spontaneously degrade to atomic sulfur and carbonyl sulfide or hydrolyze to form atomic sulfur

and monothiocarbamate (Beauchamp et al. 1983). Although phenobarbital pretreatment of rats can

enhance the metabolism of carbon disulfide (Dalvi and Neal 1978), it can also enhance the hepatic

toxicity of carbon disulfide. Another metabolic pathway for carbon disulfide is its conjugation with

glutathione to form 2-thiothiazolidine-4-carboxylic acid and 2-oxothiazolidine-4-carboxylic acid,which

are excreted in the urine (Van Doorn et al. 198la, 1981b). Although the extent to which glutathione
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conjugation plays a role in the metabolism of carbon disulfide is unclear, it is conceivable that

administration of cysteine may be utilized in the mitigation of the effects of carbon disulfide.

2.9.3 Interfering with the Mechanism of Action for Toxic Effects

There are no specific methods available that provide information on interfering with the mechanism of

action for toxic effects of carbon disulfide. However, decreases in carbon disulfide toxicity may be

brought about by other chemical substances. For example, the effects of carbon disulfide on the

nervous system (the primary target of exposure to carbon disulfide) appear to be influenced by the

mineral content of the diet. Rabbits given diet supplements of copper and zinc were exposed to high

levels of carbon disulfide (1,100 ppm) and did not show the usual signs of exposure-weight loss,

serum lipoprotein and total cholesterol increase, adrenal hypertrophy, and pathological changes in the

brain and spinal cord-that appeared in controls on a normal salt diet (ACGIH 1986). A proposed

biochemical basis for the antagonist effect of minerals is that carbon disulfide metabolitesdithiocarbamates- are metal chelating agents. The metal complex is more water soluble than the

dithiocarbamate alone and thus is excreted faster than the dithiocarbamate. Additional minerals hasten

the loss of the compound that causes the effects.

The formation of reactive intermediates resulting from the metabolism of carbon disulfide by the

hepatic MFO system may be involved in the hepatoxicity of this chemical. Pretreatment of rats with

phenobarbital, an inducer of MFO activity, can enhance carbon disulfide-induced hepatotoxicity (Bus

1985). Inhibition of the MFO system might potentially reduce carbon disulfide-mediated hepatoxicity.

In support of this possibility, Bond and De Matteis (1969) reported that pretreatment of rats with SKF525A, an inhibitor of cytochrome P-450-mediated metabolism, reduced the liver damage from carbon

disulfide in phenobarbital-pretreated animals.

Two possible mechanisms for the neurotoxicity of carbon disulfide have been suggested. One

mechanism involves the formation of dithiocarbamates. The inhibitory effect of carbon disulfide on

the activity of the copper-requiring enzyme dopamine-β-hydroxylase was attributed to the formation of

dithiocarbamates, which can complex copper (McKenna and DiStefano 1977b). Interference with the

formation of this metabolite may be a potential strategy, albeit untested, to reduce neurotoxicity from

carbon disulfide poisoning. An alternative mechanism postulated to explain the neurotoxic effect of

carbon disulfide is the formation of a dithiocarbamate derivative, a form of vitamin B6, of
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pyridoxamine, with carbon disulfide (Vasak and Kopecky 1967). Since transaminases and amine

oxidases require the pyridoxamine phosphate form of vitamin B6 as a cofactor, it was further

postulated that these enzymes would be inhibited in carbon disulfide poisoning. Although data are

limited, supplementation of the diet with vitamin B6 has been demonstrated to delay some of the

neurotoxic effects of carbon disulfide (Teisinger 1974).

2.10 ADEQUACY OF THE DATABASE

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with

the Administrator of EPA and agencies and programs of the Public Health Service) to assess whether

adequate information on the health effects of carbon disulfide is available. Where adequate

information is not available, ATSDR, in conjunction with the National Toxicology Program (NTP), is

required to assure the initiation of a program of research designed to determine the health effects (and

techniques for developing methods to determine such health effects) of carbon disulfide.

The following categories of possible data needs have been identified by a joint team of scientists from

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean

that all data needs discussed in this section must be filled. In the future, the identified data needs will

be evaluated and prioritized, and a substance-specific research agenda will be proposed.

2.10.1 Existing Information on Health Effects of Carbon Disulfide

The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to

carbon disulfide are summarized in Figure 2-4. The purpose of this figure is to illustrate the existing

information concerning the health effects of carbon disulfide. Each dot in the figure indicates that one

or more studies provide information associated with that particular effect. The dot does not

necessarily imply anything about the quality of the study or studies, nor should missing information in

this figure be interpreted as a “data need.” A data need, as defined in ATSDR’s Decision Guide for

Identifying Substance-Specific Data Needs Related to Toxicological Profiles (ATSDR 1989), is

substance-specific information necessary to conduct comprehensive public health assessments.

Generally, ATSDR defines a data gap more broadly as any substance-specific information missing

from the scientific literature.

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There are human data on inhalation exposure of carbon disulfide that provide information on acute and

chronic systemic effects. There are also data on immunologic, neurologic, developmental, and

reproductive effects. There are some limited data on the carcinogenic potential of carbon disulfide, but

these are preliminary and confounded by multiple exposure problems. There are no oral exposure

data from humans and only limited information on dermal exposures. The dermal data address the

occupational hazard of blister formation following accidental exposure.

Animal data on inhalation exposure cover primarily intermediate systemic, neurological,

developmental, and reproductive effects. One chronic study is available that examines systemic effects

in rats. Oral data are limited to lethality data and information on acute systemic and neurological

effects in mice and rats. Dermal data consist of some information regarding blister formation in

humans and rabbits following dermal exposure.

2.10.2 Identification of Data Needs

Acute-Duration Exposure. The data on acute inhalation exposure in humans are limited.

Transient respiratory difficulties were reported in some individuals following an accident in

transporting carbon disulfide, but the actual exposures could not be determined (Spyker et al. 1982).

Adverse effects including deaths were reported in a community in India following an accidental release

of large amounts of carbon disulfide, hydrogen sulfide, and sulfuric acid from a viscose rayon plant

(Kamat 1994). There are sufficient animal data to identify the nervous system (Liang et al. 1983;

Magos and Jarvis 1970; Magos et al. 1974; Tarkowski et al. 1980), the cardiovascular system

(Chandra et al. 1972; Tarkowski and Sobczak 1971), and the liver (Freundt et al. 1974a; Magos and

Butler 1972; Magos et al. 1973) as target organs for acute inhalation exposure. Lethality (Gibson and

Roberts 1972), decreased respiratory rate (Tarkowski and Sobczak 1971), and increased postimplantation loss (PAI 1991) have also been reported in acute studies. The acute studies have been

done primarily in rodents; additional studies on other species, for example, primates, would be useful

for generalizing to expected health effects in humans. No acute-duration inhalation MRL was derived

since potential MRL values would not have been as protective of human health as the chronic-duration

MRL. In addition, there is greater confidence in the chronic-duration MRL since it is based on human

data.
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Three case reports cited in Gosselin et al. (1984) indicate that half an ounce (concentration not

specified) caused death following ingestion. There are no other human data on acute-duration oral

exposure to carbon disulfide. There are sufficient animal data to identify the cardiovascular system

(Hoffman and Klapperstück 1990) and the liver (Jones-Price et al. 1984b; Masuda et al. 1986) as

targets for acute-duration oral exposure to carbon disulfide. Adverse effects including decreased body

weight gain (Jones-Price et al. 1984b), hind-limb paralysis (Jones-Price et al. 1984b), decreased

norepinephrine levels (Kanada et al. 1994), and developmental effects have also been reported. An

acute-duration oral MRL of 0.01 mg/kg/day was derived based on dose-dependent decreases in the

activities of liver microsomal drug-metabolizing enzymes in mice from the study by Masuda et al.

1986.

There are no human data on acute-duration dermal exposure to carbon disulfide. There is one acute

study showing blister formation in rabbit ears when carbon disulfide was applied to the skin (Hueper

1936). Given that there is a possibility of dermal exposures in occupational settings as well as from

contaminated water supplies near hazardous waste sites, additional data on dermal exposures would be

useful. No pharmacokinetic data exist that show that dermal exposures to carbon disulfide result in

patterns of distribution similar to those seen with inhalation or oral exposures. These kinds of data

would be useful for projecting the similarities of target organs across routes as people near hazardous

waste sites may be exposed by all three routes.

Intermediate-Duration Exposure. There are no human data on intermediate-duration inhalation

exposures. Most occupational exposures are considered to be chronic-duration inhalation exposures,

and there are no oral data for humans. The only dermal data for humans concern blisters on the

fingers of rayon workers following 6 weeks of exposure (Hueper 1936).

There are animal data that identify the nervous system (Jirmanova and Lukas 1984; Juntunen et al.

1977; Liang et al. 1983; Merigan et al. 1985, 1988), the cardiovascular system (Antov et al. 1985),

and the liver (Jarvisalo et al. 1977a; Tsuyoshi 1959; Wronska-Nofer 1972, 1973) as targets for

intermediate-duration inhalation exposure to carbon disulfide. NOAELs and LOAELs exist for these

exposures. Again, most of these data come from rodent studies, although some work has been done in

monkeys (Merigan et al. 1988) and dogs (Lewey et al. 1941). The toxic effects are generally the same

across species. There is some evidence that the reproductive (Tepe and Zenick 1984; Zenick et al.

1984) and developmental systems (Danielsson et al. 1984; Lehotzky et al. 1985; Tabacova and
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Balabaeva 1980b; Tabacova et al. 1983; Yaroslavskii 1969) are also targets for intermediate-duration

inhalation exposures. Lethality (Toxicogenics 1983c), decreased body weight (Rebert and Becker

1986), and hematologic (Toxicogenics 1983c) and musculoskeletal (Szendzikowski et al. 1974) effects

have also been reported in intermediate-duration inhalation studies. No intermediate-duration MRL

was derived since potential values would not have been as protective of human health as the chronic

duration MRL. There are very few data on intermediate-duration oral exposures (Pilarska et al. 1973)

and no data on intermediate-duration dermal exposures. Decreased body weight has been observed in

rats following oral exposure to carbon disulfide for an intermediate-duration period (Hoffman and

Klapperstück 1990). No intermediate-duration oral MRLs were derived because of a lack of reliable

LOAELs and a lack of definitive target organs. Additional information on inhalation, oral, and dermal

exposures would be useful for assessing the health risks to humans living near hazardous waste sites

including identification of target organs.

Chronic-Duration Exposure and Cancer. There are data on chronic occupational exposures that

identify the nervous system (Aaserud et al. 1988; Cassitto et al. 1978; Foa et al. 1976; Johnson et al.

1983; Peters et al. 1988; Putz-Anderson et al. 1983; Seppalainen and Tolonen 1974; Seppalainen et al.

1972; UK/IHSE 1981; Vasilescu 1976), the cardiovascular system (Cirla et al. 1972; Franco et al.

1982; Hernberg et al. 1970, 1971, 1973, 1976; Lieben et al. 1974; MacMahon and Monson 1988;

Nurminen et al. 1982; Swaen et al. 1994; Tiller et al. 1968; Tolonen et al. l979), the liver (El-Sobkey et

al. 1979; Mack et al. 1974; Rubin and Arieff 1945; Sidorowicz et al. 1980), and the eye (DeLaey et al.

1980; DeRouck et al. 1986; Raitta and Tolonen 1975; Raitta et al. 1974; Szymankova 1968) as

primary targets for inhalation exposure to carbon disulfide. There are no data on chronic human oral

or dermal exposures. Most of the occupational studies have limitations concerning the exposure

measurements and concomitant exposures; some are limited by the methods used to assess the health

effect end points. However, the Johnson et al. (1983) study, which evaluates nerve conduction

velocity in workers exposed by inhalation to carbon disulfide, has been found acceptable for the

derivation of a chronic-duration MRL. There is only one chronic inhalation study in rabbits (Cohen et

al. 1959) and no chronic oral or dermal animal studies. Additional data concerning the effects of

chronic low-level exposure to carbon disulfide following the inhalation, oral, and dermal routes would

be useful to establish a dose-effect relationship for the major health effects, and to identify target

organs for oral and dermal exposures. Long-term animal studies in several species, such as mice, rats,

and monkeys, that investigate several dose points could be used to determine the neurotoxic

mechanism of action.
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There are no data suggesting an increased risk of cancer from exposure to carbon disulfide.

Epidemiological data have been presented that indicate that there could be an association between

carbon disulfide exposure and lymphocytic leukemia, but these studies had several problems with

multiple comparisons, poor exposure variables, multichemical exposures, and no supporting animal or

human data (Arp et al. 1983; Checkoway et al. 1984; Wilcosky et al. 1984). In addition, the

lymphocytic leukemia may be associated with benzene impurity. A large population sample with

better exposure data covering a minimum of 20 years would be helpful for addressing the repeatability

of these findings. There are no studies regarding cancer in humans following oral or dermal exposure.

In addition, there are no studies regarding cancer in animals via inhalation, oral, or dermal routes of

exposure. A chronic animal bioassay would provide important information on effect and possibly on

mechanism.

Genotoxicity. There are no human genotoxicity data for any route of exposure. Measurements of

chromosomal aberrations or DNA adduct formation done on workers exposed via inhalation would be

useful for assessing the genotoxic potential of carbon disulfide. Data obtained in this way, or from

animals exposed in vivo, may provide evidence of some mechanism for the observed reproductive

effects and, if correlated with exposures, could offer a potential biomarker of effect. This would

provide some way of monitoring populations around hazardous waste sites. One in vivo animal study

of the genotoxicity (chromosomal aberrations in the bone marrow of rats) of carbon disulfide reported

negative results (NIOSH 1980). Bacterial mutagenicity assays (Salmonella typhimurium and

Escherichia coli) have also generally been negative (Donner et al. 1981; Hadenstedt et al. 1979).

Additional bacterial assays would not be useful at this time.

Reproductive Toxicity. There are human data that indicate that chronic inhalation exposure to

carbon disulfide can affect the reproductive system in both males and females. In males, sperm

morphology, hormone levels, and libido have been altered by occupational exposure to carbon

disulfide (Lancranjan 1972; NIOSH 1983; Schrag and Dixon 1985; Vanhoorne et al. 1994; Wagar et

al. 1981; Wyrobek 1983). In human females, menstrual irregularities have been associated with

inhalation exposure to carbon disulfide, although more serious effects such as increased miscarriage

and reduced fertility have not been universally noted (Cai and Bao 1981; Heinrichs 1983; Hemminki

and Niemi 1982; Wang and Zhao 1987; Zhou et al. 1988; Zielhuis et al. 1984). There are no human

data on the reproductive effects of oral or dermal exposure to carbon disulfide. Data on rats support

the reproductive effects seen in humans after inhalation exposure only (Tepe and Zenick 1984; Zenick
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et al. 1984). Additional reproductive studies on other species, such as mice, rabbits, dogs, and

monkeys, would be useful to determine the dose-effect relationship between exposure and reproductive

end points. It would also be useful to investigate reproductive organ pathology in a 90-day study of

toxicity via inhalation, oral, and dermal exposures. There are no oral or dermal reproductive studies in

animals.

Developmental Toxicity. There are no convincing human data that support an increased rate of

congenital malformations in children born to mothers exposed by any route to carbon disulfide (Bao et

al. 1991). Limitations of the Bao et al. (1991) study included the lack of exposure analyses and dose

response assessments. There are data on rodents that suggest an increased fetotoxicity following

inhalation exposure to carbon disulfide (Tabacova and Balabaeva 1980b; Yaroslavskii 1969). In

addition, neurobehavioral effects have been reported in the offspring of exposed animal mothers

(Lehotzky et al. 1985; Tabacova et al. 1983). Additional data from species other than rodents, for

example, monkeys, would be useful for verifying that developmental effects are a result of exposure to

this chemical. There are no animal data that provide information on the developmental effects of

either oral or dermal exposure. There is evidence that carbon disulfide can cross the placenta and is

distributed to the fetal brain, blood, liver, and eyes (Danielsson et al. 1984). Well-designed studies via

inhalation, oral, and dermal exposures show that a dose-response relationship would be useful for

determining the dose at which developmental effects could be expected to occur.

Immunotoxicity. There are no data that suggest that the immune system is a target for carbon

disulfide exposure for any route or in any species. However, the results of one study indicated that the

β-lipoprotein isolated from carbon disulfide exposed-workers (presumably exposed via inhalation) is

antigenically identical to lipoproteins isolated from healthy nonexposed controls (Bobnis et al. 1976).

There are no studies regarding immunological/lymphoreticular effects in humans following oral or

dermal exposures. Also, there are no studies concerning immunological/lymphoreticular effects in

animals following inhalation, oral, or dermal exposures. A 90-day study that investigates immune

parameters should include routine immune function parameters (e.g., macrophage activity, T-cell

activity, mitogen response, cell-mediated immune response) and immunopathology. This would be

useful information for determining if there could be an immune system effect that has been

overlooked.
CARBON DISULFIDE 109

2. HEALTH EFFECTS

Neurotoxicity. It is clear in both humans and animals that the nervous system is the primary target

organ for carbon disulfide exposure for the inhalation route. There are behavioral (e.g., depression,

decreased performance and memory), histopathological (e.g., polyneuropathy), and neurophysiological

(e.g., decreased nerve conduction velocity) data in humans (Aaserud et al. 1988; Cassitto et al. 1978;

Cirla et al. 1972; Foa et al. 1976; Johnson et al. 1983; Lancranjan 1972; Peters et al. 1986a, 1986b,

1988; Putz-Anderson et al. 1983; Seppalainen and Tolonen 1974; Seppalainen et al. 1972; Vasilescu

1976). The results of inhalation toxicity studies in animals have revealed neurophysiological (e.g.,

decreased nerve conduction velocity), neurochemical (e.g., altered noradrenalin and dopamine levels),

and neurobehavioral (e.g., hind-limb paresis) (Frentik et al. 1994; Magos and Jarvis 1970; Tarkowski

and Sobczak 1971; Wilmarth et al. 1993). A chronic-duration inhalation MRL was calculated on the

basis of reduced motor nerve conduction velocity in humans (Johnson et al. 1983). There are no

human data pertaining to neurological effects following oral or dermal exposures. There are limited

animal data on neurotoxic effects (hind-limb paralysis) by the oral route (Jones-Price et al. 1984a,

1984b), and none for the dermal route (Dietzmann and Laass 1977). Studies investigating neurotoxic

effects in animals following oral or dermal exposure would be useful for determining thresholds and

dose-response relationships for neurotoxic effects.

Epidemiological and Human Dosimetry Studies. There are many epidemiological studies that

address the effects of inhalation exposure to carbon disulfide. These studies include both

occupational- and community-based cohorts and have investigated neurological (Aaserud et al. 1988;

Cassitto et al. 1978; Cirla et al. 1972; Foa et al. 1976; Johnson et al. 1983; Peters et al. 1988; PutzAnderson et al. 1983; Seppalainen and Tolonen 1974; Seppalainen et al. 1972), cardiovascular

(El-Sobkey et al. 1979; Franco et al. 1982; Hernberg et al. 1970, 1971, 1973, 1976; Lieben et al.

1974; MacMahon and Monson 1988; Nurminen and Hernberg 1985; Nurminen et al. 1982; Rubin and

Arieff 1945; Sidorowicz et al. 1980; Sugimoto et al. 1978; Tiller et al. 1968; Tolonen et al. 1975,

1979; UK/HSE 1981), and reproductive (Cai and Bao 1981; Heinrichs 1983; Hemminki and Niemi

1982; Lancranjan 1972; NIOSH 1983; Wagar et al. 1981; Wang and Zhao 1987; Zhou et al. 1988)

effects. These studies have found positive associations between carbon disulfide exposure and adverse

health effects. These findings are not universal, however. The epidemiological studies have the

limitation of poor exposure measurements that are not individualized to the study participants. In

addition, the exposures postulated to have occurred in these cohorts cover a wide range of levels,

making extrapolations from one study to another difficult; many of these studies also documented

concomitant exposures to other chemicals, most notably hydrogen sulfide. A principle components
CARBON DISULFIDE 110

2. HEALTH EFFECTS

exposure index has been developed for simultaneous exposures to hydrogen sulfide and carbon

disulfide by Vanhoorne et al. (1995). Nonetheless, they provide data on human health effects, and the

weight of the evidence is that the environment where carbon disulfide is used exerts a range of effects

at different exposure levels. Clearly, occupational workers, as well as communities around hazardous

waste sites or point-emission sources, are at risk for exposure to levels of carbon disulfide that have

been associated with adverse health effects. The biggest drawback in the existing studies is the lack of

the ability to establish a dose relationship between exposure and effect. More precise measurements of

exposure, control of exposure to other chemicals, and long-term follow-up of occupational cohorts

may lead to a better understanding of the dose-effect of carbon disulfide. Monitoring of populations

around hazardous waste sites where carbon disulfide is known to be present would be useful, providing

specific biomarkers of exposure could be identified.

Biomarkers of Exposure and Effect

Exposure. Biomarkers of exposure for carbon disulfide include levels of carbon disulfide in exhaled

breath (Philips 1992), blood (WHO 1979), and urine (Djuric 1967; McKee et al. 1943) and carbon

disulfide thiometabolites in the urine (Beauchamp et al. 1983; Campbell et al. 1985). These

measurements can indicate whether acute-, intermediate-, or chronic-duration exposure to carbon

disulfide has occurred. The presence of carbon disulfide in various biological media is the most

specific biomarker of exposure. However, few studies have been able to demonstrate a straightforward

correlation between the above parameters and actual carbon disulfide exposure. There are two possible

explanations for this observation. The first one is that too many variables tend to confound the

measurements of carbon disulfide in the blood, breath, and urine of exposed individuals, rendering

these biomarkers somewhat unreliable for quantitative evaluation. The second possibility is that the

limitations of the protocols and analytical methods employed for measuring carbon disulfide in

biological media have largely precluded acquiring data related to ascertaining the reliability of these

biomarkers. Therefore, with the development of new and more sensitive methods, blood, breath, and

urine levels of carbon disulfide may become even more useful biomarkers of exposure. More

quantitative, correlative studies are necessary in order to assess this possibility.

At the present time, the biomarkers that correlate best with exposure are metabolite levels in the urine

(Baselt 1980; Beauchamp et al. 1983; Campbell et al. 1985; Lieben 1974i; WHO 1986). The iodineazide and the TTCA tests, which measure the presence of urinary carbon disulfide metabolites, have
CARBON DISULFIDE 111

2. HEALTH EFFECTS

been shown to correlate well with actual exposure. However, the iodine-azide test is nonspecific (Dox

et al. 1992). TTCA is produced in humans after exposure to Antabuse and in rats after exposure to

Captan (Cox et al. 1992). Moreover, other investigations are necessary in order to determine whether

the interaction of carbon disulfide with other substances (such as hydrogen sulfide, drugs, carbon

tetrachloride, malathion, and alcohol), disease states, and variations in diet and in individual

metabolism, as well as other factors, could confound the results of the iodine-azide test and the TTCA

test for carbon disulfide exposure. Baseline urine, breath, and blood samples are necessary to correct

for non-workplace exposures For exposures around hazardous waste sites, the influence of workplace

exposures must also be corrected for in this manner

Effect. Few specific biomarkers of effect have been identified for carbon disulfide. However, many

biological parameters have been tentatively linked with carbon disulfide’s effects on certain enzyme

systems, on the liver and the kidneys, and on the nervous, cardiovascular, reproductive, and endocrine

systems (Baselt 1980; Beauchamp et al. 1983; Cai and Bao 1981; Campbell et al. 1985; Djuric 1967;

El-Sobkey et al. 1979; Heinrichs 1983; Hernberg et al. 1971; Lancranjan 1972; Lewey et al. 1941;

Lieben 1974; McKee et al. 1943; Prerovska and Drdkova 1967; Toyama and Sakurai 1967; Valentine

et al. 1993; Wang and Zhao 1987; WHO 1979, 1981, 1986; Zhou et al. 1988). No studies attempting

to quantitatively correlate these parameters with carbon disulfide effects are available. CT-scan

(computerized tomography) and electromyographical parameters as well as measurements of nerve

conduction velocity may serve as indicators of nervous system effects (Beauchamp et al. 1983; WHO

1981). High serum lipid content (in particular cholesterol) may be linked with cardiovascular effects

(El-Sobkey et al. 1979; Lewey et al. 1941; Prerovska and Drdkova 1967; Toyama and Sakurai 1967).

Reduction in steroid hormone synthesis may indicate early reproductive system effects (Cai and Bao

1981; Heinrichs 1983; Lancranjan 1972; Wang and Zhou 1987; Zhou et al. 1988). Also higher plasma

creatinine levels and elevated blood sugar could signal renal dysfunction due to carbon disulfide

exposure (Hernberg et al 1971; Lewey et al. 1941). Changes in various enzyme systems (for

example, lowered succinic-oxidase activity) may prove useful as biomarkers of effect (McKee et al.

1943). The effect of carbon disulfide on membrane spectrin of nerve and blood membranes should be

investigated further (Valentine et al. 1993). However, changes in these biological parameters are not

specific to carbon disulfide exposure, and future studies are needed to determine the extent to which

they quantitate the results of carbon disulfide exposure. In addition, these studies should evaluate

whether such biological parameters may serve as reliable and accurate biomarkers of carbon disulfide

exposure. However, since many different things can cause these effects, biomarkers may never be
CARBON DISULFIDE 112

2. HEALTH EFFECTS

specific for exposure to carbon disulfide. Nervous system effects are well documented for inhalation

exposures but not for oral or dermal exposures.

Absorption, Distribution, Metabolism, and Excretion. There are human and animal data that

address the absorption, distribution, metabolism, and excretion of carbon disulfide following inhalation

exposure (Abramova 1966; Bond and DeMatteis 1969; Brieger 1967; Cohen et al. 1958, 1959; Dalvi

and Neal 1978; Dalvi et al. 1974, 1975; DeMatteis 1974; DeMatteis and Seawright 1973; Djerassi and

Lumbroso 1968; Djuric 1967; Freundt et al. 1975; McKee et al. 1943; McKenna and Distefano 1977a,

1977b; Okayama et al. 1988; Pergal et al. 1972a, 1972b; Santodonato et al. 1985; Snyderwine and

Hunter 1987; Soucek 1957; Strittmatter et al. 1950; Teisinger 1974; Van Doorn et al. 1981a, 1981b;

Vasak and Kopecky 1967). Data indicate rapid and extensive absorption of inhaled carbon disulfide,

distribution through the body, and primary excretion by exhalation. Carbon disulfide is metabolized

by cytochrome P-450 to an unstable oxygen intermediate that in turn can either degrade to sulfur and

carbonyl sulfide or hydrolize to sulfur and monothiocarbamate. Biotransformation of carbon disulfide

in humans exposed by the inhalation route causes TTCA, OTCA, and thiourea to be excreted in the

urine, and carbonyl sulfide and carbon dioxide in the breath. The data that exist for humans are

largely supported by animal studies (rabbits and dogs) for this route. However, there are very few

animal and human data regarding the pharmacokinetics of carbon disulfide following oral or dermal

exposure, making an assessment of relative rates very difficult (Cohen et al. 1958; DeMatteis and

Seawright 1973; Dutkiewicz and Baranowska 1967). The limited data indicate that a range fraction of

orally administered carbon disulfide is absorbed by rats. Carbon disulfide is appreciably absorbed via

the dermal route in rabbits. Animal data suggest that there are two major pathways. Steady-state

phenomena do play a role in the retention and excretion of carbon disulfide, with less exposed

individuals retaining more of the chemical than chronically exposed individuals (Beauchamp et al.

1983). Additional information regarding the pharmacokinetics of carbon disulfide following oral and

dermal exposure would be useful. The use of TTCA as a relatively selective biological marker of

exposure to carbon disulfide is now well accepted (ACGIH 1994). Since the critical TTCA

concentration is tied to the TLV-TWA for inhalation, more research is required to ensure that the

TLV-TWA is truly protective.

Comparative Toxicokinetics. Both human and animal data indicate that the target organs for

carbon disulfide are similar across species (Cohen et al. 1958; DeMatteis and Seawright 1973;

Dutkiewicz and Baranowska 1967; Freundt et al. 1975; McKee et al. 1943; Soucek 1957; Teisinger
CARBON DISULFIDE 113

2. HEALTH EFFECTS

and Soucek 1949; Toyama and Kusano 1953). There are no studies that directly compare the

toxicokinetics across species. Most of the animal studies on toxicity end points have used high doses.

The studies in rats, mice, and rabbits have generally been consistent in their conclusions regarding the

pharmacokinetics of carbon disulfide. Data from species other than rodents would also be useful for

determining the species most comparable to humans, so that animal toxicity data can be better

evaluated. No striking differences between the results of rodent studies and those from human studies

were noted except that sulfate excretion is far more important in animals than in humans except in the

latter for exposure to high doses of carbon disulfide (Strittmatter et al. 1950). Additional information

on the comparative pharmacokinetics following exposure from the oral and dermal routes would be

useful, as most of the data currently available are from inhalation studies. The volatility of carbon

disulfide may well affect kinetic parameters measured in dermal exposures, and metabolic parameters

following oral exposures could differ from those following inhalation exposure.

Methods for Reducing Toxic Effects. Reduction of absorption of carbon disulfide may result

from treatment with activated carbon and with sodium bicarbonate solutions (Dreisbach and Robertson

1987; Stutz and Janusz 1988). Some of the treatment methods currently available for use in carbon

disulfide exposure, such as activated charcoal, gastric lavage, and induced emesis, support the survival

of the exposed individual. Other treatments, such as reversal of central nervous system depression by

administration of caffeine and sodium benzoate or providing excess zinc or copper salts, may provide

only temporary relief of symptoms (Morgan 1982). Additional information on the ultimate mechanism

of carbon disulfide toxicity is needed before insights may be gained regarding treatment of exposure

victims.

2.10.3 On-going Studies

No studies of carbon disulfide were reported in the Federal Research in Progress database (FEDRIP

1995).

A 13-week inhalation study in rats sponsored by the National Toxicology Program (NTP) has been

completed, but the results were not published as of March 1996. The NTP has also reported that an

inhalation carcinogenicity study in rats has been planned, but no details on this study are available.

Preliminary reports on NTP-funded genotoxicity studies indicate positive results in a sister chromatid
CARBON DISULFIDE 114

2. HEALTH EFFECTS

exchange assay (in vitro) and negative results in both a chromosome aberration assay (in vitro) and in

two Salmonella tests. No further data on these studies were available.

The following studies, reported in Federal Research in Progress (FEDRIP 1989), have not been

published as of this date.

K. Boekelheide (Brown University) is studying the mechanism involved in testicular injury in rats

from exposure to carbon disulfide and other industrial and environmental toxicants.

B. Gold (Rutgers University Medical and Dental School) is conducting studies on the neurotoxicity of

carbon disulfide in rats.

R. Rubin (Johns Hopkins University) is evaluating the interaction of alcohols and solvents on the

toxicity and kinetics of carbon disulfide in rats, mice, and hamsters.

D.W. Lynch (NOSH) is studying the adverse effects of carbon disulfide on the cardiovascular system

in rats.
CARBON DISULFIDE 115

3. CHEMICAL AND PHYSICAL INFORMATION

3.1 CHEMICAL IDENTITY

The chemical identity of carbon disulfide is located in Table 3-l.

3.2 PHYSICAL AND CHEMICAL PROPERTIES

The physical and chemical properties of carbon disulfide are located in Table 3-2.



CARBON DISULFIDE 119

4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL

4.1 PRODUCTION

Carbon disulfide was first manufactured commercially around 1880 (Timmerman 1978). Until about

1950, the primary industrial-scale production method was by heating charcoal to 750-900°C in the

presence of vaporized low-ash sulfur. However, in the United States, extensive research was devoted

to finding alternative sources of carbon disulfide, and by 1965 the coal-burning method was largely

replaced by a reaction involving natural gas hydrocarbons such as methane, ethane, and ethylene

(Timmerman 1978; Windholz 1983). Carbon disulfide is normally available both in technical and

reagent grades (up to 99.9% pure with a trace benzene contaminant) (Sax and Lewis 1987;

Timmerman 1978) and in alkali (thiocarbonates) as emulsions or solutions for soil treatment (Spencer

1982; Worthing 1987). Trade names for preparations include Weeviltox and Caswell No. 162 (HSDB

1995).

Trends in carbon disulfide production have closely paralleled those of the viscose rayon industry, one

of its largest users (HSDB 1995; Mannsville Chemical Products Corp. 1985; Timmerman 1978; WHO

1981). Production increased by nearly 50% between 1941 and 1969, from 242,000 to 362,000 metric

tons. This increase was partly due to a sudden rise in demand for carbon tetrachloride, an intermediate

in the production of fluorocarbon propellants and refrigerants; carbon disulfide is used in the

production of carbon tetrachloride. The 1969 production level remained relatively stable until about

1974 when it declined sharply to the 1975 level of 217,000 metric tons (Timmerman 1978). Carbon

disulfide production levels continued to decline, with fluctuations, to 168,000 metric tons in 1984

(Mannsville Chemical Products Corp. 1985; Timmerman 1978). In 1985, production was estimated to

be 143,000 metric tons (Mannsville Chemical Products Corp. 1985). No information was found on

production levels after 1985.

Because of a long-term decline in the demand for viscose rayon and cellophane and restrictions on the

use of fluorocarbon propellants, future production levels of carbon disulfide are uncertain. However, it

is expected that demand for this chemical in many other specialty areas will continue at relatively

stable levels (Mannsville Chemical Products Corp. 1985; Timmerman 1978).
CARBON DISULFIDE 120

4. PRODUCTION, IMPORT, USE, AND DISPOSAL

In the United States, the principal manufacturers of carbon disulfide include Lenzing Fibers Corp.,

ELF Atochem N.A. Inc., and PPG Industries (TRI93 1995). For additional information on companies

that manufacture or process carbon disulfide, refer to Table 4-l. According to the 1993 Toxics

Release Inventory (TRI), 80 facilities manufactured or processed carbon disulfide in 1993, 9 fewer

than in 1991 (TRI93 1995). Seventy-nine (79) of these facilities reported the maximum amount of

carbon disulfide that they would have on site. These data are listed in Table 4-l. The TRI data

should be used with caution since only certain types of facilities are required to report. Carbon

disulfide is also produced in 14 foreign countries, including 4 producers in Canada, 7 in South and

Central America, 9 in Asia, 8 in Europe, and 1 in Australia (CIS 1989). The total annual capacity of

the 13 principal foreign manufacturers in 1977 was 911,000 metric tons.

4.2 IMPORT/EXPORT

Imports of carbon disulfide have fallen at a fairly steady rate from 2,700 metric tons in 1980 to

1,400 metric tons in 1985. Exports, on the other hand, fell sharply from 5,900 metric tons in 1980 to

900 metric tons in 1982. Exports continued to decline to 450 metric tons in 1983 and then rose to

1,400 metric tons in 1984 (Mannsville Chemical Products Corp. 1985). No information was found on

export levels after 1985.

4.3 USE

Carbon disulfide has been an important industrial chemical since the 1800s because of its many useful

properties, including its ability to solubilize fats, rubbers, phosphorus, sulfur, and other elements (Sine

1989; Timmerman 1978; Windholz 1983). Because of its ability to dissolve phosphorus, it was once

widely used to produce matches but was later replaced by another chemical. Carbon disulfide’s fat

solvent properties also made it indispensable in preparing fats, lacquers, and camphor; in refining

petroleum jelly and paraffin; and in extracting oil from bones, palmstones, olives, and rags. It was

also used in processing India rubber sap from tropical trees. In all of these extraction processes,

however, carbon disulfide has been replaced by other solvents (Davidson and Feinleib 1972).

Its fat, rubber, and metal solvent properties have made carbon disulfide highly suitable for a variety of

other continuing industrial applications including the following: vulcanization and manufacture of



CARBON DISULFIDE 124

4. PRODUCTION, IMPORT, USE, AND DISPOSAL

rubber and rubber accessories; production of resins, xanthates, thiocyanates, plywood adhesives, and

flotation agents; solvent and spinning-solution applications primarily in the manufacture of rayon;

polymerization inhibition of vinyl chloride; conversion and processing of hydrocarbons; petroleumwell cleaning; brightening of precious metals in electroplating; thin film deposition of nickel; as an

agent to increase corrosion and wear-resistance in metals; rust removal from metals; and removal and

recovery of metals and other elements from waste water and other media (Davidson and Feinleib 1972;

EPA 1978a; Sine 1989; WHO 1981; Windholz 1983; Worthing 1987). It has also been used in industry

as a means to promote sulfation in the synthesis of rare earth sulfides used in semiconductors, as a

regenerator for transition metal sulfide catalysts, as a development restrainer in photography and

lithography, and as a solvent to remove printing on recycled plastics (Timmerman 1978).

Carbon disulfide’s most important industrial use, however, has been in the manufacture of regenerated

cellulose rayon by the viscose process (viscose rayon) and of cellophane (Davidson and Feinleib 1972;

EPA 1978a; NIOSH 1977; Timmerman 1978; WHO 1981). In 1974, over 80% of the carbon disulfide

manufactured was used to make viscose rayon and cellophane (Austin 1974). This proportion fell to

50% in 1984, but the rayon and cellophane uses still accounted for the greatest fraction of carbon

disulfide production (Mannsville Chemical Products Corp. 1985). Since 1989, the consumption of

carbon disulfide in the production of carbon tetrachloride has increased to 38%, while the rayon

industry’s consumption has dropped to 34% (HSDB 1995).

Another principal industrial use for carbon disulfide has been as a feedstock for carbon tetrachloride

production (Mannsville Chemical Products Corp. 1985; NIOSH 1977; Timmerman 1978). While only

10% of U.S. carbon disulfide production was used to produce carbon tetrachloride in 1960, this

increased to 32% in 1974, largely because of a rapid increase in the demand for carbon tetrachloride

for the production of fluorocarbon propellants and refrigerants (Timmerman 1978). Although most

chemical manufacturers have switched to methanol as a raw material for carbon tetrachloride,

beginning in 1985, Akzo America, Inc., continued to use carbon disulfide for this purpose (Mannsville

Chemical Products Corp. 1985). Beginning in 1989, 38% of the carbon disulfide produced was used

to manufacture carbon tetrachloride (HSDB 1995).

In the food industry, carbon disulfide has been used to protect fresh fruit from insects and fungus

during shipping, in adhesives for food packaging, and in the solvent extraction of growth inhibitors

(Timmerman 1978).
CARBON DISULFIDE 125

4. PRODUCTION, IMPORT, USE, AND DISPOSAL

In agriculture, carbon disulfide has been widely used as a fumigant to control insects in stored grain,

normally when mixed with carbon tetrachloride to reduce the fire hazard (Sine 1989; Worthing 1987).

It has also be used to remove botfly larva infestations from the stomachs of horses and ectoparasites

from swine (Rossoff 1974). Use of carbon disulfide as a grain fumigant was voluntarily cancelled

after 1985 (EPA 1985a). An intensive specialty use is to desorb charcoal sampling tubes in NIOSH

methods for airborne organics (NIOSH 1984b). Carbon disulfide is used extensively in research

laboratory chemical synthetics methods (Dunn and Rudolf 1989).

In 1989, the estimated distribution of carbon disulfide utilization was as follows: 34% of production

went to manufacture viscose rayon, 6% to produce cellophane, 38% to produce carbon tetrachloride,

7% to produce rubber chemicals, and 15% to produce pesticides and to solubilize waxes and oils

(HSDB 1995). Future use patterns remain uncertain, although it is expected that less may be used to

produce viscose rayon, cellulose, and carbon tetrachloride, products for which the demand has declined

and for which alternate production processes may be found (HSDB 1995; Mannsville Chemical

Products Corp. 1985; Timmerman 1978). Unless substitutes for carbon disulfide are found, its use

levels may depend largely on relative import and export levels of textiles and apparel (Mannsville

Chemical Products Corp. 1985). Carbon disulfide use for many other specialty industrial purposes is

expected to continue (HSDB 1995; Timmerman 1978).

4.4 DISPOSAL

Carbon disulfide is a very flammable liquid that bums to produce carbon dioxide and sulfur dioxide.

Therefore, it is a good candidate for controlled incineration, provided that a sulfur dioxide scrubber is

used. Some methods proposed by the EPA (HSDB 1995) include liquid injection incineration at a

temperature ranging from 650°C to 1,600oC, rotary kiln incineration at a temperature range of

820-1,600oC, and fluidized bed incineration at a temperature range of 450-980°C. Carbon disulfide

can be removed from waste water by air stripping (HSDB 1995). Adsorption to activated coal with

hydrogen sulfide in the absence of free oxygen yields a process that can regenerate large percentages

of sulfur for reuse (HSDB 1995). It is not recommended that landfills be used as a disposal method

because of the high flammability of this compound (HSDB 1995). No information was found on

quantities and locations of disposal. The EPA CERCLA guideline for reportable quantities is

100 pounds (EPA 1995m).

CARBON DISULFIDE 127

5. POTENTIAL FOR HUMAN EXPOSURE

5.1 OVERVIEW

The primary disposition of carbon disulfide in the environment is related to its use as an industrial

solvent and chemical intermediate. Releases from industrial processes are almost exclusively to the

atmosphere. Releases of the compound to surface waters and soils are expected to partition rapidly to

the atmosphere through volatilization. Hydrolysis and biodegradation do not appear to be important

processes in determining the environmental fate of carbon disulfide. It has been detected at generally

low levels in ambient air, surface water, groundwater, drinking water, food products, and human milk.

Concentrations in environmental media are greatest near source areas (e.g., industrial point sources,

oceans and marshes, volcanoes).

Inhalation of carbon disulfide in workplace air is generally the main route of human exposure to the

compound, with skin exposure also important when the solvent is handled manually.

Carbon disulfide has been identified in at least 200 of the 1,430 current or former EPA National

Priorities List (NPL) hazardous waste sites (HazDat 1996). It is not known how many of the

1,430 sites have been evaluated for carbon disulfide. As more sites are evaluated by EPA, this

number may change. The frequency of these sites within the United States can be seen in Figure 5-1.

Of these sites, 1 is located in the Commonwealth of Puerto Rico.

5.2 RELEASES TO THE ENVIRONMENT

According to the Superfund Amendments and Reauthorization Act (SARA), Section 313, Toxics

Release Inventory (TRI93 1995), an estimated total of at least 93, 308, 704 pounds of carbon disulfide

were released to the environment from manufacturing and processing facilities in the United States in

1993 (see Table 5-l). This total includes an estimated 2,805 pounds that were released through

underground injection. The TRI data must be viewed with caution, however, since only certain types

of facilities are required to report.



CARBON DISULFIDE 131

5. POTENTIAL FOR HUMAN EXPOSURE

5.2.1 Air

There are several known natural sources of carbon disulfide, including wetlands (Hines et al. 1993),

oceans (Chin and Davis 1993), and microbial activity in soils (Banwart and Bremner 1975; Kanda et

al. 1995). The quantity of carbon disulfide emitted from such natural sources as volcanic and

geothermal activity is not known but is thought to be small compared to anthropogenic sources,

particularly combustion of fossil fuels and other carbonaceous material (Chin and Davis 1993).

Certain crop plants and trees emit small amounts of carbon disulfide as well (Batten et al. 1995; Hartel

and Reeder 1993).

Historically, carbon disulfide was used in the processing of rubber, but changing technology made the

old practices outmoded. Nevertheless, the use of sulfur to crosslink rubber during the vulcanization

process may account for the carbon disulfide released from ground tire treads in laboratory

experiments (Pos and Berresheim 1993). Automotive tire wear has been suggested as a potential

source of atmospheric carbon disulfide. Currently, the largest single use of carbon disulfide is in the

viscose rayon industry. For every kg of viscose used, 20-30g of carbon disulfide are emitted (WHO

1979). The largest nonpoint source of man-made levels of carbon disulfide results from its use in the

laboratory and as a fumigant and from the degradation of rubber products (EPA 1975b). Small

amounts of carbon disulfide have also been detected in a landfill simulator (Vogt and Walsh 1985) and

in the odoriferous emissions from a sewage treatment plant (Ruby et al. 1987).

Point sources of carbon disulfide include the biological degradation and incineration of wastes such as

municipal refuse, sewage sludge, and industrial wastes (EPA 1975b). Monitoring of air over the North

Atlantic Ocean found the highest levels of carbon disulfide off the New Jersey/New York coast,

downwind of industrial pollution sources in the northeastern United States (Cooper and Saltzman

1993).

According to TRI93 (1995), an estimated total of 93,271,722 pounds of carbon disulfide, amounting

to 99.9% of the total environmental release, was discharged to the air from manufacturing and

processing facilities in the United States in 1993 (TRI93 1995) (see Table 5-l). The data listed in TRI

should be used with caution since only certain types of facilities are required to report.
CARBON DISULFIDE 132

5. POTENTIAL FOR HUMAN EXPOSURE

Carbon disulfide has been detected in the magmatic gas over volcanoes, during the aging of roasted

coffee, during the pressure cooking of grain-water mixtures, as a volatile constituent in the vapor of

burning cigarettes, and in the vapor space above liquid sulfur (EPA 1978a). Carbon disulfide has been

measured in atmospheric samples collected during the major eruptions of Mount St. Helens. Low

levels desorbed from volcanic ash were found to decrease with increasing distance from the volcanic

activity (Rasmussen et al. 1982).

During analytical measurements of sulfur compounds at five wetland areas in Florida, carbon disulfide

was often not detected while large amounts of dimethylsulfide were found (Cooper et al. 1987).

However, low levels of carbon disulfide were consistently detected in samples collected from the same

area using a slightly modified procedure (Hines et al. 1993). Based on their measurements and

assumptions in the study of sulfur emissions from a North Carolina salt marsh, Aneja et al. (1980)

estimated that carbon disulfide produced by marshes (0.022 g sulfur/m

2 per year) contributes less than

0.07% of biogenic sulfur and less than 8% to the stratospheric aerosol layer. DeMello et al. (1987)

speculated that carbon disulfide generation from coastal areas in Florida was related to the

concentration of organic matter in the sediment. Staubes et al. (1987) found that humic soils were

stronger sources for biogenic sulfur than soils with lower organic content; however, a low humic

content coupled with high moisture favors the production of carbon disulfide over dimethylsulfide.

In order to avoid the difficulties of naturally occurring variations in study conditions, Fall et al. (1988)

studied the emission of sulfur gases from several plant/soil systems using a flux chamber. The study

was designed so that emissions from soil could be separated from emissions from plants. Variable

amounts of carbon disulfide were emitted from wheat. The effects of light and temperature were

observed. Further work was proposed so that systematic investigation could accurately measure the

contributions of a number of sulfur compounds under varying conditions.

5.2.2 Water

According to TRI, an estimated total of at least 34,169 pounds of carbon disulfide, amounting to

0.04% of the total environmental release, was discharged to water from manufacturing and processing

facilities in the United States in 1993 (TRI93 1995) (see Table 5-l). In addition, an estimated total of

226,215 pounds, amounting to 0.24% of the total environmental release, was discharged to publicly
CARBON DISULFIDE 133

5. POTENTIAL FOR HUMAN EXPOSURE

owned treatment works. The TRI data should be used with caution since only certain types of

facilities are required to report.

Carbon disulfide is widely found in coastal and ocean waters and extensive study has been done to

determine levels over the different types of water bodies. The measurements of Carroll (1985) show

that the ocean appears to be a source of carbon disulfide, possibly via anaerobic microorganisms.

Concentrations of less than 10 nmol/L have been found in a sulfide-rich lake in Spain (Simo et al.

1993). Carbon disulfide has also been detected in the vent fluids and sediment surface waters of

undersea hydrothermal sites (Marchand et al. 1994).

Carbon disulfide was found at a concentration of 25 μg/L in groundwater samples collected from only

1 of 19 municipal solid waste landfills examined by Battista and Connelly (1989).

The South Carolina Department of Health (1986) found unspecified levels of carbon disulfide in

groundwater samples collected from 1 of 11 wells constructed in a surficial aquifer near a recycling

and disposal company that had been storing chemicals.

In a study of 63 industrial effluents collected from a wide range of chemical manufacturers from

across the United States, carbon disulfide was found in six of the effluents at concentrations less than

10 pg/L and in two of the effluents at l0-100 μg/L (EPA 1979). Analysis of influent and effluent

samples from a waste water treatment plant in Tokyo showed carbon disulfide to be the least prevalent

among five sulfur-containing odorous compounds for which testing was done (Hwang et al. 1995).

5.2.3 Soil

According to TRI, an estimated total of at least 8 pounds of carbon disulfide was discharged to soils

from manufacturing and processing facilities in the United States in 1993 (TR193 1995) (see

Table 5-l). The TRI data should be used with caution since only certain types of facilities are

required to report.

Little information was found regarding releases of carbon disulfide to soils. Fain et al. (1987) reported

0.9 mg/L carbon disulfide (dry weight basis) in a typical refinery oily waste applied to a land

treatment unit.
CARBON DISULFIDE 134

5. POTENTIAL FOR HUMAN EXPOSURE

5.3 ENVIRONMENTAL FATE

5.3.1 Transport and Partitioning

Releases of carbon disulfide to the environment as a result of industrial activity are expected to be

primarily to the atmosphere. Any carbon disulfide released to surface waters in effluent streams is

expected to partition rapidly to the atmosphere as a result of the high ratio of vapor pressure to the

solubility (Henry’s law constant = 1.01x10-2 atm • m3/mol) of the compound. Hydrolysis is not a

significant removal mechanism since the evaporation half-life from a saturated solution is estimated to

be 11 minutes (EPA 1978a).

Although no information was found evaluating the partitioning of carbon disulfide from water onto

sediments, it is not expected to be removed significantly from the aquatic phase through adsorption.

The low Koc value, calculated from water solubility data, is 54 (EPA 1986b), indicates high soil

mobility, but it probably will be less mobile in soils of high organic content.

Although Roy and Griffin (1985) did not conduct adsorption studies, they classified carbon disulfide as

a mobile solvent exhibiting a low tendency to be retained by soils. Carbon disulfide released to soils

in spills should rapidly volatilize to the atmosphere, but a portion of the compound remaining on soil

surfaces could be available for transport into groundwater since it does not have much affinity for soil

particles. Farwell et al. (1979) indicated that carbon disulfide volatilizes from a variety of soils,

although rates were not provided.

No experimental data on biomagnification were found in the available literature. Estimated

bioconcentration factor (BCF) values (equal to 2.94X103

) were calculated from solubility and Kow, (log

Kow is 2.16) data. The calculated values, 6.8 and 25.8 respectively for solubility and Kow data, indicate

that carbon disulfide will not significantly bioaccumulate in aquatic organisms (EPA 1986b).
CARBON DISULFIDE 135

5. POTENTIAL FOR HUMAN EXPOSURE

5.3.2 Transformation and Degradation

5.3.2.1 Air

Carbon disulfide reacts with hydroxyl radicals in the troposphere to produce carbonyl sulfide (Cox and

Sheppard 1980). The lifetime of carbon disulfide in the troposphere, assuming a reaction rate constant

of 4.3x10-13 cm3

 molecule-3, is =73 days (uncertain); other estimates (assuming different reaction rate

constants) range from less than 1 week to more than 10 weeks (Cox and Sheppard 1980; EPA 1978a;

Wine et al. 1981).

The photo-oxidation products of carbon disulfide in the laboratory were identified as carbon monoxide,

carbonyl sulfide, sulfur dioxide, and a polymer that adhered to the sides of the reaction vessel

(Heicklen et al. 1971). Although carbon disulfide absorbs light at wavelengths between 280 and

350 nm, dissociation does not occur under environmental conditions because of low molar absorptivity

(Atkinson et al. 1978; Wood and Heicklen 1971) and direct photolysis of carbon disulfide in the

atmosphere does not appear to be significant. EPA (1978a) stated that the information available

indicated that carbon disulfide is relatively persistent in the atmosphere. For the atmospheric oxidation

of carbon disulfide to sulfur dioxide, car-bony1 sulfide, and carbon monoxide, the half-life was

estimated to be about 12 days.

According to Wine et al. (1981), electronically excited carbon disulfide is rapidly produced in the

troposphere from absorption of solar photons. This excited carbon disulfide reacts with oxygen on a

time scale of l-2 weeks to yield car-bony1 sulfide, the predominant sulfur-containing compound in the

troposphere.

The lifetime of carbon disulfide in the atmosphere has been estimated to be 12 days, too short a time

to reach the stratosphere. Removal was suggested to occur by a hydroxyl radical reaction, or an

oxygen atom reaction but not by dissociation (Khalil and Rasmussen 1984).

Based on the estimates of a lifetime in the troposphere for carbon disulfide on the order of weeks and

the troposphere to stratosphere turnover time on the order of years, very little tropospheric carbon

disulfide is expected to be transported to the stratosphere (EPA 1986b).
CARBON DISULFIDE 136

5. POTENTIAL FOR HUMAN EXPOSURE

5.3.2.2 Water

Carbon disulfide is stable to hydrolysis in the pH region of environmental concern (pH 4-10). At

pH 13, carbon disulfide has a hydrolysis half-life at of about 1 hour at 25°C; by extrapolation, at

pH 9, carbon disulfide has a half-life of 1.1 years (EPA 1978a). In oxygenated seawater, carbon

disulfide was found to be stable for over 10 days (Lovelock 1974). The volatilization half-life from a

saturated water solution has been estimated to be 11 minutes (EPA 1978a). The compound apparently

does not undergo biodegradation at rates that are competitive with its volatilization from surface

waters.

5.3.2.3 Sediment and Soil

No data were found in the available literature on the biodegradation of carbon disulfide in soil.

However, since the chemical is rapidly volatilized (high Henry’s law constant) and probably highly

mobile in soil (low Koc), it is unlikely that it remains in the soil long enough to be significantly

biodegraded.

Microbial degradation of large amounts of carbon disulfide in soil would not be expected to be

significant since this compound is a soil disinfectant and toxic to bacteria. Hydrolysis of carbon

disulfide on wet soil surfaces is also unlikely (EPA 1986b). Oxidation of carbon disulfide by a

Thiobacillus species isolated from soil has been observed (Plas et al. 1993).

5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT

5.4.1 Air

Carbon disulfide was detected at 41 parts per trillion (ppt) in 61 rural samples and at 65 ppt in

88 urban/suburban air samples collected by Brodzinsky and Singh (1983). Carroll (1985) sampled air

in the vicinity of San Juan, Puerto Rico; Albany, New York; and Wallops Island, Virginia. Carbon

disulfide showed considerable spatial variability and a correlation with cloud activity. It was observed

that the ocean appears to be a source of carbon disulfide. The air at Wallops Island coming in from

the ocean had levels of 30 ppt. Air samples taken at Sapelo Island, Georgia, revealed carbon disulfide

levels of about 380 ppt above a saltwater marsh, about 100 ppt above a freshwater marsh, and
CARBON DISULFIDE 137

5. POTENTIAL FOR HUMAN EXPOSURE

negligible amounts above a swamp (Berresheim 1993). Levels of about 12 parts per trillion by

volume (pptv) were measured near the island of Fiji in the southern Pacific Ocean (Thornton and

Bandy 1993), while levels of 5.8 and 4.2 pptv were measured in marine and continental air,

respectively, over the North Atlantic (Cooper and Saltzman 1993). Tropospheric carbon disulfide

levels above the Atlantic Ocean were 0.5-5 pptv and l-30 pptv in areas influenced by anthropogenic

or marsh emissions, respectively (Bandy et al. 1993b).

Air in the Philadelphia, Pennsylvania, area that had been influenced by anthropogenic sources was

measured at 65-339 pptv carbon disulfide by Maroulis and Bandy (1980). Daily mean carbon

disulfide levels in Philadelphia were highly dependent on wind direction.

Air measurements in the vicinity of a municipal landfill showed downwind concentrations three to four

times higher than upwind (background) levels (Marquardt 1987). The maximum concentration of

carbon disulfide measured in samples from eight solid waste composting facilities was 150 μg/m3

(0.05 ppm) (Eitzer 1995).

Breath and air collected at sites in and around New York City were measured for carbon disulfide by

Phillips (1992). The group tested consisted of four types (male smokers, male nonsmokers, female

smokers, and female nonsmokers) with no significant divergence observed among any of the different

group types (see Table 5-2). Carbon disulfide was detected in all air and breath samples taken from

both indoor air and outdoor locations (see Table 5-3). A general population survey in Italy found low

levels of carbon disulfide in the blood of all 208 subjects tested and in the urine of all 1,256 samples

taken (Brugnone et al. 1994).

5.4.2 Water

It has been suggested that anaerobic conditions on the ocean floor result in formation of carbon

disulfide (Lovelock 1974). Measurements made off the coast of Ireland showed carbon disulfide

present at every location, with the highest concentrations in stagnant bays.

In a preliminary report to Congress, EPA (1975a) noted that carbon disulfide had been found

(detection levels unspecified) in the drinking water of two of five U.S. cities studied. Krill and


CARBON DISULFIDE 140

5. POTENTIAL FOR HUMAN EXPOSURE

Sonzogni (1986) reported on an analytical survey of municipal and private groundwater sources in

Wisconsin in which carbon disulfide was found in two private wells at concentrations lower than

830 μg/L (the published health advisory level). Carbon disulfide was also found in borings on the site

of a landfill in Jacksonville, Florida (EPA 1986c). A survey of groundwater samples in northeastern

Florida found no detectable levels of carbon disulfide in underground storage tank system sites and

only one landfill site with a measurable level of 21.5 μg/L (Pawlowicz 1993).

Carbon disulfide was measured in Lake Ontario (Kaiser et al. 1983). Mapping of the results showed

that levels were high in Toronto Harbor where textile, glass, metal, and plastic manufacturing plants

are adjacent to the lake (the highest level detected was 3.9 mg/L). Carbon disulfide was also found in

the Niagara River at 25 μg/L. Kaiser and Comba (1983) measured levels as high as 25 μg/L in

Thompson Creek near a chemical plant discharge (Welland River watershed in Ontario).

5.4.3 Sediment and Soil

Very little information is available on the levels of carbon disulfide in soils. EPA (1986d) reported

finding carbon disulfide at low pg/kg levels in the soil where paint sludges had been dumped on the

ground in a gravel pit in Michigan.

5.4.4 Other Media

An analysis of fumigated grains for carbon disulfide showed levels ranging from 0.8 to 2.2 ppm

decreasing with time after fumigation, as would be expected from the volatility of carbon disulfide

(McMahon 1971). Lovegren et al. (1979) detected 2-3 ppb carbon disulfide in dried legumes. In a

study of fumigant residues in foods, Daft (1987) reported finding carbon disulfide residues in samples

of pickling spice, mustard seed, and other grain foods. Heikes (1987) examined table-ready foods and

found carbon disulfide in plain granola, and Daft (1988a, 1988b) found carbon disulfide in raw onions,

raw radishes, corn chips, and oat cereal. The pesticide sodium tetrathiocarbonate may be converted to

carbon disulfide after application to fruit crops, and EPA has set a tolerance level of 0.1 ppm carbon

disulfide from this source for grapefruit, grapes, lemons, and oranges (EPA 1993, 1995d).

The levels of carbon disulfide and other sulfur species emitted in oil shale off-gases were measured

(Sklarew et al. 1984). The concentration of carbon disulfide ranged from 8 to 28 ppm. They
CARBON DISULFIDE 141

5. POTENTIAL FOR HUMAN EXPOSURE

concluded that strategies for the use of oil shale as an alternative fuel must include abatement

strategies.

Carbon disulfide was also found in the incinerator ash of hazardous waste incinerators (Wolbach et al.

1987). This finding was not anticipated because of the volatility of carbon disulfide. In addition,

Kallonen et al. (1985) identified carbon disulfide at low levels (less than 1 μg/L) in fire gas emissions

from the combustion of wool. Exposures at this level do not usually result in significant body

concentration of carbon disulfide.

5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE

Exposure to carbon disulfide is primarily confined to occupational situations. Inhalation is the

principal route of exposure for humans; absorption through the skin is a much less important route

than inhalation, and other routes are negligible (WHO 1979). Very little information is available

concerning exposure to carbon disulfide outside the workplace or the effects on the general population.

Teisinger and Soucek (1949) reported that, in spite of considerable variation among individuals,

absorption seems to be proportional to the concentration of carbon disulfide in inhaled air. Assuming

an inhalation intake of 20 m3

 air/day, and concentrations in urban and rural air of 65 ppt and 41 ppt,

respectively, the average daily intake of carbon disulfide via inhalation is 4.1x10-3 mg in urban areas

and 2.6x10-3 mg in rural areas.

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 (WHO

1979). However, in a study that compared 70 children living 400 meters from a factory discharging

carbon disulfide into the atmosphere with a control group of 30 children living 15 km from the

factory, physical 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).

Airborne concentrations of carbon disulfide in a domestic rayon plant were reported to range from 10

to 15 ppm (NIOSH 1977).
CARBON DISULFIDE 142

5. POTENTIAL FOR HUMAN EXPOSURE

During a 1991 study of a Belgian viscose rayon factory, workers from various departments in the

company were monitored with charcoal tubes for carbon disulfide (Vanhoorne et al. 1991). The

geometric mean for carbon disulfide ranged from 3.67 mg/m3 (1.17 ppm) to 147.23 mg/m3

(47.11 ppm) (Vanhoorne et al. 1991). Eighty-nine percent of the job classifications studied exceeded

the present TLV for carbon disulfide of 31 mg/m3 (10 ppm) (Vanhoorne et al. 1991). Typically,

workers are simultaneously exposed to both carbon disulfide (4-l 12 mg/m3) and hydrogen sulfide

(0.2-8.9 mg/m3) (Vanhoorne et al. 1995). Various studies throughout the world (see Table 5-4)

indicate that there has been a recent decline in personal exposure of workers in Western countries to

carbon disulfide, but in the Far East and Eastern Europe (Rigterink 1988) exposure to carbon disulfide

of workers is still substantial.

According to the National Occupational Exposure Survey (NOES) conducted by NIOSH from 1980 to

1983, an estimated 44,438 workers, including 4,881 women, were potentially exposed to carbon

disulfide in the workplace in 1980. The NOES database does not contain any information about the

concentration levels to which these workers may have been exposed or the frequency and duration of

the exposure (NIOSH 1989).

Carbon disulfide was found at unspecified levels in all eight samples of human breast milk tested

during a study conducted in New Jersey, Pennsylvania, and Louisiana (Pellizzari et al. 1982). Cai and

Bao (1981) measured the levels of carbon disulfide in the milk of mothers employed in rayon factories

at 68-123 μg/L and found that carbon disulfide was still present in the milk after a month or more

away from the factory.

5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES

Human exposure to carbon disulfide is expected to be highest among certain occupational groups (e.g.,

rayon plant workers). In addition, members of the general population living in the vicinity of

industrial point emission sources are exposed to higher than background levels of carbon disulfide.

The compound has been detected in both ambient air and water in low concentrations, with somewhat

higher concentrations in localized areas around industrial and disposal sites. No information was

found regarding the number of people potentially exposed in the vicinity of hazardous waste sites.

However, since carbon disulfide has been found near hazardous waste sites, people living near them

may be exposed to higher than background levels.

CARBON DISULFIDE 144

5. POTENTIAL FOR HUMAN EXPOSURE

Of particular concern would be a worker with occupational exposure to carbon disulfide who lived

close enough to the plant to be exposed to elevated levels at home as well, particularly if that worker

was in poor health from other causes (e.g., smoking, neurological problems, or heart disease).

5.7 ADEQUACY OF THE DATABASE

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with

the Administrator of EPA and agencies and programs of the Public Health Service) to assess whether

adequate information on the health effects of carbon disulfide is available. Where adequate

information is not available, ATSDR, in conjunction with the NTP, is required to assure the initiation

of a program of research designed to determine the health effects (and techniques for developing

methods to determine such health effects) of carbon disulfide.

The following categories of possible data needs have been identified by a joint team of scientists from

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean

that all data needs discussed in this section must be filled. In the future, the identified data needs will

be evaluated and prioritized, and a substance-specific research agenda will be proposed.

5.7.1 Identification of Data Needs

Physical and Chemical Properties. The physical and chemical properties of carbon disulfide are

sufficiently well defined to allow an assessment of its environmental fate (EPA 1995h; Flick 1985;

HSDB 1995; MCA 1968; NFPA 1986; NIOSH 1984b; RTECS 1995; Sax and Lewis 1987;

Timmerman 1978; Verschueren 1983; Weast 1989; Weiss 1980; Windholz 1983; Worthing 1987).

Therefore, no data needs have been identified at this time.

Production, Import/Export, Use, Release, and Disposal. Little specific information is

available on the levels of carbon disulfide emitted from industrial sources. Most of the literature

concentrates on the viscose rayon industry (EPA 1975b; Battista and Connelly 1989; Carroll 1985; CIS

1989; Cooper et al. 1987; DeMello et al. 1987; EPA 1979, 1978a; Fain et al. 1987; Rasmussen et al.

1982; Ruby et al. 1987; Sax and Lewis 1987; South Carolina DOH 1986; Spencer 1982; SRI 1989;

Staubes et al. 1987; Timmerman 1978; TRI93 1995; View 1989; Vogt and Walsh 1985; WHO 1979,
CARBON DISULFIDE 145

5. POTENTIAL FOR HUMAN EXPOSURE

1981; Windholz 1983; Worthing 1987) and natural sources (Timmerman 1978; Who 1979). Although

future production levels of carbon disulfide are uncertain because of a long-term decline in the demand

for viscose rayon and cellophane and restrictions on the use of fluorocarbon propellants, it is expected

that the demand for this chemical in many other specialty areas will continue at relatively stable levels

(Timmerman et al. 1978). Carbon disulfide is used primarily in industry. Releases from industrial

processes are almost exclusively to the atmosphere. Sources and releases of carbon disulfide to the

immediate environment should be identified and quantified, and additional information is needed on

the disposal of carbon disulfide. Current disposal methods include liquid injection incineration, rotary

kiln incineration, fluidized bed incineration, and air stripping (HSDB 1995), however, data on the

efficiency of these methods are lacking. This information will be useful in identifying the media of

concern for human exposure and populations at risk of adverse health effects from exposure to carbon

disulfide.

According to the Emergency Planning and Community Right-to-Know Act of 1986, 42 U.S.C. Section

11023, industries are required to submit substance release and off-site transfer information to the EPA.

The TRI, which contains this information for 1988, became available in May of 1990. This database

is updated yearly.

Environmental Fate. Releases of carbon disulfide to the environment as a result of industrial

activity are expected to be primarily to the atmosphere. Carbon disulfide volatilizes from a variety of

soils (Farwell et al. 1979). Carbon disulfide reacts with hydroxyl radicals in the troposphere to

produce carbonyl sulfide (Cox and Sheppard 1980). Further oxidation would produce carbon disulfide,

a major contributor to the greenhouse effect (Cox and Sheppard 1980). The lifetime of carbon

disulfide in the troposphere is ≈73 days (Cox and Sheppard 1980). Carbon disulfide is stable to

hydrolysis in the pH region of environmental concern (pH 4-10), with a hydrolysis half-life at pH 13

of about 1 year (EPA 1976). No data are available concerning the biodegradation of carbon disulfide

in soil. Concerted efforts should be made to measure the spatial and temporal variations in the

atmospheric levels of carbon disulfide in the vicinity of specific point or nonpoint sources. Although

volatilization is the primary fate of carbon disulfide released to the environment (Farwell et al. 1979;

Roy and Griffin 1985), data on the partitioning of carbon disulfide from water onto sediments and on

the hydrolysis rate of carbon disulfide in surface and groundwater could be useful in determining the

persistence of low levels of the compound in the environment. Additional information on the transport

and transformation of carbon disulfide in soils, particularly on biotransformation, would also be useful.
CARBON DISULFIDE 146

5. POTENTIAL FOR HUMAN EXPOSURE

Bioavailability from Environmental Media. Carbon disulfide is absorbed following inhalation of

contaminated ambient air (Soucek 1957; Teisinger and Soucek 1949) and from dermal contact with

contaminated soils or water (Helasova 1969; NIOSH 1989). The average daily intake of carbon

disulfide via inhalation has been estimated to be 4.1x10-3 mg in urban areas and 2.6x10-3 mg in rural

areas. Data are lacking on the bioavailability of carbon disulfide following ingestion of contaminated

soils and groundwater or foods grown with contaminated water. This information would be useful in

determining the importance of these routes of exposure.

Food Chain Bioaccumulation. An estimated bioconcentration factor (BCF) of 2.94x103 was

calculated from solubility and Kow data. Based on these data, carbon disulfide does not significantly

bioaccumulate in aquatic organisms. Although it is generally accepted that carbon disulfide does not

bioaccumulate because of its rapid metabolism (EPA 1986b), the data are insufficient to determine the

bioconcentration and biomagnification of carbon disulfide at various levels in the food chain. This

information would be particularly useful in determining the risks associated with the generally low

levels of carbon disulfide in environmental media.

Exposure Levels in Environmental Media. The monitoring data available for carbon disulfide

are too limited to allow adequate characterization of potential human exposure to the compound.

Studies of background levels in air have been conducted (Bandy et al. 1993b; Brodzinsky and Singh

1983; Carroll 1985; Cooper and Saltzman 1993; Maroulis and Bandy 1980; Marquardt 1987), but site

specific concentration data for ambient air, drinking water, and biota, particularly at hazardous waste

sites, are lacking. These data would be helpful in estimating the exposure of the general population as

well as those living near hazardous waste sites. The sites with highest concentrations of carbon

disulfide need to be determined. In addition, estimates of human intake from various media would be

helpful in assessing human exposure for carbon disulfide for populations living near hazardous waste

sites.

Reliable and current monitoring data for the levels of carbon disulfide in contaminated media at

hazardous waste sites are needed so that the information obtained on levels of carbon disulfide in the

environment can be used in combination with the known body burden of carbon disulfide to assess the

potential risk of adverse health effects in populations living in the vicinity of hazardous waste sites.
CARBON DISULFIDE 147

5. POTENTIAL FOR HUMAN EXPOSURE

Exposure Levels in Humans. Carbon disulfide can be detected in exhaled breath, blood, urine,

and milk, and metabolites can be detected in urine, exhaled air, and blood (ACGIH 1986; Baselt 1980;

Cai and Bao 1981; Campbell et al. 1985; Cox et al. 1992; Djuric 1967; Helasova 1969; Lieben 1974;

McKee et al. 1943; NIOSH 1989; Pellizzari et al. 1982; Teisinger and Soucek 1949; WHO 1979).

However, because of the rapid metabolism and elimination of carbon disulfide, these fluid and breath

levels do not correlate well with environmental levels, except for the urinary marker,

2-thiothiazolidine-4-carboxylic acid. In addition, the interaction of carbon disulfide with other

potential confounders may affect the reliability of urinary metabolites as biomarkers of exposure.

Biomarkers may therefore be of limited utility in the quantitative assessment of human exposure to

carbon disulfide at hazardous waste sites; however, biomarkers may be useful in qualitatively

establishing that possible exposure has occurred.

Additional information on biological monitoring is necessary for assessing the need to conduct health

studies on general populations and on those populations living near hazardous waste sites.

Exposure Registries. No exposure registries for carbon disulfide were located. This substance is

not currently one of the compounds for which a subregistry has been established in the National

Exposure Registry. The substance will be considered in the future when chemical selection is made

for subregistries to be established. The information that is amassed in the National Exposure Registry

facilitates the epidemiological research needed to assess adverse health outcomes that may be related

to exposure to this compound.

5.7.2 On-going Studies

As part of the Third National Health and Nutrition Evaluation Survey (NHANES III), the

Environmental Health Laboratory Sciences Division of the National Center for Environmental Health,

Centers for Disease Control and Prevention, will analyze human blood samples for carbon disulfide

and other volatile organic compounds. These data will give an indication of the frequency of

occurrence and background levels of these compounds in the general population.

The data generated as a result of the remedial investigation/feasibility studies of the 200 NPL sites

known to be contaminated with carbon disulfide should add to the current knowledge regarding the

environmental transport and fate of the compound.
CARBON DISULFIDE 148

5. POTENTIAL FOR HUMAN EXPOSURE

No long-term research projects or other on-going studies of occupational or general population

exposures were identified.
CARBON DISULFIDE 149

6. ANALYTICAL METHODS

The purpose of this chapter is to describe the analytical methods that are available for detecting, and/or

measuring, and/or monitoring carbon disulfide, its metabolites, and other biomarkers of exposure and

effect to carbon disulfide. The intent is not to provide an exhaustive list of analytical methods.

Rather, the intention is to identify well-established methods that are used as the standard methods of

analysis. Many of the analytical methods used for environmental samples are the methods approved

by federal agencies and organizations such as EPA and the National Institute for Occupational Safety

and Health (NIOSH). Other methods presented in this chapter are those that are approved by groups

such as the Association of Official Analytical Chemists (AOAC) and the American Public Health

Association (APHA). Additionally, analytical methods are included that modify previously used

methods to obtain lower detection limits, and/or to improve accuracy and precision.

6.1 BIOLOGICAL SAMPLES

A limited number of analytical techniques have been used for measuring carbon disulfide and its

metabolites in breath (expired air) and biological fluids of humans and animals. These include gas

chromatography (GC) and high resolution gas chromatography (HRGC) equipped with an appropriate

detector, high-performance liquid chromatography (HPLC), spectrophotometry, thin-layer

chromatography (TLC), combined gas chromatography and mass spectroscopy (GC/MS), and

iodineazide tests (see Table 6-l).

GC/MS was used in a 1992 study (Phillips 1992) to detect carbon disulfide in human breath and

environmental air with a detection sensitivity capable of 7.61x10-2

μg/m3 (2.44x10-2 ppb). This highly

sensitive technique can be rapidly accomplished by capturing the air sample on solid sorbent like

molecular sieves to be later thermally desorbed in the laboratory with subsequent chromatography

(Phillips 1992).

Gas chromatography equipped with a flame ionization detector (FID) and quadrupole MS have been

employed for measuring carbon disulfide concentrations in the breath of workers following exposure

to carbon disulfide (Campbell et al. 1985; Wells and Koves 1974). The MS technique is rapid and

requires no sample preparation (Campbell et al. 1985). A detection limit of 1.6 ppb (5 μg/m3

) of



CARBON DISULFIDE 153

6. ANALYTICAL METHODS

carbon disulfide in air was achieved using this technique. The FID technique is insensitive. Flame

photometric, photoionization (11.6 eV) and electron capture detectors, or elemental detectors are

sufficiently sensitive to ppb/ppm concentrations.

A spectrophotometric technique has been used for quantifying μg/rnL levels of free and acid-labile

(chemically bound) carbon disulfide in the blood of rats (Lam and DiStefano 1982, 1983). This

technique is based on measuring the absorbance at 430 nm of a yellow cupric diethyldithiocarbamate

complex that is formed by reacting carbon disulfide in blood with Viles’ reagent in the presence of

acid and heat. A headspace sampler connected to GC equipped with a sulfur-specific flame

photometric detector (FPD) has been developed for measuring low levels of free and acid-labile carbon

disulfide in the blood of shift workers exposed to carbon disulfide (Campbell et al. 1985). A detection

limit of 15.2 μg of carbon disulfide/L of blood was achieved. Concentrations of free and acid-labile

carbon disulfide have also been determined by GS/MS (Brugnone et al. 1993, 1994; Perbellini et al.

1994).

It is also possible to determine the level of metabolites in urine. Urinary 2-thiothiazolidine-4-

carboxylic acid is the best available indicator to assess the degree of occupational exposure to carbon

disulfide (ACGIH 1994; Theinpont et al. 1990). Theinpont et al. (1990) described the isolation of this

compound from urine prior to reverse phase high-performance liquid chromatography. It is based on

liquid-liquid extraction with methyl tertbutyl ether, followed by affinity chromatography on

organomercurial agarose gel. The detection limit of the procedure was 50 μg of carbon disulfide/L of

urine (Theinpont et al. 1990).

The more common method of determining the level of metabolites in urine is HPLC. HPLC has been

employed for measuring 2-thiothiazolidine-4-carboxylic acid in the urine of shift-workers following

exposure to carbon disulfide (Campbell et al. 1985; Lee et al. 1995; Simon and Nicot 1993; Van

Doorn et al. 1985a, 1985b). This technique is sensitive, specific, and noninvasive. A detection limit

of 25 μg of carbon disulfide/L of urine was obtained (Lee et al. 1995). The iodine-azide test has been

used for the detection of metabolites of carbon disulfide in the urine of humans and animals following

exposure to carbon disulfide (Baselt 1980; Djuric 1967; WHO 1979). This method is based on the

measurement of the time to decolor iodine, as catalyzed by sulfur-containing metabolites of carbon

disulfide most notably thiourea and dithiocarbamates. However, the iodine-azide test is nonspecific

and has relatively poor sensitivity for measuring the metabolites of carbon disulfide in the urine
CARBON DISULFIDE 154

6. ANALYTICAL METHODS

(Baselt 1980; Djuric 1967). TLC has also been employed to detect 2-mercapto-2-thiazolin-5-one and

thiocarbamide (metabolites of carbon disulfide) in the urine of workers exposed to carbon disulfide

(Pergal et al. 1972a, 1972b; WHO 1979). GC/MS is used to confirm 2-mercapto-2-thiazolin-5-one,

thiocarbamide, and TTCA.

Carbon disulfide has also been detected in mother’s milk using HRGC/MS and spectrophotometry (Cai

and Bao 1981; Pellizzari et al. 1982). Sample preparation for HRGC/MS involves purging the sample

with helium and then trapping the analyte on a Tenax cartridge, followed by thermal desorption

(Pellizzari et al. 1982). Sensitivity, precision, and recovery were not reported. For the

spectrophotometric technique, sample preparation involves purging by aeration and trapping in a

bubbler containing diethylamine-copper solution for calorimetric determination at 420 nm (Cai and

Bao 1981). Recovery (90%) was excellent and sensitivity is in the μg range. Precision was not

reported.

6.2 ENVIRONMENTAL SAMPLES

High-resolution GC equipped with an appropriate detector is the most common analytical technique

for measuring the concentrations of carbon disulfide in air and various foods (e.g., grains, grain-based

foods, fruits, and beverages). The choice of a particular detector will depend on the nature of the

sample matrix, the detection limit, and the cost of the analysis. Because volatile organic compounds

in environmental samples may exist as complex mixtures or at very low concentrations,

preconcentration of these samples prior to quantification is usually necessary (see Table 6-2 for

details).

The primary method of analyzing carbon disulfide in air is by adsorption on an activated charcoal tube

followed by solvent elution for subsequent quantification. GC equipped with either an electron capture

detector (ECD), photo-ionization detector (PID), or FPD has been used for measuring carbon disulfide

after elution from the solid phase. Detection limits of low ppm levels of carbon disulfide in the air

sample were achieved with these techniques (McCammon et al. 1975; Peltonen 1989; Smith and

Krause 1978; UK/HSE 1983). NIOSH has recommended GC/FPD (method 1600) for determining

carbon disulfide in air. The range of quantification is 3-64 ppm for a 5-L air sample (NIOSH 1984b).



CARBON DISULFIDE 158

6. ANALYTICAL METHODS

Gas chromatography with ECD has also been used to detect carbon disulfide in air (Johnson and Bates

1993). In this system, carbon disulfide is separated by chromatography, converted to sulfur

hexafluoride (SF6), and then detected by ECD. The ECD detector is 10-100 times more sensitive than

the FPD detector and requires smaller sample volumes (Johnson and Bates 1993).

A.R. Bandy, D.C. Thornton, and A.R. Driedger (Drexel University, Philadelphia) have developed a

GC/MS technique with isotopically labelled internal standards capable of real-time measurement of

carbon disulfide and other volatile sulfur compounds in the air with a detection limit of 0.2 ppt. This

technique is approximately 10 times more sensitive than GC/FPD for measuring carbon disulfide in the

air and has improved precision and accuracy (Bandy et al. 1993a).

A less commonly used technique for quantifying carbon disulfide in air is atomic absorption

spectrophotometry (AAS) for copper in a copper chelate whose concentration is related directly to

carbon disulfide concentration (Kneebone and Freiser 1975). Analysis of carbon disulfide in air for

AAS quantification involves desorbing the carbon disulfide from an activated charcoal tube with

isoamylacetate containing pyrolidine. The eluate is shaken with acidified copper sulfate solution to

form a copper chelate, which is quantified by AAS (Kneebone and Freiser 1975). A detection limit of

0.7 μg of carbon disulfide/m3

 of air was obtained. Carbon disulfide is usually isolated from various

foods by liquid-liquid extraction and steam distillation (AOAC 1984; Bielorai and Alumot 1966;

Clower et al. 1986; Daft 1988a, 1988b; Heuser and Scudamore 1968; Malone 1970; McMahon 1971).

GC equipped with ECD or the Hall electrolyte conductivity detector (HECD) is the method of choice

for measuring ppb levels of carbon disulfide in foodstuffs (Bielorai and Alumot 1966; Daft 1988a,

1988b; Heuser and Scudamore 1968).

6.3 ADEQUACY OF THE DATABASE

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with

the Administrator of EPA and agencies and programs of the Public Health Service) to assess whether

adequate information on the health effects of carbon disulfide is available. Where adequate

information is not available, ATSDR, in conjunction with the NTP, is required to assure the initiation

of a program of research designed to determine the health effects (and techniques for developing

methods to determine such health effects) of carbon disulfide.
CARBON DISULFIDE 159

6. ANALYTICAL METHODS

The following categories of possible data needs have been identified by a joint team of scientists from

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean

that all data needs discussed in this section must be filled. In the future, the identified data needs will

be evaluated and prioritized, and a substance-specific research agenda will be proposed.

6.3.1 Identification of Data Needs

Methods for Determining Biomarkers of Exposure and Effect. GC (equipped with either

FID, FPD, or MS), HPLC, spectrophotometry, and the iodine-azide test have been used for measuring

carbon disulfide and its metabolites in the breath, urine, blood, and milk of humans and animals

(Baselt 1980; Cai and Bao 1981; Campbell et al. 1985; Djuric 1967; Lam and DiStefano 1982, 1983;

Pellizzari et al. 1982; Pergal et al. 1972a, 1972b; Wells and Koves 1974; WHO 1979). GC and HPLC

are sensitive enough to measure background levels in the population, as well as levels at which

biological effects might occur. Analysis of the parent compound is complicated by the chemical’s

high volatility and short half-life in biological materials, making detection of urinary metabolites a

more reliable approach. Sensitive and selective methods of measuring urinary metabolites of carbon

disulfide exist, but further studies might be useful in correlating measured levels of metabolites with

carbon disulfide exposure levels and levels at which biological effects might occur.

No specific biomarkers of effect have been exclusively associated with carbon disulfide exposure.

Some biological parameters, e.g., decreased nerve conduction velocity and changes in lipid

metabolism, have been tentatively linked to carbon disulfide exposure, but there are insufficient data

with which to assess the analytical methods associated with measurement of these potential

biomarkers. Further investigations into these potential biomarkers, in conjunction with improvements

in their detection methods might aid in establishing reliable biomarkers of effect for carbon disulfide.

At present, no specific biomarkers of exposure or effect other than the parent compound or its

metabolites are available for carbon disulfide. However, the covalent cross-linking of erythrocyte

spectrin by carbon disulfide may serve as a potential biomarker (Valentine 1993). There are no data

to indicate whether a biomarker, if available, would be preferred over chemical analysis for monitoring

exposure to carbon disulfide.
CARBON DISULFIDE 160

6. ANALYTICAL METHODS

Methods for Determining Parent Compounds and Degradation Products in

Environmental Media. A GC/MS method that uses an isotopically labelled variant of the analyte as

an internal standard has been developed (Bandy 1985, 1993b). It is an accurate technique for the

determination of ppt levels of carbon disulfide in the atmosphere. GC in combination with an electron

capture sulfur detector is also sensitive enough to measure ppt levels in the atmosphere. GC equipped

with either ECD, HECD, FPD, or PID is also used for measuring low ppm to ppb levels of carbon

disulfide in air (Kneebone and Freiser 1975; McCammon et al. 1975; Peltonen 1989; Smith and

Krause 1978) and in various foodstuffs such as grains, fruits, and beverages (AOAC 1984; Bieloral

and Alumot 1966; Clower et al. 1986; Daft 1988a, 1988b; Heuser and Scudamore 1968; Malone 1970;

McMahon 1971; NIOSH 1985; UK/HSE 1983). GC/MS is the analytical method used to measure low

ppm to ppb levels of volatile organic compounds (VOCs) in water, soil, and solid waste (DOD 1991;

EPA 1984b, 1984c). The air and foodstuffs are the media of most concern for potential human

exposure to carbon disulfide. GC techniques are sensitive for measuring background levels of carbon

disulfide in these media and levels of carbon disulfide at which health effects might begin to occur.

NIOSH has recommended GC/FPD as the method (Method 1600) for measuring low levels of carbon

disulfide in air. GC equipped with either ECD or HECD is the method of choice for measuring ppb

levels of carbon disulfide in various foodstuffs. No additional analytical methods for measuring

carbon disulfide in these environmental media appear to be necessary at this time. Although carbon

disulfide was not one of the analytes mentioned in EPA methods for measuring VOCs in water, soil,

and solid waste, the GC/MS method would be appropriate for measuring carbon disulfide in these

media since it is a volatile compound.

6.3.2 On-going Studies

The Environmental Health Laboratory Sciences Division of the National Center for Environmental

Health, Centers for Disease Control and Prevention, is developing methods for the analysis of carbon

disulfide and other volatile organic compounds in blood. These methods use purge and trap

methodology, high-resolution gas chromatography, and magnetic sector mass spectrometry, which

gives detection limits in the low parts per trillion (ppt) range.
CARBON DISULFIDE 161

7. REGULATIONS AND ADVISORIES

Table 7-l summarizes international, national, and state regulations and guidelines on human exposure

to carbon disulfide. No EPA, NTP, or IARC cancer classifications were reported for carbon disulfide.

ATSDR has derived an inhalation MRL of 0.3 ppm for chronic-duration inhalation exposure in

humans exposed 8 hours/day, 5 days/week; this MRL is based on a LOAEL of 7.6 ppm (Johnson et al.

1983). In addition, ATSDR has derived an oral MRL of 0.01 mg/kg/day for acute-duration oral

exposure; this MRL is based on a LOAEL of 3 mg/kg/day in mice (Masuda et al. 1986).

An oral reference dose (RfD) of 0.1 mg/kg/day has been derived by EPA for carbon disulfide (IRIS

1995). The RfD is based on a NOAEL of 11 mg/kg/day carbon disulfide for fetal toxicity in rabbits

following inhalation exposure (Hardin et al. 1981). An inhalation reference concentration (RfC) of

0.7 mg/m3 (0.2 ppm) was also derived for carbon disulfide (IRIS 1995). The RfC was based on a

benchmark concentration (human-equivalent) of 19.7 mg/m3

 (6.3 ppm) divided by an uncertainty

factor of 30 (Johnson et al. 1983).

The Clean Air Act regulates carbon disulfide for equipment leaks of volatile organic compounds in the

synthetic organic chemical manufacturing industry (EPA 1995g).

OSHA has limited the 8-hour workplace exposure to carbon disulfide to 20 ppm (OSHA 1995a). This

OSHA exposure value reflects the limit that was in effect prior to the issuance of the new limits

(carbon disulfide was 4 ppm (PEL), 12 ppm (STEL) and 500 ppm (IDLH)) on January 19, 1989,

which were vacated by the Eleventh Circuit Court of Appeals on July 7, 1992. NIOSH has

recommended a TWA of 1 ppm and a STEL of 10 ppm (NIOSH 1994). The ACGIH has recommended

a TLV-TWA of 10 ppm (ACGIH 1995).





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