### TOXICOLOGICAL PROFILE FOR CARBON DlSULFlDE

U.S. DEPARTMENT OF HE ALTH AND HUMAN SERVICES Public Health Service Agency for Toxic Substances and Disease Registry

August 1996CARBON 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 revise d and republished as necessary, but no less than once every three years. For information regarding th e update status of previously rele ased 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 30333vi *Legislative Background The toxicological profiles ar e developed in response to th e Superfund A m endm ents and Reauthorization Act (SARA) of 1986 (Public Law 99-499) which amended the Comprehensive Environm ental Response, Co m pensation, and Liability Act of 1980 (CERCLA or Superfund). This public law directed ATSDR to prepare toxicologica l profiles for hazardous substances most commonly found at facilities on the CERCLA Nati onal Priorities List and that pos e 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 s ubstances, see Federal Register notices dated April 17,1987 (52 FR 12866); October 20, 1988 (53 FR 41280) ; October 26,1989 (54 FR 43619); October 17,199 0 (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 a m ended, directs the Adm i nistrator of ATSDR to prepare a toxicological pr ofile 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 FO LLOWING ATSDR INTERNAL REVIEWS:
1. Green Border Review. Green Border reviewassures 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 consider s 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 di sulfide. The panel consisted of the following members: 1. Dr. Henry Peters, Professor of Neurol ogy, 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 phys ical and chemical properties, toxicokinetics, key health end points, mechanis ms of action, human and animal exposure, and quantification of risk to humans. All reviewers were selected in conformitywith 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 (ATS DR) 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, exis ts as part of the administrativ e 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 c ontent of this profile lies with the ATSDR.CARBON DISULFIDE 1 

### 1. PUBLIC HEALTH STATEMENT
This public health statement tells you about carbon disulfide and th e effects of exposure.
The Environmental Protection Agency (EPA) identi fies the most serious hazardous waste sites in the nation. These sites make up the Nationa l Priorities List (NPL) and are the sites targeted for long-term federal cleanup. Carbon di sulfide has been found inat 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 ar e evaluated, the sites wi th 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 ar ea, 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 witha pleasant odor that sm ells sweet, The impure carbon disulfide that is usually used in most industrial pr ocesses, however, is a yellowish liquid with an unpleasant odor lik e that of rotting radishes. Carbon disulfide evaporates at room temperature, and the vapor is more thantwice as heavy as ai r. 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. Commer cial carbon disulfide is made by combining carbon and sulfur at very high temperatures. Se veral industries use car bon disulfide as a raw material to make such things as rayon, cell ophane, 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 th e chemical and physical properties, use, and environmental fate of carbon disulfide.

1.2 WHAT HAPPENS TO CARBON DlSU LFlDE WHEN IT ENTERS THE ENVIRONMENT?

Carbon disulfide evaporates rapidly when rel eased to the environment. The amount of carbon disulfide released into the ai r through natural processes is di fficult 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 EP A research sites around the country, but the number of research sites thathave carbon disulfide is small.

Once released to the environment, carbon disulfid e moves quickly to the air. Once in the air, carbon disulfide stays close to the ground because itis 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 fa irly quickly. Carbon di sulfide accidentally released to soils normally evaporates rapidl y. However, since carbon disulfide does not bind tightly to soils, the amount th at does not evaporate can eas ily move down through the soil into groundwater. Since it is very mobile, it is not likely to stay inthe 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 di sulfide is not taken up in sign ificant 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

m any areas
. One m easure m ent shows that car bon disulfide produced by m arshes contributes less than 8% of the sulfur in the upper atmosphere.

Small amounts of carbon disulfid e can enter the air by evapor ation and as a by-product of several manufacturing processes. It is not clear how long car bon disulfide stay s in the air. Estimates range from 1 to 10 weeks. The peopl e 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 secon d arily 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 car bon disulfide by breathing ai r that contains it. Carbon disulfide easily and rapidly enters your bl oodstream through the lungs. Carbon disulfide can also enter your body through your sk in, or by eating or drinking foods that are contaminated with the chemical. About l0-30% of carbon di sulfide that the body ab sorbs leaves through the lungs; less than 1% leaves in the urine. The rest of the abso rbed carbon disulfide (70-90%) is changed in the body and leaves th e body in the urine in the form of other chemicals. Small amounts of carbon disulfide al so 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 disu lfide 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 disulf ide can damage the heart. People who breathed carbon disulfide near an accide nt involving a railroad car show ed changes in breathing and some chest pains. Among workers who breathe d 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, ti redness, and trouble sleeping. However, the workers may have been exposed to other ch emicals 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 thatcarbon disulfide can affect the normal functions of the brain, liver, and heart. However, the amount of carbon di sulfide in the air to which animals in these studies were exposed was much higher than th e amounts in the air th at the general public usually breathes. The brains, livers, and hear ts 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 pe ople 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 supplie s. When pregnant animals received large doses of carbon disu lfide in their diet, some of the newborns died or had birth defects.
Skin contact with spilt carbon disu lfide can lead to burns at th e 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 TE S T TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO CARBON DISULFIDE?

Carbon disulfide itself can be measured in br eath, urine, and blood. It breaks down in the body into other chemical substances called me tabolites. These substances can be found and measured in the urine. After carbon disulfide ente rs your body, these subs tances reach higher levels than normally found. One chemical test using urine can be done to tell whether the levels of these breakdown substances from car bon 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 becaus e 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 te st can be used for determining longer term exposure to carbon disulfide. A second test base d on a specific metabolite is more sensitive and specific. It also require s special equipment and cannot tell you exactly how much carbon disulfide you were exposed to or predict wh ether 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 TH E 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 Administ ration (OSHA) regulates levels of carbon disulfide in the workplace (see Table 7-l). OSHA requires that workroom air contain noCARBON 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 disulf ide 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, pl ease 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 lo cation of the occupational and environmental health clinics. These clinics specialize in the recognition, ev aluation, 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 offici als, physicians, toxicologists, and other interested individuals and groups with an ov erall perspective on th e toxicology of carbon disulfide. It contains descript ions and evaluations of toxicolo gical studies and epidemiological investigations and provides conclusions, where possibl e, on the relevance of t oxicity 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 E FFECTS BY ROUTE OF EXPOSURE
To help public health professionals and others ad dress the needs of persons living or working near hazardous waste sites, the information in this s ection is organized first by route of exposure - inhalation, oral, and dermal; and th en by health effect - death, sy stemic, immunological, neurological, reproductive, developmental, genotoxic, and carcinoge nic 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-effe ct levels (NOAELs) or lowest observed- adverse-effect levels (LOAELs) reflect the actual doses (l evels of exposure) used in the studies. LOAELs have been classified into “less se rious” 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 thatare not expected to cause significant dysfunction or death, or those w hose significance to the organism is not entirely clear. ATSDR acknowledges that a considerable am ount of judgment may be required in establishing whether an end point should be classified as a NOAEL, “less seri ous” 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 guid elines and policies thatare used to classifyCARBON DISULFIDE 8 2. HEALTH EFFECTS these end points. ATSDR believes that there is suffici ent merit in this approach to warrant an attempt at distinguishing between “less se rious” and “serious” effects. The distinction between “less serious” effects and “serious” effects is cons idered to be important because ithelps the users of the profiles to identify levels of exposure at which major healtheffects start to appear. LOAELs or NOAELs should also help in determining whether or not the eff ects 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 E xposure (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 pos ing minimal risk to humans (Minimal Risk Levels or MRLs) may be of interest to he alth 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 define d as an estimate of daily human exposure to a substance that is likely to be wi thout an appreciable risk of adve rse effects (noncarcinogenic) over a specified duration of exposure. MRLs are derived wh en 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 noncancer ous 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 methodol ogy does not exist to develop MRLs for dermal exposure.
Although methods have been established to deri ve these levels (Barnes and Dourson 1988; EPA 1989b), uncertainties are associat ed with these techniques. Furthermore, ATSDR acknowledges additional uncertainties inhere nt 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 h ealth effects data become available and methods to assess levels of significant human exposur e improve, these MRLs will be revised.CARBON DISULFIDE 9 2. HEALTH EFFECTS A User’s Guide has been provided at the end of th is profile (see Appendix A) . This guide should aid in the interpretation of the tabl es and figures for Levels of Significant Exposure and the MRLs.

2.2.1 Inhalation Exposure

Carbon disulfide can exist in ai r as vapor. Table 2-l and Figur e 2-l summarize the available quantitative information on the health effects th at 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 am ong workers in viscose rayon plants who were occupationally exposed to carbon disulfide as well as other chemi cals (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 defini tive or consistent conclusions can be drawn from these studies because of concomitant exposur e to other chemicals, uncertainty about exposure concentrations, and the likelihood of multiple routes of exposure.
In a 10-year (1975-1985) epidem iological study of 251 workers e xposed to carbon disulfide and 124 controls in two viscose rayon f actories in Czechoslovakia, increa ses in total and cardiovascular mortality were noted in spinne rs 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 th an 9.6 to 48 ppm. However, insufficient data were provided to fully support their conc lusions. An approximately 15% incr ease in deaths resulting from circulatory disease was observe d among Dutch viscose rayon workers exposed to carbon disulfide concentrations which were descri bed as “at least 7 ppm, and possi bly higher” (Swaen et al. 1994). The increased risk of dying from circulatory diseas e was greatest 20-30 year s after the start of the exposure.CARBON DISULFIDE 10 2. HEALTH EFFECTS The approxi m ate L C 50 for a 60

- m inute exposure in m ale m i ce 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 LC 50 values for male mice and the LOAEL value for female rats for the acute-duration category are record ed in Table 2-l and plotted in Figure 2-l.

2.2.1.2 Systemic Effects
No studies were located regardi ng musculoskeletal and dermal effects in humans or animals after inhalation exposure to car bon disulfide. Information on respirator y, cardiovascular, gastrointestinal, hematological, hepatic, renal, endocrine, ocul ar, body weight, and other systemic effects after inhalation exposure is presented below. Th e 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 railroa d 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 part ial 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 di sulfide, hydrogen sulfide, and su lfuric acid from a viscose rayon plant in India (Kamat 1994). Exposure concentrations were not stated.
White male Wistar rats exposed to 803 ppm carbon di sulfide for 18 hours show ed 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 di sulfide 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 dis ease 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 e xposure levels were not available, it is impossible to establish a doseresponse relationship or a NOAEL. In addition, coronary heart disease has a mu lticausal 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 diet ary habits, diabetes, and physical inactivity. A combination of two or more risk factors greatly incr eases the incidence of coronary heart disease, and therefore carbon disulfide may be a cofactor in the presence of other ri sk factors (WHO 1979). Another limitation with occupati onal studies reported from the vi scose rayon industry is concurrent exposure to other chemicals such as hydrogen su lfide (Hernberg et al. 1970; Rubin and Arieff 1945; Swaen et al. 1994; Tolonen et al. 1979).
A retrospective mortality study re vealed that 223 viscose rayon process workers employed for more than 10 years and exposed to carbon disulfide at c oncentrations 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 (Ti ller et al. 1968). Over the 30-year study period, 42% of all deaths in rayon process workers were attributed to corona ry heart disease; the proportion was 24% for other rayon workers and 17% for othe r local males used as controls. The excess mortality was more pronounced in the 1940s a nd declined towards 1960, indicating a strong dependence on the intensity of exposure, which ha d 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 industr y. These factors limit the value of this study. Other limitations include an inappropriately selected control group, fa ilure to control for other coronary heart disease risk factors such as smoking, diet ary habits, physical inactivity, and obesity, and failure to monitor blood pressure and blood lipid leve ls. 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 h eart disease (Tolonen et al. 1979). Two cohorts were followed over a 10 -year period, 1967-1977; 343 visco s e 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 1960sCARBON 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 contro l group. Periodic health surveys during the study reve aled an increased incidence of angina and increased blood pressure compared to a well-matched control group (Tolone n 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 t oo 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 Hali k 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 hi ghly exposed group compared to controls. However, this study should be interpre ted 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 pathologi cal 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 fi nding 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 disu lfide 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 gr oup (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; To lonen et al. 1975). In a subsequent study, the original relative risk estimate s were adjusted for potential c onfounding effects of hypertension andCARBON DISULFIDE 23 2. HEALTH EFFECTS aging. After these adjustments, carbon disulfide e xposure 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 leng th 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 po ssible 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 (Nurmi nen and Hernberg 1985). Exposure to carbon disulfide varied greatly (approxi m ately 22 ppm to < l0 pp m ) , witha decrease in exposures after 1972. Within the first 5 years of follow-up (1967-1972), ther e was a 4.7-fold increase in ischemic and heart disease mortality compared witha 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 year s 1974-1982. This study indicates that the cardiotoxic effects of carbon disu lfide may be reversible with rem oval 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 comprise d 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 le vels 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. Card iovascular effects on 50 viscose rayon workers occupationally exposed to anaverage 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 m ean blood pressures were hi gher in the control group. Differences were not stat istically significant (p ≥ 0.10). The use of a questionnaire, confirmed by electrocardiography, determined one cas e of arrhythmia and one case of coronary heart disease in the exposed group, with no cases reported for the contro l group. The one case of coronary heart disease suggests there is some cardiac eff ect of carbon disulfide, but no general conclusions can be reached byCARBON DISULFIDE 24 2. HEALTH EFFECTS this study. The results further suggest that occ upational exposure below 9.6 ppm (maximum exposure concentration) for up to 12 years does not cause r ecognizable 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 year s at risk. In addition, workers were exposed to mean average concentrations of 3.2-8 ppm carbon disu lfide. If carbon disulfid e exerts effects through an arteriosclerotic process, th is 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 cardiovascul ar system of 1,498 rayon workers were evaluated in comparison to 481 acetate work ers (Lieben et al. 1974). An electrocardiogram, blood pressure level, total cholesterol level, and occupational exposure history were obtained for each worker. The only statistically signi ficant finding was a higher averag e 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 e xposures to other chemicals. Incr eased retinal arterial pressure but not brachial arterial pressure was observed in viscose rayon work ers 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 befo re and after 114 workers were exposed to carbon disulfide for 5 years (Chrostek-Maj and Czeczotko 199 5a). Cardiovascular effects, as assessed by blood pressure and electrocardiogram s, were not observed. Exposure con centrations were stated as a

m ean of 0-21 ppm and a median of 0-l.1 pp m . C arbon disulfide m etabolites in the urine ranged from 0 to 950 mg/L. Cardiovascular effects, as a ssessed by blood pressure, blood coagulation, and measurement of serum creatine ki nase activity, were not observed in 247 workers exposed to carbon disulfide at a median concentrati on of 4 ppm for a median duration of 4 years (Drexler et al. 1995b).

As described in Section 2.7, an in teraction between car bon 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 myo cardial vessels, irregular thickening of the aortaCARBON DISULFIDE 25 2. HEALTH EFFECTS wall, as well as microscopic histological ch anges). Although an increas e in the enzyme activity (fructose-1,6-phosphatase, glutamate dehydrogena se, and glucose-6-phosphate dehydrogenase) was reported at the lowest concentration (3.2 ppm), th e 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 we re administered an atherogeni c diet, there wa s an increase in mortality, a decrease in albumin and increase in gl obulin fractions in the serum, and serious metabolic and structural changes in the myocar dium and the aorta (Antov et al. 1985).
Rats chronically administered 321.1 ppm carbon di sulfide (5 hours a day, 6 days a week, for 15 months) did not develop any gross or histological lesions in the aorta; however, lip id droplets were occasionally noted on histological examination of th e coronary arteries (Wr onska-Nofer et al. 1980). In this same study, rats simultaneously fed an ather ogenic diet had more advanced lipid infiltrates of the coronary arteries, which suggests that car bon disulfide may have an accelerating effect on atherosclerotic changes induced by dietary hyper cholesterolemia. 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). Howe ver, 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 inhalati on (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 observ ed in rats treated withcarbon 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 vi scose rayon plant had a prevalence of symptoms (Vigliani 1954), and in another, viscose worker s (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). Significan t associations with nausea,CARBON DISULFIDE 26 2. HEALTH EFFECTS vomiting, and flatulence were also found in 119 carbon disulfide-exposed worker s in a cross-sectional study by Vanhoorne et al. (1992b). Workers were expo sed to l-36 ppm for an average of 4.2 years. These studies, however, are of limited value be cause of fluctuating exposure concentrations, concomitant exposure to other chemicals, and the fa ct that the reported symptoms are nonspecific and may have several etiologic agents.
No studies were located regardi ng gastrointestinal effects in an imals after inhalation exposure to carbon disulfide.

Hematological Effects. Relative to 18 unexposed persons, fi brolytic activity was decreased in 57 workers exposed to carbon disulfide at 59-169 ppmfor 2-8 years (Visconti et al. 1967). Serum plasmin concentrations decreased with increas ing 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 year s (Chrostek-Maj and Czeczotko 1995a).

In animals, there is limited information that hema tological effects occur fo llowing inhalation exposure. Brieger (1949) studied the bone marrow of four rabbits acutely e xposed (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 sign ificantly increased pseudo-eosinophilic cells with a corresponding reduction in lymphocytes. It can be concluded that carbon di sulfide increases the relative number of cells in the gr anulocytic 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 a dverse alterations in blood chemistr y except for a slight decrease in the serum albumin level after 2 weeks (Lewey etal. 1941). Significant de pression 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). Thes e studies suggest that hematologic effects are not consistent across species. Furthermore, these eff ects 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 or ally administered amidopyrine (Mack et al. 1974). In another st udy, Vanhoorne et al. (1992b) reported significantly increased liver size and γ -glutamyltransferase (GGT) activity in 119 carbon disulfide exposed workers compared toCARBON 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, th is study should be interpreted with caution.

There is some evidence for increased serum chol esterol 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-de nsity cholesterol. Theref ore, 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) expos ures 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, work ers chronically exposed to carbon disulfide in a viscose factory were clas sified by exposure duration of less th an (n=17) or greater than (n=17) 20 years (El-Sobkey et al. 1979). Thirteen worker s 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-re lated mean values of thyroxine and higher mean values of free, esterified, and total cholesterol than controls. The study authors s uggested that depression of serum thyroxine may be a key manifestation in hypercholesterolemia among carbon disulfide-exposed workers. The small sample size, lack of info rmation on other exposures, and poorly characterized exposure concentrations preclude establishing conclusions from this study.
A significant positive trend for lo w-density lipoprotein cholesterol (L DL-Ch), total cholesterol, and diastolic blood pressure in worker s exposed to carbon disulfide was observed in a cross-sectional study by Egeland et al. (1992). The Eg eland study used existing data (Fajen et al. 1981) on 165 carbon disulfide-exposed workers and 245 unexposed c ontrols recruited in 1979. The persons using medications to control ischemic heart disease and hype rtension, as well as thos e using corticosteroid or thyroid medications, were exclude d. 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-Chsince 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 heartCARBON DISULFIDE 28 2. HEALTH EFFECTS disease have been attributed to increased LDL-Ch, the correlati on between carbon disulfide exposure and arteriosclerotic heart disease is not definitiv e 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 sy stolic and diastolic blood pressure indicative of increased coronary risk we re noted in 115 carbon disulf ide-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 associat ed with cardiovascular disease were noted, no significant increases in prevalence of angina, myocar dial 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 inexposed workers; this too may be related to the toxic effects of carbon disulfide exposure. Although the length of e xposure 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 interp reted with caution since simultaneous exposure to low levels of H 2 S 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 unde restimation 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 ye ars 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 valu es were examined by duration of carbon disulfide exposure. Rather than being a he patic effect, the investigators s uggest that the effect may be on hormone production by the ovaries resu lting in altered lipid metabolism.

No effects on serum cholesterol levels were not ed in workers chronically exposed to l0-30 ppm carbon disulfide (Hernberg et al. 1971), and severa l 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 fromCARBON DISULFIDE 29 2. HEALTH EFFECTS 6.4 to 12.8 ppm for 5-20 years exhibited a statistic ally significant reducti on in blood cholesterol levels; a nonsignificant reduction in total lipid levels was also observ ed. This study is of limited value because of the small sample size and the like lihood of concurrent exposure to other chemicals (Sidorowicz et al. 1980). Another study of 70 men exposed to carbon di sulfide in a viscose plant who were matched to unexposed men working in a diffe rent division of the pl ant found no statistically significant differences in blood lipid profiles (total cholesterol, HDL -Ch, and triglycerides) (Franco et al. 1982). Carbon disulfide concentrations we re less than 11.2 ppm from 1972 to 1979. Workers (n=420) in a rayon filament factory chronica lly 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 contro ls (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 (Fre undt 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, hepato toxicity characterized by hydropic degeneration in parenchymal cells of the centrilobular zone wa s observed in rats pretreated with phenobarbitone to induce the liver mixed-function ox idase system and subsequently exposed to 642 ppm for 4 hours (Magos and Butler 1972; Magos et al. 1973). St arvation further potentiated the phenobarbitoneinduced liver lesions in rats subse quently treated withcarbon 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 inlipid peroxidation (Jarvi salo 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 lip id metabolism in the rat has beenextensively studied (WronskaNofer 1972, 1973; Wronska-Nofer et al. 1978, 1980). Serum cholesterol, phospholipids, andCARBON DISULFIDE 30 2. HEALTH EFFECTS triglyceride levels were signifi cantly 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) in crease 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 enhancedrate of aortic cholesterol synthesis (WronskaNofer and Parke 1978). Rats maintained on an athero genic 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. Thes e results suggest that carbon disulfide may increase arteriosclerotic changes resulting from diet-induced hyperchol esterolemia (Wronska-Nofer et al. 1980).
Total serum cholesterol and fatty acids became el evated, but cholesterol esters decreased, in dogs administered 400 ppm carbon disulfide and simultane ously fed high-fat diets (Lewey et al. 1941). These data suggest that carbon disulf ide, in conjunction with a high-fat diet, may lead to increases in cholesterol levels above those e xpected 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 liv er 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 crea tinine 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 ki dney 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 rabbitsCARBON 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 ne phritis (Cohen et al. 1959).

Endocrine Effects. The available human studies provide conf licting evidence on the adverse effects of carbon disulfide on thyroid func tion. 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 disulfid e 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 c oncentration 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 concentrat ions 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 hypercholesterole mia 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 fr om 72 to 96 ppm. The study authors concluded that carbon disulfide did not induce thyroi d alterations or disorders of li pid metabolism. In another study, the effect of long-term exposure to carbon disulfid e (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-hydroxycort icosteroids (formed from precursors of adrenal origin) and 17-ketosteroids (from both adrenal and gonadal sour ces) was reduced in workers exposed to carbon disulfide at 59-169 ppm for up to 8 years (Cavalle ri et al. 1967). In a study that was designed to examine the effects of carbon disulf ide on the sympathetic/adrenal sy stem, 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 a ffected 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 regardi ng endocrine effects in animals after inhalation exposure to carbon disulfide.

Ocular Effects. Ophthalmological changes of various ty pes, such as increased frequency of microaneurysms, related to the duration and inte nsity of exposure, have been found in Japanese workers. Severe ocular effects characterized by do t hemorrhages or microaneurysms of the retina were observed in Japanese workers exposed to carbon di sulfide at levels betw een 5 and 15 ppm after 1955 and between 15 and 30 ppm earlier. The mean durat ion 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 (l ow group). Retinopathy, characterized by microaneurysms, was observed in 35% (43/124) of those exposed to ai r 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 incr eases were statistically significant . The incidence and severity were shown to increase with longer durations of exposur e 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 ch emicals 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 si milar levels of carbon disulfide. The comparison showed that the differences in values obtained inthe 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 ob served in 25% (103/419) of the Japanese workers with chronic exposure to mean atmospheric leve ls of carbon disulfide of 15-35 ppm during the 1950s and below 20 ppm (5-15 ppm) since 1955, as comparedto 4% (15/391) of the controls. However, no significant increase in the incide nce 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 affect ed 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 worker s, different actual exposures, or the fact that no attempt was made in either study to account for the known risk factor s for retinopathy (i.e., diab etes, hypertension). TheCARBON 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 indivi duals. However, delayed peripapillary filling of the choroi d (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 add ition, the mean widths of eight reti nal vessels and the smallest vein were significantly greater in the exposed group, ag ain attributed by the study authors to hemodynamic alterations with exposure. The study was limited by the difficulty in charact erizing exposure levels because of the possibility that individual exposure varied widely and errati cally 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 effect s of carbon disulfide (Raitta and Tolonen 1975). In this follow-up, 38 male viscose rayon workers expos ed to carbon disulfide were compared to 40 unexposed workers (previously examined neuro-ophthalmologically). Measurements were taken by oculosphygmography and were combined with individua l electrocardiograms to statistically analyze the characteristics of the ocular pulse wave. Resu lts showed that the exposed group of workers had a significantly lower pulse wave thanthat of the unexposed group, sugge sting an increased rigidity of the ocular vascular bed in the viscose rayon worker s. This study provided further evidence that carbon disulfide was not retinopathic in this Finnish cohort and in additi on suggested a possible mechanism for the ocular effects of carbon disulfide.
To determine the effect of carbon disulfide exposure on retinal vasculature, Am erican subjects from a viscose rayon plant (156 exposed, 233 unexposed) unde rwent pupillary dilation (with a short-acting mydriatic), direct ophthalmoscopy, and retina l photography with monochromatic light (NIOSH 1984a). Photographs were read by an ophthalmologi st 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 theCARBON DISULFIDE 34 2. HEALTH EFFECTS combined exposed groups than in the comparison group (p ≤ 0.04). There was a con centration-related increase in the incidence of both definite and uncertain microaneurysms with exposure to carbon disulfide. No such trend was apparent for he morrhages, nor for definite aneurysms alone. The combined exposed groups had almost 20% retinal microaneurysms (both de finite 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 uncer tain) 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 th e findings. Evidence regard ing the occurrence of retinopathies due to carbon disulfide exposure is not uncomplicate d. It appears that there may be a group of individuals, both Eastern and Western, w ho 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; Ra itta and Tolonen 1975; Raitta et al. 1974; Sugimoto 1977; Tolonen 1975; Tolonen et al. 1976). The diffe rences in response by various populations have not been resolved.
Thirty workers in a viscose rayon plant were di vided into two groups based on carbon disulfide exposure concentrations. The control group was expos ed to average concentr ations of 3.2 ppm, while the exposed workers experien ced 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 affect s several ocular structur es and functions at low exposure levels. However, this study is limite d by a small sample population, probable concomitant exposure to other chemicals, and an inappropriate ly chosen control group th at was also exposed to carbon disulfide. In another study, viscose worker s (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 Arie ff 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 s ilk plant exposed 6 hours a day, 5 days a week, for 0.5-30 years to less than 3.2 ppm carbon disulf ide were reported by Szymankova (1968). Disturbances were manifested as vascular or inflammatory degenerative changes in the retinas of 12CARBON DISULFIDE 35 2. HEALTH EFFECTS out of 75 (16%) of the exposed workers, whic h 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 e ffects were secondary to the effects on the optic

nerve.
Body Weight Effects. Significant associations with anorexiawere found in a cross-sectional study of 119 workers exposed to l-36 ppm carbon disulfid e 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 af ter 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 inha lation exposure for 10 weeks (Tepe and Zenick 1984). During a 14-day exposure (10 hours/day) to car bon disulfide at 600 ppm, male rats lost 14% of their body weight (Wilmarth et al. 1993). This conc entration also resulted ina 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 wei ght 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) cause d a 16-30% decrease in body weight gain in both sexes (Toxigenics 1983a, 1983b). The percent of decrea se in body weight gain depended on the strain of rat used (Toxigenics 1983a, 1983b). Inhalation expos ure of Wistar rats to 546 ppm for 8 months or to 482 ppm for up to 14 months produced decrea ses 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 elevatedplasma sodium and chloride ions and decreased erythrocyte potassium and calcium (Pines 1982). However, the large variance in the el ectrolyte measurements among workers, the concomitant exposure to other ch emicals, the fluctuating exposure concentrations, and the lack of a dose response for blood electrol yte alterations limit th e 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 week s that revealed increased adrenal weight, hyperplasia of adrenal cortex, and mild hemosi derosis of the spleen (Cohen et al. 1959). No information was given as to whether the contro ls 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 e ffect 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 identica l 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 regardi ng immunological or lymphoreticular effects after carbon disulfide exposure in either humans or animals.
2.2.1.4 Neurological Effects The primary target of carbon disu lfide 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 expos ure to high concentrations of carbon disulfide can result in fainting and loss of consciousness. Thes e effects were observed in 36-39% of 123 persons exposed to carbon disulfide followi ng an accidental release of carbon di sulfide, 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 eff ects of carbon disulfide in humans comes from occupational epidemiology studies. These exposures are considered to o ccur via inhalation, although some dermal exposures could have conceivably occurred, especially under conditions that may have prevailed 40-50 years ago. Separati ng 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 con centration of between 10 and 20 ppm revealed that the carbon disulfide- exposed workers had reduced maximal motor conduction velocity of the median, ulnar, deep perone al, and posterior tibia1 nerves when compared to the controls (workers in a paper mill) (Seppala inen 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 exam ination 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 divisi on of people with either normal or decreased conduction velocities compared to a greater percentage of decreased velo cities in individuals ab sent for 0-4 years. The authors of this study had earlier reported on neurophy siological findings in 36 workers exposed to high levels of carbon disulfide and described dimi nished nerve conduction velocities indicating polyneuropathy in many subjects (Seppalainen et al. 1972). Polyneuritis was repo rted to be present in almost all workers occupationally exposed to carbon disulfide for an average of 40 months at unspecified concentrations (Lan cranjan et al. 1972). Overt polyneu ropathy was reported in 9 of 17 male workers exposed to 150-300 ppm carbon disulfid e for greater than 2 years, while 19 workers exposed to 15-150 ppm also had some sympto ms of polyneuropathy (Chu et al. 1995). Nerve conduction velocities were signi ficantly different in subjects with overt polyneuropathy when compared to subjects with subclinical effects and insubjects with subclinical effects when compared to unexposed controls.
Three groups of grain workers in three different work facilities (grain in spectors, malt laboratory workers, and grain elevator workers) showed vari ous neurological effects. Their symptoms included distal sensory shading indicated by decreased sensit ivity 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 disulfid e were made (Peters et al. 1988). All individuals reported being able to smell the fumigant mixtures of carbon disulfide and carbon tetrachloride, and itCARBON DISULFIDE 38 2. HEALTH EFFECTS is suggested that at this point safe levels had beenexceeded. Possible contribut ions 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 Park inson’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 formerlyexposed 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 indicate d brain organic changes in 13. The authors of this study believed that long-term e xposure to carbon disulfide involve d 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 quantit ation of individual exposures, however, and no adjustment was made to account for other possibl e 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 Cze czotko 1995b). The changes were observed most frequently in the frontal lobe. CT-scans were only completed in th e 20 individuals with the worst psychiatric effects. Exactly what was being measur ed 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 “pse udoneurotic” symptoms increased from 8.4% to 43%. A similar increase was not observed among 62 une xposed control workers. Peters et al. (1988) noted that magnetic resonance imaging findings in 2 out of the 3 grain storag e workers were indicative of central demyelination.
Regional cerebral blood flow was examined us ing 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 flowpatterns were observed in 8/14 workers, all of whom had encephalopathies consistent with car bon disulfide exposure. However, when the results were corrected to adjust for a possible influence of pCO 2 , the values did not differ between the exposed workers and referents. No clear conclusi ons 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 di sulfide poisoning, and who show ed evidence of polyneuropathy (Vasilescu 1976). The patients showed decreased conduction velocity in sensory nerves. These decreases were greater than those seen in the motor nerv e 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 exposure s or the chemicals that may have contributed to the total exposure history of the patients. Car bon disulfide was one of the major contaminants.
Workers exposed to carbon disulfide (n=145) were evaluated for its effect s on the peripheral nervous system and compared to a group of nonexposed artif icial fiber plant worker s (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 expos ure 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/m 3 ), ranging from 0.6 to 16 ppm (1.9-50 mg/m 3 ). Carbon disulfide levels showed variab ility 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 ne rve conduction velocity (S CV) 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 e xposure group and in the average exposure group. However, the reductions were withinthe range of normal values. The study authors considered this to indicate minimal neurot oxicity. A chronic-duration MRL of 0.3 ppm was established for this effect, using 7.6 ppm as the L OAEL. In addition, reductions in the peroneal nerve conduction velocity appeared to be related to the workers’ cumu lative exposure to carbon disulfide. This study reported health-related e ffects at average levels of exposure much less than those usually reported for occupational cohort studies. Howeve r, 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 disulfideCARBON 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 af ter 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 exposur e measurements showed more anxiety, introversion, and depression than the other workers. They also di d significantly worse on tests designed to measure number facility, sustained attent ion, speediness, and carefulness. Th ere 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 pe rceptive ability were observed inviscose 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 di sulfide rather than the low concentrations. Other studies have indicated that grain storage workers had intense exposures interspersed often with pe riods of more minimal c ontact with anti-weevil ch emicals (Matthews et al. 1990; Peters et al. 1982, 1986a, 1986b, 1988).
Behavioral examinations (psychological tests, ps ychomotor tests, and cogni tive-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 synthe tic fibers. Exposure and companion (control) groups and exposure levels are th e same as those described for the Johnson et al. (1983) study. The workers comple ted 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 neur obehavioral 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 m easured in the plant were generally below 20 ppm, suggesting that these levels may be too low to identify be havioral changes (Put z-Anderson et al. 1983).
A study of neuropsychological variables in carbon di sulfide-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 consiste d of three intelligence tests, three personality questionnaires, a test of memory involving measur es of perception, recognition, and free recall, and two performance measures. Workers were grouped a ccording to exposure categories (none; low, about 20 ppm; medium, between 20 and 38 ppm; and hi gh, greater than 38 ppm). The no-exposure and low-exposure categories were combined for analys is. Differences in the groups’ measurements were statistically analyzed and reveal ed decreased intelligence scores , performance, and memory andCARBON 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 effect s in 50 viscose rayon workers occupationally exposed to an average concentration ranging from 3.2 to 9.6 ppm carbon disu lfide 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 dia gnosis revealed only one exposed worker with minimal neuropathy. Furthermore, four exposed and two unexposed workers we re clinically diagnosed with the nontoxic syndrome and radiculopathy, and no cases of polyneuropathy were found in either group. Clinical diagnosis of centr al impairment was found in two exposed workers and no unexposed workers with psychoorganic syndrome. The number of neuropathy or psyc hoorganic 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 part icular 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 audito ry 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 curr ent 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 work ers 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 th e 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 neuropathol ogical examinations were performed on 16 viscose rayon workers in Norway exposed to 3.2-28.9 ppm for an averag e of 20 years (Aaserud et al. 1990). Workers were also exposed to hydrogen sulfide (80 mg/m 3 ) 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 neurologi cal 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 inEMG. Decreased nerve impulse conduction and motor, sensory, and mixed motor/sensory neuropathies were demonstr ated. Cerebral or cereb ellar atrophy was noted in 13/16 workers, and neurophysiological examinations showed psychomotor retardation and coordination difficulties. Study defi ciencies 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 mark ers 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 th e 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 veloc ity in both fast and slow motor ne rve fibers (peroneal nerve) was observed in exposed workers. Sensory conduction ve locities were reduced and the refractory period of the sural nerve was increased. Th e 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 transmi ssion and visual stimuli was examined in a group of 21 patients with chronic carbon disulfide exposure in a rayon pr oduction plant for 20-36 years and control groups of 25 or 36 healthy unexposed males (Sikora et al. 1990). A signi ficant correlation was observed in latency and amplitude of response. Th e correlations suggest cer ebral dysfunction of the visual pathway and diminished ability to transform visual information to moto r 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 res ponses 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 de tected using computerized techniques and Parkinsonian tremor detected visually on neurol ogical 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 re miniscent of tremor in idiopathic Parkinson’s disease. These findings suggest th at the measurement of subtle tremor frequency changes may provide an early indication of chronic carbon disulfide poi soning. However, the study was limited by the lack of exposure concentrations and th e use of only symptomatic cases.
Animal studies on the neurotoxicity of carbon disulf ide have usually been done in rats and provide histopathologic and neurochemical data that s upport a neurotoxic effect for carbon disulfide. In general, the doses used in these animal studies ar e considerably higher thanthe 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 seiz ure discharge was 1,370 ppm in male rats and 2,600 ppm in female mice.
Short-term exposures to inhaled car bon 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 d ecreased noradrenaline, increased dopamine, and elevated tyrosine in the brain (Magos and Jarvis 1970). The authors proposed th at 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 indicat es 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 br ain adenosine triphosphate (ATP) levels compared to controls (Tarkowski et al. 1980). However, no hist opathological changes were noted in brain tissue. Under the same experimental conditions, rats e xposed to 257 ppm for 5 hours a day, 5 days a week,CARBON DISULFIDE 44 2. HEALTH EFFECTS for 10 months showed biochemical changes thatinvolved 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 a pproximately 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 unexpos ed 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 di sulfide 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 paresi s, and the acute dosing caused severe narcosis, reduced cardiac and respiratory rate, straight ening of hind limbs, and lower body temperature. However, brain mitochondria in both groups of anim als exhibited the same types of disturbances in oxidative phosphorylation-unc oupling of oxidative phosphorylat ion, decreased phosphorus-oxygen (P:O) ratio, and a lower AT P-inorganic phosphorus (ATP-P i ) exchange rate (Tarkowski and Sobczak 1971). Although this study used only six or seven anim als and one dose, the results were consistent and do not conflict with other information regard ing 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. Neurob ehavioral 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 week s 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 th e availability of brainCARBON DISULFIDE 45 2. HEALTH EFFECTS noradrenaline for release. This e ffect also disappeared by 3 weeks after exposure (T ilson 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 decr eased in the brains of acutely exposed rats.
Motor capacity (static endurance and dynamic performance at for ced motor activity) was studied in a total of 96 albino rats that were repeatedly e xposed to 0 (42 males/group), 48, 385, or 770 ppm carbon disulfide via inhalation (18 male s/group) (Frantik 1970). Acute toxi city was measured 0-60 minutes after termination of exposure, and chronic toxi city 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 experime nts. 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 firs t 8 weeks. The study is limited by the lack of quantitative measur ement 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 startl e test (Clerici and F echter 1991). Neuromuscular integrity was shown to be compromised based on aud itory startle reflex amplitude; animals showed a 70% recovery 4 weeks postexposure. No clinical sign s 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 respons es at 200 ppm indicated only slight conduction dysfunction. Rats recovered 2-6 week s 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 dege neration, damage of the terminal axons, myelin indentation, fiber breakdown, and distended mitochondr ia 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 contro l 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 periphera l nerve conduction activity. Their work with rats showed that visual-evoked potentials and conducti on 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 statisti cally 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 (Mer igan et al. 1988). Visual acuity thresholds in two macaque female monke ys 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; th e other showed no improvement (Merigan et al. 1985).
Neurological effects such as hind-limb motor di fficulties, 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 e xposure. The improvement continued up to the 18th week of recovery, suggesting that the pro cess may be reversible. This study was limited by the use of a single carbon disulfide do se. In another study, para lysis of hind limbs was observed in Wistar rats exposed to 546 ppm for 8 mo nths (5 hours a day, 6 days a week); this effect was not seen at 321 ppm (Wronska-Nofer 1973).
Morphological changes in the periph eral nerve and the spinal cord were studied in rats and mice exposed to 50, 300, or 800 ppm carbon disulfide, 6 hour s a day, 5 days a week, for 90 days (Gottfried et al. 1985; Toxigenics 1983a, 1983b, 1983 c ). Rats exposed to 50 ppm showed no changes in any parameters; rats exposed to 300 ppm showed only o ccasional swelling of axons in dorsal corticospinalCARBON DISULFIDE 47 2. HEALTH EFFECTS fibers of the lumbar spinal cord; and rats e xposed to 800 ppm showed extensive neurofilamentous axonal swelling in the spinal cord. Neurofilament ous axonal swelling was particularly seen in the distal portion of long fiber tracts, including prominent swellings in th e dorsal ascending sensory fibers, whereas it was only intermittently seen in the do rsal corticospinal fibers. In addition, extensive peripheral nerve changes were seen at the level of the posterior tibi a1 nerve. The sciatic nerve showed no appreciable loss and only oc casional axonal swelling. Ultrastr ucturally, the axonal swellings contained abundant disorganized neurofilaments, d ecreased microtubules, and thin or absent myelin. Brain and body weight were decreased in proportion to the concentration, withthe decrease in brain weight statistically sign ificant in the 800-ppm group.
The highest NOAEL values and all reliable LOAEL va lues 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 i nhalation 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 incr eased incidence of spontane ous abortion at levels as low as about 2 ppm (6-7 mg/m 3 ) (Heinrichs 1983; Wang and Zhao 1987). Other epidemiological studies have not corroborated thes e 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/m 3 ) had significantly more menstrual disorders than nonexposed women; however, there was no incr ease 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 wo rkers 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 c oncentrations 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 hi gher previously. Serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were significantly increased inthe exposed workers. The study authors concluded that this was a sign of prim ary gonadal insufficiency. However, no changes were seen in serum testosterone or thyroid functions. E xposures were not well ch aracterized, only a small number of workers were examined, and semen anal ysis was not performed; these limitations preclude developing conclusions from this study. In a Natio nal 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 be tween 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 d i fficult to quantify or other ( O =19 workers). A further limitation was the possibility that the poor rate of worker particip ation (50%) in the semen sampling could have affected the results. In an other 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 (Vanhoo rn e et al. 1994). R e productive histories did not reveal any effects on fertility. Examination of semen from 43 expos ed 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 repor ting of data, there is enough evidence to warrant concern about the effects of car bon disulfide on the female reproductive system. Reported adverse effects included menstrual disturbances, endocrine al terations, 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 (L ancranjan 1972). Studies have stressed the importance of assessing the statis tical power of a test for comparing sperm count or morphology (Wyrobek 1983) and the need for more clearly de fining the link between ch anges in morphology and altered fertility (Schrag and Dixon 1985). The relationship between paternal exposure to carbonCARBON DISULFIDE 49 2. HEALTH EFFECTS disulfide and pregnancy was studied in 540 worker s and their wives (NIOSH 1983). Patterns of fetal loss, number of births, and time between live bi rths were examined by comparing pregnancies conceived after paternal exposure to carbon disulf ide to pregnancies occu rring 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 reproduc tive 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 behavi or and a decrease in ejaculated sperm counts by the 4th and 7th weeks of exposure, respectively. Cauda l epididymal sperm counts were not depressed and testes appeared histologically no rmal. The plasma testosterone le vels 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 effect s in animals are recorded in Table 2-l and plotted in Figure 2- 1.

2.2.1.6 Developmental Effects
Developmental effects of carbon disu lfide have been reported in se veral animal studies. Inhalation exposure of pregnant rats did not produce congen ital malformations at levels of 3.2 and 0.01 ppm. However, administration of 3.2 ppm was also associat ed with viability impair ments and retardation of morphological and sensory development, and 0.1 ppm was associated with behavioral changes (Tabacova and Balabaeva 1980b). To study the reprodu ctive toxicity and teratogenicity of carbon disulfide, other inhalation exposur e studies of pregnant Wistar or Sprague-Dawley rats and New Zealand white rabbits exposed to 20 or 40 ppm car bon disulfide were conducted (Hardin et al. 1981; NIOSH 1980). Results showed an absence of maternal toxicity, fetal toxic ity, and teratogenicity. These studies were limited by the absence of information regard ing exposure conditions and the presentation of results as a summary of 10 test ed chemicals with little experimental detail.
A developmental study was conducted using New Zeal and White rabbits, which are more sensitive than rats to the effects of car bon disulfide (PA1 1991). In this study, rabbits (24/group) were exposed by inhalation to 0, 60, 100, 300, 600, or 1,200 ppm, 6 hour s a day, on gestation days 6-18. AnimalsCARBON 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 consum ption, wheezing) in the 1,200-ppm group, with some sporadic hematologic alterations at 600 ppm (for ex ample, decreased hematocrit on gestation day 19). These effects were not seen in an initial range-findi ng 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 gr oups. 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 Fi scher 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 14 C-labelled carbon disulfide, carbon disulfide and its metabolites pass the placenta at a ll stages of gestation and localize selectively in tissues reported to be target organs for the eff ects of this chemical (brain, blood, liver, and eye) (Danielsson et al. 1984). This fi nding provides evidence that carbon di sulfide or its metabolites may exert effects directly on the embryo.
Maternal reproduction and fetal pa rameters 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). Matern al toxicity for the animals exposed to 400 or 800 ppm was evidenced by the signif icant 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 freque ncy than in the controls ; however, the one fetus affected in one litter at 400 ppm and the seven fe tuses affected in five litters at 800 ppm were notCARBON 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 anoma lies or major skeletal anomalies were present in any treated groups.

Behavioral and neurotoxic effects inthe offspring of rats exposed vi a 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). Exposur e to 642 ppm carbon disulfide throughout pregnancy for 2 hours daily produced no malformations of fetuses inrats or mice but did increase the death rates of the embryos at all stages of intr auterine development (Yaroslavski 1969).
In a developmental study in which only the dams of both F 0 and F 1 generations were dosed during gestation, the F 1 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 pos tnatally exposed to the same exposure concentrations for the same duration (Tabacova et al. 1983). Both the F 1 and F 2 generations showed a marked increase in malformations and behavioral and learning changes at th e highest concentration, but the F 2 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 thatcarbon disulfide causes preconditioning to increased effect s in the next generation. There are, however, no other data that support a conditioning effect of car bon disulfide. This study is limite d by the lack of information on chemical exposure (including chemi cal purity, atmosphere verification, or analytical t echniques) on the control animals, and on the methods used to select F 1 and F 2 generations. In addition, there was in excess of a 300-fold difference in concentration be low 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 (separat e control animals were used for higher and lower exposure animals); animal diet a nd housing conditions were notspecified; 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 substant iated in subsequent inhalation studies by Saillenfait et al. (1989) and PAI (1991). However, the de sign of the Tabacova et al. (1983) study was significantly different from both the Saillenfait et al. (1989) and PAI (1991) studies. The lack ofCARBON DISULFIDE 52 2. HEALTH EFFECTS substantiation of the Tabacova etal. (1983) study may be due to di fferences in the designs of the Saillenfait et al. (1989) and PAI (1991) studies.
All reliable LOAEL values for developmental eff ects are recorded in Table 2-l and plotted in Figure 2-1.

2.2.1.7 Genotoxic Effects
No studies were located regardi ng genotoxic effects in humans af ter inhalation exposure to carbon disulfide.
Carbon disulfide failed to produ ce significant chromoso mal aberrations in the bone marrow of rats inhaling 20 and 40 ppm for either acute or intermediate periods (NIOSH 1980).
Other genotoxicity studies ar e 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 mort ality 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 disulfid e 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, trichlor oethylene, trichloroethane, and 13 others). This odds ratio was higher than that detected for benzene, which was not statisticallyCARBON 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 th ese 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 nonoccupationa l 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 regardi ng cancer in animals after inhalation exposure to carbon disulfide.

2.2.2 Oral Exposure
Humans are not likely to be e xposed 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 (con centration not specified) caused death following ingestion.
In mice, Gibson and Roberts (1972) determ ined the median oral lethal dose (LD 50 ) over a 24-hour period to be 3,020 mg carbon disulfide/kg. In Wist ar rats, a single dos e of carbon disulfide administered by gavage at doses up to 632 mg/kg di d 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 di sulfide 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, rena l, dermal, or ocular effects in humans or animals after oral exposure to carbon disulfide. Information on cardiovascular, hematological, musculoskeletal, hepatic, and body we ight 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 inTable 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 expose d 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 contro ls (Hoffman 1987). In addition, the heart rate measured before the procedure was significantly lower in exposed rats than in the c ontrols (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 ch anges in an electrocardiograph (Hoffmann and Klapperstück 1990). When coronary ligation was performed 1 hour after exposure, these animals showed an earlier appearance of cardiac arrhythmia s, delay in acotroitine-induced arrhythmia, and decreased survival. No exposure-re lated effects occurred at a lower dose level (126 mg/kg). This study also examined the effect s 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 QT c . Heart rate was decreased at 632 mg/kg. No significant changes in contractile force of the le ft 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 hoursCARBON 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 observe d in rats after receivi ng 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 car bon disulfide/kg/day for 60 days developed normochromic and normocytic anemia, eo sinopenia, and an increase in reticulocyte cell numbers. No changes in leukocyt e or platelet numbers were obs erved, however. No other studies were found on the hematological effects in an imals after oral exposure to carbon disulfide.

Musculoskeletal Effects. No studies were located regardi ng 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 Venkatakrishn a-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 responsivenes s may be a result of a block of calcium influx, a delay of the calcium efflux, an inhibition of the uptake of cal cium, a decreased sensitivity to calcium by the muscle, or a combination of these mechanisms.

Hepatic Effects . No studies were located re garding 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 expos ed to 3-300 mg/kg/day (1-14 days) have shown rapid, reversible, dose-related s uppression 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 activi ties of liver microsomal drug-metabolizing enzymes in mice (MasudaCARBON 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 per oxidase activity. In addition, a decrease in cytochrome P-450 content and total heme content was observed. The inhibition of enzyme ac tivities was reversible. There were no effects on the activities of NADH-ferricyanide reductase, NADPH-cytochrome c reductase, flavin-containing monoxygenase, UDP-glu curonyltransferase, glucose-6-phosphatase, heme oxygenase, and glutathione S -transferase. Also, the c ontent of cytochrome b 5 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 increase d liver weight. These effects are significantly enhanced by pretreatment with a microsomal en zyme 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 intotal liver water and electrolytes (Wilkie et al. 1985). This study is of limited value becau se of its lack of controls to eliminate or account for possible synergis tic 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), ma le 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 toxi city 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 regardi ng 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 regard ing neurological effects in human s after oral exposure to carbon disulfide.
Compared to untreated rats, sign ificant decreases in noradrenaline in the midbrain, hypothalamus, and medulla oblongata were observed in rats 2 hours after they received a si ngle gavage dose of 300 mg carbon disulfide/kg body weight (Kan ada et al. 1994). 3,4-Dihydroxyphe nylalanine 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 regardi ng reproductive effects in humans or animals after oral exposure to carbon disulfide.

2.2.2.6 Developmental Effects
No studies were located regardi ng 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, suchas transient hind-limb paralysi s and loss of body weight over the period of gestation (Jones-Price etal. 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). Averag e 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 in crease in the number of malformed fetuses in 150-mg/kg/day (highdose) animals; however, there was no characteristic pattern of carbon disulfid e-related malformations.CARBON DISULFIDE 62 2. HEALTH EFFECTS Males were affected to a greate r 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 developm ental 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 regardi ng 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 regard ing death in humans or animals after dermal exposure to carbon disulfide.

2.2.3.2 Systemic Effects
No studies were located regard ing respiratory, cardiovascular, ga strointestinal, hematological, musculoskeletal, hepatic, renal, or ocular eff ects in humans or animals following dermal exposure to carbon disulfide.CARBON DISULFIDE 63 2. HEALTH EFFECTS
Dermal Effects. Dermal contact with car bon 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 w earing rubber gloves (Hueper 1936).
The implication of carbon disulfide as the causativ e agent is supported by experiments in rabbits whose ears were dermally exposed to carbon disulf ide. Blisters similar to those found in the rayon workers developed on the animals’ ears despite protective c overing (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 regard ing 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, or al, and dermal routes. Absorbed carbon disulfide is distributed throughout the body. Because of its lipophi lic nature, its distribution is greatest in organs such as the brain and liver where it is metabolized to thio carbamates. Carbon disulfide is metabolized by cytochrome P-450 to an unstable oxygen intermediate which either spontaneous ly degrades to atomic sulfur and carbonyl sulfide or hydrolyzes to fo rm atomic sulfur and monothiocarbonate. CarbonylCARBON DISULFIDE 64 2. HEALTH EFFECTS sulfide is converted to monothiocarbonate by carbonic anhydrase. Monothi ocarbonate degrades to generate carbonyl sulfide or forms carbon dioxide and hydrogen sulfide. Unlike in animals, oxidation of sulfur to inorganic sulfate doe s not contribute signifi cantly to the metabolism of carbon disulfide in humans. Despite the differences in the metabolis m of carbon disulfide between animals and humans, dithiocarbamates are the common metabolites formed in these species after re action with amino acids. These metabolites contribute in part to th e neurotoxic effects of carbon disulfide.
The kidneys are the primary route of excretion of carbon disulfide metabolite s. Conjugation of carbon disulfide or carbonyl sulfid e with endogenous glutathione results information of thiozolidine-2-thione4-carboxylic acid and 2-oxythiazolidine- 4-carboxylic acid, respectivel y, which are excreted in the urine. The unmetabolized carbon disulfide is ex creted unchanged in the breath, and small amounts (<l%) have been det ected in the urine.

2.3.1 Absorption

2.3.1 .1 Inhalation Exposure
Studies conducted on human subjects reported rapid and extensive absorp tion 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 measuri ng 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 disulf ide 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 expo sure 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 hour s after exposure. In another retention study involving exposure to vapor for anunspecified period (Soucek 1957), about 10-30% of the retained carbon disulfide was exhaled, and le ss than 1% was excreted in ur ine as carbon disulfide. The concentration of inhaled carbon disulfide wa s not reported. About 70-90% was metabolized.CARBON DISULFIDE 65 2. HEALTH EFFECTS Studies in animals indicate thatcarbon disulfide is rapidly abso rbed following inhalation exposure. Absorption of carbon disulfide was studied by eval uating pulmonary and urinary excretion of carbon disulfide during and after exposure. Studies in rabbits indicate thatan equilibrium concentration of carbon disulfide is reached after inhalation e xposure to 20-150 ppm for 1.5-2.0 hours (Toyama and Kusano 1953). About 70-80% of the inhaled carbon disulfide was absorbe d. 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 di sulfide, equilibrium concentrations in blood were attained after 0.5-2.0 hours (McKee et al. 1943). Desaturati on of blood carbon disulfide was almost complete within the first 30-60 minutes af ter exposure. Approximately 8-13% of the retained carbon disulfide was exhaled, less than 0.5% was excreted in the ur ine, 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 af ter 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 bl ood of 35 minutes and in the liver of approximately 1 hour.
The data presented above indicate that carbon disulfide is absorb ed by humans and animals following inhalation exposure and reaches equilibrium rapidly (0.5-8 hours) ac ross a wide range of doses and exposure durations.

2.3.1.2 Oral Exposure
No studies were located regard ing absorption of carbon disulfide following oral exposure of humans. In rats, intragastric administration of 10 mg/kg 14 C-carbon disulfide resulted in exhalation of 63% of the dose within 4 hours as unchanged carbon disulfide (DeM atteis and Seawright 1973). It is evident from these results that a large fr action of orally administered car bon 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 pe rformed to investigate th e 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 Baranow ska 1967). Absorption was calculated indirectlyCARBON DISULFIDE 66 2. HEALTH EFFECTS by determining carbon disulfide elimination by the lung or directly by measuring carbon disulfide concentration in the solutions be fore 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 pe riod; in the latter, only 3% was eliminated in the expired air. These findings sugge st that carbon disulfide ex cretion varies with the route of absorption. This study provided only brie f details of the experimental procedure, and therefore factors other than abso rption 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 skinconditions has also been noted to increase the dermal absorption of carbon di sulfide (Drexler et al. 1995a).
The limited information available on skin absorpti on in animals indicates that carbon disulfide is appreciably absorbed. Exposure of rabbit skin to high concentrat ions of the vapor (800 ppm and above) for 1 hour resulted in detectable amounts of carbon disulfide in the br eath (Cohen et al. 1958). A linear relationship was noted be tween the dermal exposure concentration and the amount of carbon disulfide exhaled. No detectable carbon disulfid e 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 natu re 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 mother s occupationally exposed to carbon disulfide was found to contain an average of 12.3 μ g 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) result ed in a lower average milk concentration of 6.8 μ g/l00 mL.CARBON DISULFIDE 67 2. HEALTH EFFECTS The distribution of carbon disulfide following inhalation exposure has been stud ied in rabbits and rats (Toyama and Kusano 1953). In rabbits, blood equili brium 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 c ontrast to rabbits, blood equilibrium concentrations for various carbon disu lfide exposures in rats were not determined. Although carbon disulfide was rapidly eliminated fr om rat tissues during the first 6-8 hours after exposure, low concentrations of carbon disulfide we re still detected in th e 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 hour s of exposure to 25-60 ppm carbon disulfide (McKee et al. 1943). Desaturation was largely complete within the first 30-60 minutes af ter inhalation exposure. Anesthetized male Sprague-Dawley rats exposed to 640 ppm carbon disulfide had an exponential increase in carbon disulfide in the blood which reach ed an apparently steady state after 90 minutes of exposure. After discontinuation of exposure, the blood concentration decreased rapidly, with elimination half-lives repo rted to be 6 and 85 minutes for the fast and slow components, respectively. In all tissues except fat, the car bon disulfide concentration approach ed 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 hour s postexposure (McKenna and DiStefano 1977a).
Inhalation exposure of pregnant mice to carbon disu lfide during gestation resu lted 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 ( μ Ci) 35 S- or
14 C-carbon disulfide for 10 minutes on day 9, 14, or 17 of gestation. The levels of 35 S-labelled metabolites in the embryonic neuroepithelium were highe r in the fetal brain thanin the maternal brain during early gestation (day 9). Th e concentrations in the fetal br ain, eyes, and skeleton exceeded that of other fetal organs during mid-gest ation (day 14). In late gestation (day 17), the levels in the fetal and maternal brain were relatively low, but high uptak e of radioactivity was seen in the placenta, fetal blood, liver, and eyes. During early gestation, the distribution of 14 C-labelled metabolites was similar to that of 35 S-labelled metabolites with an immedi ate 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 fe tal liver and blood at late gestation (day 17). In contrast to 35 S-labelled metabolites, 14 C-labelled metabolites were retained longer (up to 24 hours) in the fetal br ain and liver. High concentrations of 14 C-labelled metabolites were also seen in the fetal urinary tract. Thus, the distribution pattern vari ed with the age of theCARBON DISULFIDE 68 2. HEALTH EFFECTS conceptus and also with the radiol abel of carbon disulfide. These resu lts indicate that carbon disulfide and its metabolites pass through the pl acenta at all stages of gestat ion and localize selectively in various tissues of the body.

2.3.2.2 Oral Exposure
No studies were located regardi ng distribution of carbon disulfide in humans or animals following oral exposure.
2.3.2.3 Dermal Exposure
No studies were located regard ing 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 ca rbon disulfide liberated by acid hydrolysis was investigated in the tissues of white rats afte r a large, single subcutan eous dose (approximately 361 mg/kg) of carbon disulfide (B artonicek 1957, 1959). Results of these studies indicate that following absorption, free carbon disulfide is rapidl y 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 bl ood was noted when radiolabelled
35 S-carbon disulfide was administered parenterallyto guinea pigs (Strittmatter et al. 1950). About 20-50% of intracardially injected 35 S-carbon disulfide was retained; the amount of material retained depended on the concentration of dose administered. Th e largest amount of radiolabel appeared in the liver (0.43 μ g) and the least amount in the brain (0.05 μ g) 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 disu lfide vapors (13.6-25.7 ppm), the brain and blood contained more 35 S-label relative to th e liver. Forty-eight hour s later, 30-50% of 35 S-label remained in the tissues such as blood, liver, brain, kidney, and skin. The urinalyses revealed that urinary 35 S-labelCARBON DISULFIDE 69 2. HEALTH EFFECTS was about 30% of the retained s u lfur, with about 85% or 90% of it appearing in the first 24-ho ur output, the larger part of the metabol ized material in the urine being ex creted as inorganic sulfate. The feces contained about 5-15% metabolized 35 S-label, the amount of which increased with the increasing dose of carbon disulfide.
Only metabolites of carbon disulfid e were found 3 hours after a dose of 14 C- or 35 S-labeled carbon disulfide was intraperitoneally administered (Snyderwine and Hunter 1987). Distribution varied with the age of the rat and the radiolabel inject ed. Following intraperiton eal administration of 14 C-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 di sulfide which were covalently bound remained in tissues from rats of all ages. Twenty-four hours after dosing with 35 S-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 irre spective of the route of exposure.

2.3.3 Metabolism

Limited information is available on the biotrans formation 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 me tabolism of carbon disulfid e (Beauchamp et al. 1983) are depicted in Figure 2- 3, reactions i-x. Reaction i ha s 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 meta bolic pathways of carbon disulfid e in animals and humans. Carbon disulfide is metabolized by cyto chrome P-450 to an unstable oxygen intermediate (reaction i). The intermediate may either spontane ously degrade to atomic sulfur and carbonyl sulfide (reaction ii) or hydrolyze to form atomic sulfur and monothiocarbonate (reaction iii). The atom ic sulfur generated in these reactions may either covale ntly bind to macromolecules (reactio n iv) or be oxidized to products such as sulfate (reaction v). The carbonyl sulfid e formed in reaction ii may be converted to monothiocarbonate by carbonic anhydrase (reaction viii). M onothiocarbonate may further spontaneously degrade in reaction ix, regenerati ng carbonyl sulfide or forming carbon dioxide andCARBON DISULFIDE 71 2. HEALTH EFFECTS sulfide bisulfide ion (HS ) (reaction vii). The HS - formed in reaction vii can subsequently be oxidized to sulfate or other nonvolatil e metabolites (reaction vi).
Dithiocarbamates are the products of the reaction of car bon disulfide with amino acids (Brieger 1967). In vitro studies demonstrated that carbon disulfide re adily combines with the amino acids in human blood, the half-life of this reaction being appr oximately 6.5 hours (Soucek 1957). Thiocarbamide has been found in the urine of exposed workers (Per gal et al. 1972b). After i nhalation exposure of male subjects, up to 90% of the reta ined 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 disulf ide by inhalation (Pergal et al . 1972a, 1972b). Van Doorn et al. (1981a, 1981b) reported conjugation of carbon di sulfide or carbonyl su lfide with endogenous glutathione to yield thiazolidin e-2-thione-4-carboxylic acid and 2-oxythiazolidine-4-carboxylic acid, respectively. High concentrations (approximately 320 mM) of thia zolidine-2-thione-4-carboxylic acid (TTCA) were detected in the urine of wo men exposed to approximately 32 ppm (100 mg/m 3 ) carbon disulfide through inhalati on (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 car bon disulfide in humans. A marked increase in inorganic sulfate excretion in th e 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 durati on were not presented in the study.
Carbon disulfide is oxidized by the liver mixed-f unction oxidase (MFO) system to carbonyl sulfide, which then undergoes further desulf urization, releasing elemental sulf ur. This reaction has been shown to occur in vitro (Dalvi et al. 1974; DeMatteis 1974). In vivo studies in rats using 14 C-labelled carbon disulfide demonstrated that significant amounts (80%) of 14 CO 2 , 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 ph enobarbital to induce liver micros omal enzymes (DeMatteis and Seawright 1973). Snyderwine and Hunt er (1987) found that 4-9% of anintraperitoneally administered dose of 14 C-carbon disulfide was excreted as 14 CO 2 in expired air, with 30- and 40-day-old ratsCARBON DISULFIDE 72 2. HEALTH EFFECTS excreting more (9% versus 4%) 14 CO 2 , than 1-20-day-old rats. This wa s attributed to the increased hepatic MFO of carbon disulfide to car bon dioxide in 30-40-day-old rats.
The metabolic formation of carbonyl sulfide fr om carbon disulfide was confirmed in an in vivo study (Dalvi and Neal 1978). After intraperitoneal injection of 14 C-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 am ount of excretion of car bon dioxide than carbonyl sulfide. In both experiments, excretion of 14 C-carbonyl sulfide and carbon dioxide accounted for 14-43% of the total administered radioactivity, with about twice as mu ch carbon dioxide. These results indicate that phenobarbital treatment cau sed 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 metabolis m of carbon disulfide to TTCA, rats were treated with nothing, ethanol, phe nobarbital, 3-methylchol anthrene, or phenobarbital and ethanol before being exposed to carbon disu lfide at 50 ppm for 6 hours (Kivisto et al. 1995). After 7 days the pretreatment regimens were rep eated 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 inve stigators 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 concentrati ons. 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 disu lfide metabolism to TTCA in rats following oral exposure has also b een studied (Kivisto et al. 1995). The rats were pretreated with nothing, acetone, phenobarbital, 3-me thylcholanthrene, or three inhi bitors of glutathione production,CARBON DISULFIDE 73 2. HEALTH EFFECTS namely phorone, diethylmaleate, or buthionine sulfoxi mine, before being given a single gavage dose of carbon disulfide at 26-34 mg/kg. Phenobarbital de creased the output of TTCA by 21% during the first 12 hours of the urine coll ection. None of the other P-450 inducers had any effects on TTCA excretion, and the investigators s uggested that the effect of phenobarbital may have been a result of cytochrome P-450 aggregation. Buth ionine sulfoximine, an inhibi tor of glutathione production, reduced the total output of TTC A 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 unmetabo lized carbon disulfide in humans is exhalation. In one study itwas estimated that 6-10% of th e 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 availabl e. A correlation was established between carbon disulfide exposure of rayon workers and urinary excr etion of a metabolite or metabolites that catalyzed the reaction of iodine with sodi um azide (Djuric 1967). This testindicated 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 result ed in excretion of 15-30% of the absorbed carbon disulfide via the lung and le ss than 0.1% by the kidney after termination of exposure (Toyama and Kusano 1953).CARBON DISULFIDE 74 2. HEALTH EFFECTS In guinea pigs, carbon disulfide metabolites are excr eted as inorganic sulfur compounds in the urine (Strittmatter et al. 1950). I nhalation exposure to 14 ppm 35 S-carbon disulfide for 8 hours or to 26 ppm
35 S-carbon disulfide for 40 hours result ed in excretion of the administ ered dose mainly in the urine (63%) and expired air (30 %) within 48 hours of exposure. The me tabolized material was excreted in the urine predominantly in the form of inorgani c 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 r oute 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 regard ing excretion of carbon disulfide in humans after oral exposure.
Rats administered 10 mg 14 C-carbon disulfide/kg by gavage excr eted 63% of the dose as unchanged carbon disulfide in the breath (D eMatteis and Seawright 1973).

2.3.4.3 Dermal Exposure
Following dermal exposure of humans to aqueous solutions of carbon di sulfide of increasing concentrations (0.33-1.67 g/L) for 1 hour, only 3% of the absorbed carbon disu lfide 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 amount s of carbon disulfide in the breath of animals (Cohen et al. 1958). A linear relationship was noted betw een 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 car bon disulfide are excreted unchange d 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 disulfideCARBON DISULFIDE 75 2. HEALTH EFFECTS are excreted in the sweat and sa liva of exposed individuals. In mi ce injected intraperitoneally with 30-42 μ g of 35 S-carbon disulfide, about 13-23% of the radiolabel was excreted via the lung (Strittmatter et al. 1950). Rats receiving 10 mg 14 C-carbon disulfide/kg by intr aperitoneal injection excreted about 70% of the dosed material as unchanged carbon disulfide in the breath (DeMatteis and Seawright 1973). Rats receiving 19 mg/kg 14 C-carbon disulfide intraperitoneally excreted 58-83% free carbon disulfide in expired ai r in the 3 hours following dosi ng (Snyderwine and Hunter 1987). Younger rats expired signif icantly more free carbon disulfide than older rats. In another study (Dalvi and Neal 1978), intraperit oneal administration of 14 C-carbon disulfide to rats resulted in excretion of carbonyl sulfide by the lungs in grea ter quantities than carbon dioxid e. Pretreatment of rats with phenobarbital, however, resulted in a greater am ount of excretion of car bon dioxide than carbon disulfide. In both expe riments, excretion of 14 C-carbonyl sulfide and car bon dioxide accounted for 14-43% of the total administer ed 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 forme d. These may in part account for the neurotoxic effects of carbon disulfide. Formation of dith iocarbamates has been demonstrated in both in vitro and in vivo studies in these species. Metabol ism studies in animals clearly i ndicate that carbon disulfide is metabolized by two distinctly different pathways (s ee Figure 2-3): it can form dithiocarbamates and glutathione conjugates, or it canbe 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 toxi city of carbon disulfide remain to be determine d. Both metabolic pathways suggest several potential mechanisms of toxicity. Formation of dithiocarbamates may in part account for peripheral neurotoxicity. Furthermore, the none nzymatic reaction of car bon disulfide with free amino groups suggests a potential interaction with biological macrom olecules such as proteins and nucleic acids. In contrast, the formation or generation of reactive sulfur may inhibit the microsomal monooxygenase system and disturb the metabolis m 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.CARBON DISULFIDE 76 2. HEALTH EFFECTS 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-la bile carbon disulfide, readily destroyed at low pH, was also consistent with significant in vivo formation of dithiocarbamate metabolites (McKenna and DiStefano 1977a; Snyderwine and H unter 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 meta bolized to acid-labile carbon disulfide metabolites. The formation of acid-labile carbon disulfide meta bolites may continue to increase at steady-state concentrations of carbon disulfide as long as free ca rbon disulfide is availabl e 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 metabol ites continued to accumulate in several tissues after steady-state levels of carbon disulfid e were reached (McKenna and DiStefano 1977a).
The formation of the carbon disulfide metabolite, dithiocarbamate, may explain the mechanism of carbon disulfide-induced neurotoxic effects. Fo r example, McKenna and DiStefano (1977b) found a decrease in the ac tivity of copper-requiring enzyme, dopamine- β -hydroxylase, in response to increased inhalation exposure to car bon disulfide (0.1-2.0 mg/L for 8 hours) . The effect of carbon disulfide was attributed to the formation of dithiocarbamates, wh ich complex with copper, since in vitro inhibition of purified dopamine- β -hydroxylase by carbon disulfide was depe ndent on preincubation with amines capable of dithiocarbamate formation (McKenna and DiStefano 1977b). The inhibition of dopamineβ -hydroxylase decreased progre ssively 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 th e neurotoxic effect of carbon disulfide is the formation of a dithiocarbamate derivative of pyridoxamine, a form of vitamin B 6 , with carbon disulfide (Vasak and Kopecky 1967). Investig ators postulated that transaminases and amine oxidases would be inhibited because these enzymes require th e pyridoxamine phosphate form of vitamin B 6 , as a cofactor. In subsequent in vivo studies, evidence of altere d tryptophan metabolism (consistent with an inhibition of B 6 -requiring enzymes) appeared to support th is hypothesis (Abramova 1966). Furthermore, supplementation of the diet with vitamin B 6 , delayed some of the neurot oxic effects of carbon disulfide (Teisinger 1974). However, continued research coul d not detect any change in the tissue content of vitamin B 6 in rats after chronic exposure to carbon di sulfide (Okayama et al. 1988), and in a laterCARBON DISULFIDE 77 2. HEALTH EFFECTS study the authors suggested that the abnormalitie s in tryptophan metabolism caused by exposure to carbon disulfide were not related to vitamin B 6 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, kynur enine-3-hydroxylase, and kynureninase in the high-concentration group (800 ppm) were found; th is may indicate activation of the kynurenine pathway upon carbon disulfid e exposure rather than vitamin B 6 deficiency (Okayama et al. 1988).

The effects of carbon disulfide on the microsomal dr ug metabolizing system were demonstrated in rats by Freundt et al. (1975). Exposure of rats by inhalation to low con centrations of carbon disulfide (20-400 ppm for 8 hours) inhibited microsomal dr ug 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 withprotein nucleophiles resul ting 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 suggest s 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 ami nopeptidase activity in the thalamus and cerebellum of the brain (de Grandarias et al. 1992). The ro le of aminopeptidase activity in carbon disulfide neurotoxicity was postulated.
It has been postulated that carbon disulfide cardiotoxicity may be me diated 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 vesse l epithelium and changes in lipid metabolism.
It has been postulated that the reduced thyroid activity in worker s exposed to carbon disulfide may be related to a central involv ement of catecholamine metabolism (Cavalleri et al. 1978).CARBON DISULFIDE 78 2. HEALTH EFFECTS

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 re sidents near hazardous waste si tes and occupationally exposed individuals. The principal adverse health eff ects noted in humans exposed via inhalation are neurotoxic and cardiovascular e ffects (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 humandata are derived from occupational studies. Although these are somewhat limited by the difficultie s in estimating the exac t 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 a ddition, the toxicokinetic studies and the derivations of mechanisms of action are consiste nt 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 e xposure to carbon disulf ide. 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 re sponse was achieved, the effect was considered minimal since the reductions in motor nerve conditi on 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 de rived since potential MRL values would not have been as protective of human healthas the chronic-duration MRL. In addition, there is greater confidence in the chronic-durati on MRL since it is based on human data.CARBON DISULFIDE 79 2. HEALTH EFFECTS Oral

• An MRL of 0.01 mg/kg/day was derived for acute exposure to carbon disu lfide. This MRL was derived based on the inhibition of enzyme activi ties, 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 we re derived because of a lack of reliable LOAELs and a lack of definite target organs.

Death. Several epidemiology studies have reported incr eased 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 sa mpling done at different times and with different methods. Moreover, historical exposure data are l acking in most of the studies, and occupational studies frequently encompass concomitant exposures to other chemicals. However, decreased survival associated with ventricular fibr illation in rats has be en 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 di sulfide is manifested primarily as cardiovascular, hepatic, and ocul ar effects in both humans and an imals following inhalation exposure.

Respiratory Effects. Some transient respirator y 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 addr ess respiratory function changes in exposed animals. DecreasedCARBON DISULFIDE 80 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 e xposed individuals have documented an increased incidence of elevated blood pressure (E geland et al. 1992; Hernberg et al. 1971; Tolonen et al. 1979; Vanhoorne et al. 1992a). This indicates th at an elevation in bl ood pressure could be one mechanism for the adverse cardiovascular effect s of carbon disulfide. C oncomitant occupational exposure to hydrogen sulfide may be a confounding f actor. At relatively low concentrations (median 1.1 or 4 ppm) cardiovascular effect s 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 st udies on animals attest to the a dverse effects of carbon disulfide on the cardiovascular system (Antov et al. 1985; Chandra et al. 1972; Wrons ka-Nofer et al. 1980). These effects included lipid dropletinfiltration in the coronary ar teries, metabolic and structural changes in the myocardium and the aorta, and myocar dial lesions characterized by necrosis, interstitial edema, and cellular infiltrate.

Gastrointestinal Effects. Gastrointestinal symptoms are comm only 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 effect s 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). Re d blood cell and white blood cell counts were not significantly different from preemployment values in workers exposed to car bon disulfide for 5 years (Chrostek-Maj and Czeczotko 1995a).
There are limited animal data concerning hemato logical effects after inhalation exposure. No hematological effects were seen in rabbits acu tely exposed to 1,100 ppm carbon disulfide for 12 days (Briegor 1949). However, exposure to 300 ppm for 48 days resulted in signifi cant increase in pseudoeosinophils. Significant decr eases 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 elevationCARBON DISULFIDE 81 2. HEALTH EFFECTS 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 inthe liver and kidney (Beauchamp et al. 1983).

Musculoskeletal Effects. No studies were located regarding mu sculoskeletal 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 noradrena line was observed relative to the vehicle-treated controls (Gandhi and Venkatakris hna-Bhatt 1993). The response of th e 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 (M ack et al. 1974; Vanhoorne et al. 1992b). Similar changes were seen in animals without accompa nying histological evidence of liver damage (Magos and Butler 1972; Magos et al. 1973; Tsuyoshi 1959). Ho wever, hepatoxicity characterized by hydropic degeneration in parenchymal cells of the centrilobul ar 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 triglycer ides, have been seen in workers exposed by inhalation to carbon disulfide (Krstev et al. 1992; Stanosz et al 1994b; UK/HSE 1981). Serum cholesterol, phospholipid s, and triglyceride levels were significantly elevated in rats following inhalation exposure to carbon disulf ide (Wronska-Nofer 1972, 1973). One postulated mechanism involved in the toxicity of carbon disu lfide 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 othe r chemicals with carbon disulfide woul d then result from the loss of the capability to detoxify other harmful chemicals.

An acute-duration oral MRL was calculated on the ba sis of decreases in th e 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 disulfid e refer to renal effects in humans, no studies were located th at specifically address renal t oxicity (Beauchamp et al. 1983; WHO 1986). Rabbits exposed to a wide range of leve ls of carbon disulfide for 38 weeks showed anCARBON DISULFIDE 82 2. HEALTH EFFECTS 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 fi ndings in animals with regard to adverse effects in humans is not known.

Endocrine Effects. The available data in humans provide c onflicting evidence regarding the adverse effects of carbon disulfide exposure on thyroid func tion (El-Sobkey et al. 1979; Lancrajan et al. 1972; Wagar et al. 1981). Based on decreases in the ur inary 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 etal. 1994a). These studies also i nvolved 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 stud ies in rabbits in which similar blisters could be induced by carbon disu lfide 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 type s including fundus anomalies, retinal microaneurysms, retinopathy, and burning eyes have been reported inworkers occupationally exposed to carbon disulfide (DeLaey et al. 1980; NIOS H 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 c ould result in ophthalmological changes.

Body Weight Effects. A 14-day exposure to carbon disulfide ata 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 w ith 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 decrease d erythrocyte potassium and calcium levels (PinesCARBON DISULFIDE 83 2. HEALTH EFFECTS 1982). In ani m als, increased adrenal weight, hyperpl a sia of adrenal cortex, and m ild he m osiderosis 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 th e increase of arteriosclerotic lesions found in carbon disulfide -e xposed workers.

Neurological Effects. The primary target organ for carbon disulfide toxicity is the nervous system. In humans, behavioral changes, neurophysiol ogical 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 remova l from exposure; other studies have indicated no improvement. One of the major problems has been inestablishing levels of exposure associated with the onset of symptoms.
In occupational settings, exposure levels vary daily and over th e course of years. Improved technology and an awareness of the harmful effects of carbon disulfid e exposure have resulted in a marked decrease in the ambient levels in the wo rkplace from approximately 60 ppm to about 10 ppm. Concomitant exposures to other chemicals re main a problem. Animal data suggest serious neurological effects from carbon di sulfide exposure, but most of th e studies are single-dose studies using levels of carbon disulfide one to two orders of magnitude larger thanthose 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 represen t no-effect levels for neurotoxicity in humans. The mechanism of neurot oxicity appears to invo lve 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 pept ides 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 e xposure is greatly crosslinked. Externally, the nerves show sw ellings paranodally, retraction of myelin from specific nodes, and degeneration of the distal axon (especially long ones). The isothiocyanate adducts formed fromCARBON DISULFIDE 84 2. HEALTH EFFECTS dithiocarbamate adducts cause cro sslinking 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 pro ceeded 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). Th e calculated chronic-durati on 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 an alysis 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 frequent ly reported effects. In exposed women, possible disruptions of the neur ohormonal-endocrine balance necessary for normal ovarian and uterine cycles may lead to amenorrh ea, 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 increas e 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 effect s are supported by animal studies, primarily in male rodents, that report decreased sperm c ount, abnormal coital behavior, and reduced plasma testosterone (Tepe and Zenick 1984; Zenick et al. 1984). These e ffects are supported by data from intraperitoneal exposures to rats. No effects on the testicular structures we re 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 th e workplace (Bao et al. 1991), the data are inadequate to draw any definitive conclusion. The Bao et al. (1991) study was re ported as an abstract, and there was a lack of exposure analysis and dose-response assessment. Ther e are reports of congenital malformations in the offspring of rats exposed via inhalation (Tabac ova and Balabaeva 1980a), but the general finding inCARBON DISULFIDE 85 2. HEALTH EFFECTS the animal studies of developmental effects is one of increased embryotoxic ity (Lehotzky et al. 1985; Yaroslavskii 1969). In a prelimin ary study reported only in abstract form, increases in early resorptions and decreases in viab le 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 expo sures could produce effects in humans is not identifiable at this time.

Genotoxic Effects. There are some data on in vitro genotoxicity of car bon disulfide. Haworth et al. (1983) evaluated carbon disulfid e at five doses both with and without S9 activation in the Salm onella /m icroso m e assay. All results we r e neg ative. Oth e r stu d ies in Salmonella typhimurium and Escherichia coli, both with and without activation, were also negative (D onner 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, th e results are equivocal in this regard (NIOSH 1980). A response curve suggestive of carbon disulfide-induced unscheduled deoxyri bonucleic acid (DNA) synthesis was observed in human WI-38 cells, but the results faile d to meet the criteria indicative of a positive response (NIOSH 1980). Carbon disulfid e 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 monooxygena se system that suggests a requirement for microsomal activation to form a highly reactive me tabolite. Carbon disulfide wa s 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 eff ect 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 si gnificant chromosomal aberrations in the bone marrow of rats inhaling carbon disulfide for either acute or intermediate pe riods (NIOSH 1980). There are no mutagenicity data on humans exposed occupati onally to carbon disulfide, so at this time it is difficult to predict effects of carbon disulfide at the DNA level.CARBON DISULFIDE 86 2. HEALTH EFFECTS Cancer. There are no definitive data in humans or anim als 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 bi ologic 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 popul ation is very limited. A biomarker of exposure is a xenobiotic substance or its metabol ite(s), or the product of an inte raction 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 e xposure 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 biomarke rs 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 condi tions (e.g., duration and r oute 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 mi neral nutrients such as copper, zi nc, 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 r ecognized as an establ ished or potential health impairment or disease (NAS/NRC 1989). This defini tion encompasses biochemical or cellular signals of tissue dysfunction (e.g., increased liver enzyme ac tivity 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 thatthese markers are not often subs tance specific. They also may notCARBON DISULFIDE 87 2. HEALTH EFFECTS be directly adverse, but can in dicate potential health impairment (e.g., DNA adducts). Biomarkers of effects caused by carbon disulfid e are discussed in Section 2.6.2.
A biomarker of susceptibility is an indicator of an i nherent or acquired lim itation of an organism’s ability to respond to the challenge of exposure to a specific xenobi otic substance. It can be an intrinsic genetic or other characteristic or a preexisti ng disease that results in an increase in absorbed dose, a decrease in the biologica lly effective dose, or a target tissue response. If biomarkers of susceptibility exist, they are discussed in Secti on 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 th rough the lungs unchanged as carbonyl sulfide or as carbon dioxide, or it is converted to water-soluble metabolites, wh ich are excreted by the kidneys. Metabolites of carbon disulfide f ound in the urine are often utili zed as biomarkers of exposure. Sulfates, for example, are nonspecific products of the metabolism of carbon disulfide and many other compounds. Some investigators have obs erved an increase in total urin ary 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 spec ific 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 individua ls in small quantities. These measurements have not been shown to quan titatively correlate withcarbon disulfide exposure. The concentration of carbon disulfide in the feces is very low and ther efore has also not been routinely used as a biological marker of exposure (Djuric 1967).CARBON DISULFIDE 88 2. HEALTH EFFECTS 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 disu lfide exposure. More research, however, needs to be done in order to determine whether a direct corr elation exists between th ese parameters and carbon disulfide exposure.
The following paragraphs describe reasonably spec ific biomarkers for carbon disulfide exposure in humans that correlate with expos ure 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 fo r 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 refl ect 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 disulfid e exposure are further confounded by the fact that absorption and elimination rates of carbon disu lfide 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 lowe r 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. Howeve r, 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 de tection technique were used. A quadrupole mass spectrometer makes the measurement of carbon disulf ide 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 m easuring uptake that had taken place l-2 hours before the test. Carbon disulfide levels in the breathwere 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 exhale d carbon disulfide remains an equivocal biomarker of exposure.CARBON DISULFIDE 89 2. HEALTH EFFECTS Blood carbon disulfide levels may also serve as a biomarker of exposure. Data from blood tests, however, have not shown consistentcorrelation with carbon disulfide exposure levels in past studies. Blood carbon disulfide concentrati on 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 disu lfide exist in the blood. “Fr ee” carbon disulfide is unbound carbon disulfide that is still dissolve d in blood plasma; “bound” or “acid-labile” carbon disulfide refers to an appreciable amount of carbon disulf ide 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 meas urements less reliable for calculating exposure dose. Moreover, bound carbon disulfid e’s rate of release into othe r body systems may vary also. A head-space gas chromatography detect ion technique used to measure acid-labile car bon disulfide may bear investigation. Carbon disulfide levels are usua lly measured in acid-treated whole blood; however, it is suspected that the greate r percentage of carbon disulfide in the blood is bound to blood cell membranes because of its affinity for lipids and pr oteins (Campbell et al. 1985). This means that the lack of correlation of blood plas ma levels of carbon disulfide with exposure data may be due to a significant portion of the carbon disu lfide not being measured at al l as it is not in the plasma.
Some investigators have measured levels of carbon di sulfide in urine as a bi omarker of exposure, but this is probably optimal only for measuring hi gh 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. Mo reover, 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 s uggested as a marker of nerve protein crosslinking damage that leads to slower conduction velo cities and abnormal nerves due to protein adduct formation initially with dithiocar bamates which decompose to form isothiocyanate adducts (Valentine et al. 1993). These latter adducts can then cau se the actual crosslinking of both spectrin and nerve protein. As new red blood cells mu st be made to replace the damaged spectrin, the crosslinking of this protein may serve as a l onger term biomarker of carbon disulfide exposure.CARBON DISULFIDE 90 2. HEALTH EFFECTS The iodine-azide test measures possible carbon disulfide exposure, based on the decolorization of iodine in the presence of urinary carbon disulfide thiometa bolites. The iodine-azide test is a means for determining longer term carbon disulfide expo sure at air concentrations of 50 mg/m 3 (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 se nsitive test for exposure at lowe r concentrations of concern to OSHA. The iodine-azide test measures the catalysi s of the reaction between iodine and sodium azide by the following metabolites of carbon disulfide acting as biomarkers of exposure: thiourea, which is the m ain urinary thio m etabolite inv o lved in this t e st, 2-thi o - 5

- thi a zolidino n e, and a th ird un identi f i ed metabolite. The latter two chemicals are present in very small quantities and are not as important in catalyzing the iodine-azide reac tion (Beauchamp et al. 1983). However, even though exposure can be detected, the utility of such measurements is lim ited by the lack of the co rrelation between exposure and urinary carbon disulfide describe d in the previous paragraph; thatis, level or duration of exposure cannot be quantified.
Measuring the total concentrati on of urinary thio compounds (i ncluding glutathi one conjugates, mercapturic acids, and other sulfur-containing carbon disulfide metabolites) can serve as a good marker of exposure. The level of total thio co mpounds correlates with carbon disulfide exposure levels and is a more sensitive biomarker of exposur e than the iodine-azide test (Beauchamp et al. 1983; Van Doo rn et al. 1981a). This bio m arker detects an exposure to 6 ppm carbon disul f ide for 8 hours (Beauchamp et al. 1983). These compounds ar e not absolutely specific for carbon disulfide exposure.

TTCA is used as an indicator to assess the de gree 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 no t provide data on carbon di sulfide exposure levels.
In a rayon production factory, exposure to carbon disu lfide 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/m 3 (4 ppm). The study authors established a calculated biological limit value of 0.77 mg TT CA/g creatinine (0.57 mmol/mol creatinine) to correspond with 95% confidence, to a TWA air con centration lower than th e threshold limit value (TLV) of 30 mg/m 3

.CARBON DISULFIDE 91 2. HEALTH EFFECTS Measuring levels of one particul ar urinary thiometabolite of carbon disulfide may serve as an even more sensitive and specific biomarker of e xposure. TTCA, which is a product of glutathione conjugation, is quantitatively related to carbon di sulfide uptake (Beauchamp et al. 1983; Campbell et al. 1985; Drexler et al. 1994). Car bon disulfide exposure levels of 2.5 ppm and above are detected by this analytical method. Carbon disulfide exposure co rrelates 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 concentrat ions (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 br assica vegetables (e.g., cabbage) (Simon et al. 1994). Therefore, in persons who eat large amounts of these vegetables, m easurements 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 r ecommended 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 inthe urine. The iodine-azide and TTCA tests can be conducted to measure urinary levels of carbon di sulfide metabolites as they have been shown to correlate with exposure (Basel t 1980; Beauchamp et al. 1983; Campbell et al. 1985; Lieben 1974; WHO 1986), with the TTCA test being more sensit ive and specific than the iodine-azide test.
For more information concerning absorption, di stribution, metabolism, and excretion of carbon disulfide, refer to Section 2.3.CARBON DISULFIDE 92 2. HEALTH EFFECTS 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 biomar kers of effect are conf ounded by their occurrence in response to other epidemiological, nutritional, and environmental factors. Their significance as biomarkers is further reduced by th e fact that these eff ects 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 ac tual carbon disulfide exposur e and their reliability and consistency is necessary before they can be u tilized 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 ce rebral/cerebellar atrophy in humans (B eauchamp 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 con centrations following long- term carbon disulfide exposure in humans may be an appropriate indicator of ensuing arterioscleros is, clinical vasculopathy, and increased risk of cardiovascular disease (E l-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 paramete rs, however, may prove to be useful in the future. Changes have been observed in lipid metabolism when a cytochem ical enzymological examination of leukocytes andCARBON DISULFIDE 93 2. HEALTH EFFECTS platelets was carried out for over 600 exposed wo rkers (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 choles terol 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 di ets had normal serum lipid content (Lewey et al. 1941).
In exposed women, possible disruptions of the ne urohormonal-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 b een 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 su ch biomarker of renal effects may be the blood sugar level. Higher than normal blood sugar leve ls in response to car bon 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 car bon disulfide exposure on enzyme systems of carbohydrate metabolism, McKee et al. (1943) observed that the succinic-oxi dase 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 act ivity may serve as an appropriate bi omarker of nervous system effects (McKee et al. 1943).
In conclusion, the following summarizes possible correlative biological markers of early carbon disulfide poisoning: (1) electr omyographical indications of ne ural lesions; (2) decreased neuromuscular conduction velocity; (3) abno rmal 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, cardiova scular, endocrine, and reproductiveCARBON DISULFIDE 94 2. HEALTH EFFECTS

toxicity. Also, these biological markers are not specific for carbon disulfide. One or a combination of these markers may prove to be a useful biomarke r 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 disu lfide appear to be related to loss of microsomal cytochrome P-450. Carbon disulfide suppresses th e hepatic cytochrome P-450 microsomal enzyme system. Elimination of phenazone, a drug often us ed in the study of hepatic microsomal enzyme activity, is signifi cantly and reversibly inhibited in rabbi ts exposed to 193 ppm carbon disulfide for 5 hours a day, 6 days a week, for 6 months (Orzechow ska et al. 1984). It has been proposed that the active sulfur atoms released following carbon di sulfide metabolism suppre ss the cytochrome P-450 enzymes, thus inhibiting detoxifica tion of other drugs or chemicals.
The influence of carbon disulfide exposure on th e cardiovascular actions of adrenaline and noradrenaline was examined in urethane-anestheti zed 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; Klappe rstück 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 conditi on, while total lactate dehydrogenase activity was not, a change that has been associated with ad aptation 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 de velopment of cardiac arrhythmias induced either by ischemia (c oronary ligation) or by aconitin e 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 tetraethy lthiuram disulfide (TETD) produces carbon disulfideCARBON DISULFIDE 95 2. HEALTH EFFECTS 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 disulfid e exposure and ethanol inge stion indicate that, at low (20 ppm) and medium (400 ppm) levels of car bon disulfide exposure and blood alcohol levels of approximately 0.75%, there is a carbon disulfrde inhibition of aldehyde dehydrogenase with an increase in acetaldehyde con centrations in the blood. Howeve r, these increased acetaldehyde concentrations were not considered great e nough to indicate the Antabuse syndrome. The study authors asserted that the Antabuse syndrome is not likely to occur insubjects 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 isozym e of cytochrome P-450 in the metabolism of carbon disulfide has been examined (S nyderwine et al. 1988). Rats were administered various alcohols (methanol, ethanol, isopropanol, and isobutanol) by gavage. Eighteen hours after alcohol administration, rats were admini stered carbon disulfide intraper itoneally 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 th e 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 hour s 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. Additiona l studies indicate biochemi cal alterations in the central nervous system and increased β -glucuronidase activity; ultrastructural studies show degeneration in the peripheral ne rvous system, particularly in th e myelin sheath. These authors reported that the effects from combined exposures are greater than those from each substance alone. Wronska-Nofer et al. (1986) investig ated the hepatotoxicity of comb ined ethanol and carbon disulfide in the rat. Rats were chroni cally exposed to 482 ppm (1.5 g/m 3 ) of carbon disulfide 5 hours a day, 5 days a week, for 5 months and given a 10% ethano l solution as their sole source of fluids. EthanolCARBON DISULFIDE 96 2. HEALTH EFFECTS 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 re ticulum (development of giant mitochondria and degranulation of the rough endoplasmic reticulum).
An occupational epidemiological study of grain work ers indicates that ther e 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, opti c 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 tetrachlori de could not be ruled out. EPA banned the use of 80/20 carbon tetrachloride/carbon disulfide fumigants af ter 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 tetrach loride and carbon disulfide, whether given simultaneously or separated by 6 hours (carbon disulfide then carbon te trachloride), is effective in controlling liver fluke (Seawright et al. 1972). Carbon tetrachloride can be hepatotoxic in sheep; when itis administered with carbon disulfide, however, the toxicityis significantly reduced. The m echanism by which carbon disulfide protects against carbon tetrachloride toxicity in rats was investig ated by Seawright et al. (1980). Carbon tetrachloride requires microsomal metabolis m in the liver to exert a toxic effect. Carbon disulfide is effective in decreas ing microsomal metabolic activitythrough 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; th is effect increases with duration of exposure to carbon disulfide (C aroldi et al. 1987). Freundt et al . (1974b) have found that the effect of sodium phenobarbital pretreatment on rat liv er 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 phenobarb ital-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 accumu lation in the liver. Extrapolation to human beings is difficult, but the study authors asserted that the sens itivity of hepatic MFOs to carbon disulfide is similar qualitatively and quantitatively in rats and human s. 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).CARBON DISULFIDE 97 2. HEALTH EFFECTS Carbon disulfide interacts with several or ganophosphorus compounds including the insecticides malathion and parathion. Metabolism of malathion and parathion requires cytochrome P-450 and is thus inhibited by carbon disulfid e (Dalvi and Howell 1978). It is important to note that carbon disulfide would potentiate the t oxic effect of compounds that re quire cytochrome P-450 microsomal metabolism for detoxification.
Oral administration of diethylthiocarbamate and car bon 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 mi crosomal mono-oxygenase system by the thiono-sulfur groups of diethylthiocarbamate and carbon disulfide because chlorofo rm requires metabolic activation in the kidney to induce nephrotoxicity. Carbon di sulfide also protects mice from 1,2-dimethylhydrazine-induced neoplasia of th e large intestine (W attenberg 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 choles terol, choleic acid, and vitamin D2), which was used to develop the scle rotic 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 th e cardiotoxicity and enhanc ed the sclerotic process. Although changes in enzyme activity (statistical significance not repo rted) were noted, no substantial structural changes occurred in the heart muscle or aorta at the lowe st dose of carbon disulfide tested (3.2 ppm) without the atherogenic di et. Histological changes charac terized by vacuolar dystrophy and interstitial fibrosis occurred at 16 ppm carbon disulfide and became more advanced at higher concentrations (64 ppm). The study authors conclude d that carbon disulfide has an arteriogenic effect.
Carbon disulfide was reported to inhibit the mutage nic activity of 1,2-di methylhydrazine 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.CARBON DISULFIDE 98 2. HEALTH EFFECTS

2.8 POPULATIONS THAT AR E 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 car bon disulfide in the environment. Reasons include genetic make-up, developmental stage, age, health and nutritional status (inc luding dietary habits that may increase susceptibility, such as inconsistent di ets or nutritional defici encies), and substance exposure history (including smoking) . These parameters may result in decreased function of the detoxification and excretory proce sses (mainly hepatic, renal, and respiratory) or the pre-existing compromised function of target organs (including effects on clearance rate s and any resulting endproduct metabolites). For these reasons we expect the elderly with declini ng organ function and the youngest of the population with immature and developi ng organs will generall y be more vulnerable to toxic substances than healthy adul ts. Populations who are at greate r risk due to their unusually high exposure are discussed in Section 5.6, “Popul ations With Potentially High Exposure.”

There are studies that have inves tigated particular metabolic trai ts that may result in hypersusceptibility to carbon disulf ide (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 i ndustrial air limit of 20 ppm (60 mg/m 3 ) (controls), 21 who had been exposed to levels higher than 20 ppm but ha d shown no signs or symptoms of carbon disulfide intoxication (resistant), and 33 who had polyneur itis or other signs of overexposure and had been removed from exposure (susceptibles ). All individuals were administ ered an oral dose of 0.5 g of disulfiram (Antabuse), a compound that produces car bon disulfide when metabolized. It was assumed that carbon disulfide and disulfiram are metaboli zed 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 excreti on of DDC was significantly lowest in the susceptible group (49.70 μ g/mg creatinine) when compared to both the control (160.05 μ g/mg creatinine) and resistant (90.04 μ g/mg creatinine) groups. These results led to the suggestion that the reduced ability of the symp tomatic workers to metabolize this compound would lead to hypersusceptibility to carbon disulfide and w ould 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 wo rkers; thus carbon disulfide exposure produced aCARBON DISULFIDE 99 2. HEALTH EFFECTS disturbance in the metabolism of sulfur compounds. They also suggested that in the susceptible worker group this decreased metabo lic conversion appeared to persis t even 5-10 years after exposure, and thus carbon disulfide exposure may have led to an irreversible metabo lic 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 pr oblematic issue of whether it is possible to establish that a prior hype rsusceptibility existed in testing wo rkers who had been exposed for long periods of time and whose differences in metabolis m 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 pr ocess (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 invol ves 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 Antabu se), those with neuropsychic diso rders, and those with vitamin B 6 deficiency (Djuric et al. 1973; Le faux 1968; Peters et al. 1982). Car bon disulfide reduces the levels of vitamin B 6 , which in turn upsets carbohydrate metabo lism, particularly th e cerebral carbohydrates (Lefaux 1968).

2.9 METHODS FOR REDUCI NG TOXIC EFFECTS
This section describes clinical practice and resear ch concerning methods for reducing toxic effects of exposure to carbon disulfide. However, because some of the treatments discussed may be experimental and unproven, this se ction should not be used as a gui de for treatment of exposures to carbon disulfide. When specific exposures have occurred, poison control centers and medical toxicologists should be c onsulted for medical advice.CARBON DISULFIDE 100 2. HEALTH EFFECTS 2.9.1 Reducing Peak Absorption Following Exposure
There are no specific methods available to re duce the absorption of car bon 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 be en suggested for treatment of carbon disulfide ingestion. However, the use of emetics is controversial (Bronstein and Currance 1988; Stutz and Janusz 1988). If contamination occu rs 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 ha s been recommended to inactivate free carbon disulfide in the blood; intravenous admi nistration of large doses of vitamin B 6 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 (S oucek 1957). Therefore, increasing ventilation and urinary output may be potential methods to facili tate mitigation of the e ffects of carbon disulfide. However, such methods have not been attempted w ith regard to carbon disu lfide within a clinical setting. Removing the patient from the contaminated area followed by supportive care is the suggested basic form of treatment (Bronstein and Curranc e 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). Al though phenobarbital pretreatment of rats can enhance the metabolism of carbon di sulfide (Dalvi and Neal 1978), it can also enhance the hepatic toxicity of carbon disulfide. Another metabolic pathway for carbon disulfid e is its conjugation with glutathione to form 2-thiothiazo lidine-4-carboxylic acid and 2-oxothi azolidine-4-carboxylic acid,which are excreted in the urine (Van Doorn et al. 198l a, 1981b). Although the extent to which glutathioneCARBON DISULFIDE 101 2. HEALTH EFFECTS conjugation plays a role in the metabolism of car bon disulfide is unclear, it is conceivable that administration of cysteine may be utilized in the mitigation of the e ffects 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 di sulfide. 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 coppe r 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 choleste rol increase, adrenal hypertrophy, and pathological changes in the brain and spinal cord-that appeared in contro ls on a normal salt diet (ACGIH 1986). A proposedbiochemical 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 interm ediates resulting from the meta bolism of carbon disulfide by the hepatic MFO system may be involved in the hepatoxic ity of this chemical. Pr etreatment of rats with phenobarbital, an inducer of MFO activity, can enhance carbon disulfide-induced hepatotoxicity (Bus 1985). Inhibition of the MFO system might potentiall y reduce carbon disulfide- mediated hepatoxicity. In support of this possibility, Bond and De Matteis (19 69) reported that pretreatment of rats with SKF525A, an inhibitor of cytochrome P-450-mediated metabolism, reduced the liver damage from carbon disulfide in phenobarbit al-pretreated animals.
Two possible mechanisms for the neurotoxicity of carbon disulfide have been suggested. One mechanism involves the formation of dithiocarbamat es. 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 (McKe nna 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 altern ative mechanism postulated to explain the neurotoxic effect of carbon disulfide is the formation of a dithio carbamate derivative, a form of vitamin B 6 , ofCARBON DISULFIDE 102 2. HEALTH EFFECTS pyridoxamine, with carbon disulfide (Vasak an d Kopecky 1967). Since transaminases and amine oxidases require the pyridoxamine phosphate form of vitamin B 6 as a cofactor, it was further postulated that these enzymes w ould be inhibited in carbon disu lfide poisoning. Although data are limited, supplementation of the diet with vitamin B 6 has been demonstrated to delay some of the neurotoxic effects of car bon 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 Se rvice) to assess whether adequate information on the health effects of carbon disulfide is avai lable. Where adequate information is not available, ATSDR, in conjunc tion with the National Toxicology Program (NTP), is required to assure the initi ation of a program of research designe d to determine the health effects (and techniques for developing methods to determin e 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 substanc e-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 rese arch 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 e ffects of carbon disulfide. Each do t in the figure indicates that one or more studies provide information associated with that particular effect. The dot does not necessarily imply anything about th e 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 Pr ofiles (ATSDR 1989), is substance-specific information necessary to conduct comprehensive public health assessments. Generally, ATSDR defines a data gap more broadl y as any substance-specific information missing from the scientific literature.CARBON DISULFIDE 104 2. HEALTH EFFECTS 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 potentia l 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 prim arily 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 th e 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; Tarkow ski 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 reporte d in acute studies. The acute studies have been done primarily in rodents; additiona l studies on other species, for ex ample, primates, would be useful for generalizing to expected heal th effects in humans. No acute-duration inhalation MRL was derived since potential MRL values would not have been as protective of humanhealth as the chronic-duration MRL. In addition, there is greate r confidence in the chronic-duration MRL since it is based on human data.CARBON DISULFIDE 105 2. HEALTH EFFECTS Three case reports cited in Gosselin et al. (1984) indicate that half anounce (concentration not specified) caused death following ingestion. Ther e are no other human data on acute-duration oral exposure to carbon disulfide. There are sufficient an imal 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 e xposure to carbon disulfide. Advers e effects including decreased body weight gain (Jones-Price et al. 1984b), hind-lim b paralysis (Jones-Pric e et al. 1984b), decreased norepinephrine levels (Kanada et al. 1994), and developmental eff ects have also been reported. An acute-duration oral MRL of 0.01 mg/kg/day was de rived 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 applie d to the skin (Hueper 1936). Given that there is a possibility of dermal e xposures in occupational se ttings as well as from contaminated water supplies near hazardous waste si tes, additional data on dermal exposures would be useful. No pharmacokinetic data ex ist that show that dermal expos ures to carbon di sulfide result in patterns of distribution similar to those seen with inhalation or or al exposures. These kinds of data would be useful for projecting the similarities of target organs across rout es as people near hazardous waste sites may be exposed by all three routes.

Intermediate-Duration Exposure. There are no human data on inte rmediate-duration inhalation exposures. Most occupational exposur es are considered to be chro nic-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), th e cardiovascular system (Antov et al. 1985), and the liver (Jarvisalo et al. 1977a; Tsuyos hi 1959; Wronska-Nofer 1972, 1973) as targets for intermediate-duration inhalation exposure to car bon 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 effect s 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 andCARBON DISULFIDE 106 2. HEALTH EFFECTS Balabaeva 1980b; Tabacova et al. 1983; Yaroslavskii 1969) are also targets fo r intermediate-duration inhalation exposures. Lethality (Toxicogenics 1983c), decreased body weight (Rebert and Becker 1986), and hematologic (Toxicogenics 1983c) and musc uloskeletal (Szendzikowsk i et al. 1974) effects have also been reported in intermediate-duration inhalation studi es. No intermediate-duration MRL was derived since potential values would not have b een as protective of human health as the chronic duration MRL. There are very few data on intermed iate-duration oral exposur es (Pilarska et al. 1973) and no data on intermediate-duration dermal expos ures. 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 identificati on 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-Ande rson 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; Lieb en 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 Tolone n 1975; Raitta et al. 1974; Szymankova 1968) as primary targets for inhalation exposure to carbon di sulfide. 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 ev aluates nerve conduction velocity in workers exposed by inhalation to car bon disulfide, has been found acceptable for the derivation of a chronic-duration MRL. There is onl y 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-eff ect 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 point s could be used to determine the neurotoxic mechanism of action.CARBON DISULFIDE 107 2. HEALTH EFFECTS There are no data suggesting anincreased risk of cancer fr om exposure to carbon disulfide. Epidemiological data have been presented that in dicate 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, mu ltichemical 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 larg e population sample with better exposure data covering a minimum of 20 years would be helpful for a ddressing the repeatability of these findings. There are no stud ies regarding cancer in humans following oral or dermal exposure. In addition, there are no studies re garding cancer in animal s via inhalation, oral, or dermal routes of exposure. A chronic animal bioassay would provid e 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 m echanism for the observed reproductive effects and, if correlated with e xposures, could offer a potential bi omarker of effect. This would provide some way of monitoring populati ons 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 (Donne r et al. 1981; Hadenstedt et al. 1979). Additional bacterial a ssays 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 re productive system in both males and females. In males, sperm morphology, hormone levels, and libido have beenaltered by occupationa l exposure to carbon disulfide (Lancranjan 1972; NI OSH 1983; Schrag and Dixon 1985; Vanhoorne et al. 1994; Wagar et al. 1981; Wyrobek 1983). In human females, menstr ual irregularities have been associated with inhalation exposure to car bon disulfide, although more serious eff ects such as increased miscarriage and reduced fertility have not been universallynoted (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 inha lation exposure only (Tepe and Zenick 1984; ZenickCARBON DISULFIDE 108 2. HEALTH EFFECTS et al. 1984). Additional reproduc tive studies on other species, such as mice, rabbits, dogs, and monkeys, would be useful to determine the dose-e ffect relationship between exposure and reproductive end points. It would also be usef ul 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 th at support an increased rate of congenital malformations in childre n born to mothers exposed by any r oute to carbon di sulfide (Bao et al. 1991). Limitations of the Bao etal. (1991) study included the lack of exposure analyses and dose response assessments. There are data on rodents th at suggest an increased fetotoxicity following inhalation exposure to carbon disulfide (Tabacova and Bala baeva 1980b; Yaroslavskii 1969). In addition, neurobehavioral e ffects have been reported in the o ffspring of exposed animal mothers (Lehotzky et al. 1985; Tabacova et al. 1983). Additio nal data from species other than rodents, for example, monkeys, would be useful for verifying th at 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 eviden ce that carbon disulfide cancross 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 exposur es show that a dose-response re lationship would be useful for determining the dose at which developmenta l effects could be expected to occur.

Immunotoxicity. There are no data that suggest that th e immune system is a target for carbon disulfide exposure for any route or in any species. However, the resu lts of one study indicated that the β -lipoprotein isolated from carbon disulfide expose d-workers (presumably e xposed via inhalation) is antigenically identical to lipoproteins isolated fr om healthy nonexposed controls (Bobnis et al. 1976). There are no studies regarding immunological/lymphor eticular effects in humans following oral or dermal exposures. Also, there are no studies c oncerning immunological/lymphoreticular effects in animals following inhalation, oral, or dermal e xposures. 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 coul d 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 inhalati on route. There are behavioral (e.g., depression, decreased performance and memory), histopathol ogical (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 To lonen 1974; Seppalainen et al. 1972; Vasilescu 1976). The results of inhalation to xicity studies in animals have revealed neurophysiological (e.g., decreased nerve conduction velocity), neurochemical (e.g., altere d 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 chroni c-duration inhalation MRL was calculated on the basis of reduced motor nerve conduction velocity in humans (J ohnson et al. 1983). There are no human data pertaining to neurolog ical effects following oral or de rmal exposures. There are limited animal data on neurotoxic effects (hind-limb paraly sis) by the oral route (Jones-Price et al. 1984a, 1984b), and none for the dermal route (Dietzmann and Laass 1977). Studies i nvestigating neurotoxic effects in animals following oral or dermal exposur e 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. Thes e 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; He rnberg 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 Ba o 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 associati ons between carbon disulfide exposure and adverse health effects. These findings are not universal, however. The ep idemiological studies have the limitation of poor exposure measurements that ar e 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 componentsCARBON 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 th e 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 leve ls of carbon disulfide that have been associated with adverse health effects. The bi ggest 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 chemical s, and long-term follow-up of occupational cohorts may lead to a better understanding of the dose-e ffect of carbon disulfide. Monitoring of populations around hazardous waste sites where car bon disulfide is known to be pres ent 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 (Beauch amp et al. 1983; Campbell et al. 1985). These measurements can indicate whether acute-, interm ediate-, or chronic-dur ation exposure to carbon disulfide has occurred. The presence of carbon disu lfide in various biological media is the most specific biomarker of exposure. However, few studies have been able to dem onstrate 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, br eath, and urine of exposedindividuals, rendering these biomarkers somewhat unreliable for quantitative evaluation. The second possibility is that the limitations of the protocols and analytical me thods 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 neces sary in order to assess this possibility.
At the present time, the biomarkers that correlate be st with exposure are metabolite levels in the urine (Baselt 1980; Beaucham p et al. 1983; Cam pbell et al. 1985; Lieben 1974i ; W HO 1986). The iodineazide and the TT CA tests, which m easure the p r esence of urinary carbon disulfide m etabolites, haveCARBON 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 e xposure to Antabuse and in rats after exposure to Captan (Cox et al. 1992). Moreover, other investigations are necessaryin order to determine whether the interaction of carbon disulfide with other s ubstances (such as hydr ogen sulfide, drugs, carbon tetrachloride, malathion, and alcohol), disease stat es, and variations in diet and in individual

m etabolis m , as well as other factors, could confound the results of the iodine -azide test and the TT CA 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 beenidentified for carbon disulfide. However, many biological parameters have been tentatively linke d with carbon disulfide’s effects on certain enzyme systems, on the liver and the kidneys, and on the ne rvous, cardiovascular, repr oductive, 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; Lanc ranjan 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 ne rvous system effects (Beauchamp et al. 1983; WHO 1981). High serum lipid content (in particular choleste rol) may be linked with cardiovascular effects (El-Sobkey et al. 1979; Lewey et al. 1941; Prer ovska 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 a l 1971; Lewey et a l . 194 1 ). Changes in various enzym e syste m s (for

exam ple, lowered succinic-oxidase activity) m ay prove useful as bio m arkers of effect (McKee et al. 1943). The effect of carbon disulfide on m e m b rane spectrin of nerve and blood m e m branes should be investigated further (Val entine et al. 1993). However, changes inthese biological parameters are not specific to carbon disulfide exposure, and future studies are needed to determine the extent to which they quantitate the resu lts of carbon disulfide exposure. In addition, these studies should evaluate whether such biological parameters may serve as re liable and accurate biomarkers of carbon disulfide exposure. However, since many different things cancause these effects, biomarkers may never beCARBON 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 disu lfide 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 Seawri ght 1973; Djerassi and Lumbroso 1968; Djuric 1967; Fre undt 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; Strittm atter et al. 1950; Teisinger 1974; Van Doo rn et al. 1981a, 1981b; Vasak and Kopecky 1967). Data indi cate rapid and extensive absorpti on of inhaled carbon disulfide, distribution through the body, and primary excreti on by exhalation. Carbon disulfide is metabolized by cytochrome P-450 to an unstable oxygen intermediate that in turn can eitherdegrade to sulfur and carbonyl sulfide or hydrolize to su lfur and monothiocarbamate. Biotransformation of carbon disulfide in humans exposed by the inhalation route causes TTC A, OTCA, and thiourea to be excreted in the urine, and carbonyl sulfide and carbon dioxide in th e 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 pharmacokine tics of carbon disulfide following oral or dermal exposure, making an assessment of relative rate s very difficult (Cohen et al. 1958; DeMatteis and Seawright 1973; Dutkiewicz and Baranowska 1967). Th e limited data indicate that a range fraction of orally administered carbon disulfide is absorbed by rats. Carbon disulf ide 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 ex cretion of carbon disulfide, with less exposed individuals retaining more of the chemical than chronically exposed individuals (Beauchamp et al. 1983). Additional information regarding the pharmac okinetics 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 accep ted (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 acros s species (Cohen et al. 1958; DeMatteis and Seawright 1973; Dutkiewicz and Baranowska 1967; Freundt et al. 1975; McKee et al. 1943; Soucek 1957; TeisingerCARBON 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 st udies and those from human studies were noted except that sulfate excr etion is far more important in animals than in humans except in the latter for exposure to high doses of carbon disulfid e (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 studie s. The volatility of carbon disulfide may well affect kinetic parameters measur ed in dermal exposures, and metabolic parameters following oral exposures c ould 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 sodi um 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 ne rvous 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 need ed before insights may be gained regarding treatment of exposure victims.

2.10.3 On-going Studies
No studies of carbon disulfide were reported in th e Federal Research in Pr ogress 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 result s in a sister chromatidCARBON 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 Res earch 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 othe r 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 effect s of carbon disulfide on the cardiovascular system in rats.CARBON DISULFIDE 115
3. CHEMICAL AND PHYS ICAL INFORMATION

3.1 CHEMICAL IDENTITY
The chemical identity of carbon di sulfide 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 comm ercially 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, inthe 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% pur e with a trace ben zene contaminant) (Sax and Lewis 1987; Timmerman 1978) and in alkali (thio carbonates) 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 th e viscose rayon industry, one of its largest users (HSDB 1995; Mannsville Ch emical 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 ri se 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; Ti mmerman 1978). In 1985, production was estimated to be 143,000 metric tons (Mannsville Chemical Pr oducts 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 leve ls 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 (T R I 93 1995). For additional inform ation on co m panies that manufacture or process carbon disulfide, re fer to Table 4-l. According to the 1993 Toxics Release Inventory (TRI), 80 fac ilities manufactured or processe d carbon disulfide in 1993, 9 fewer than in 1991 (TR I 93 1995). Seventy-n i ne (79) of these facilities reported the m a xi m um amount of carbon disulfide that they would have on site. Th ese data are listed in Table 4-l. The TRI data should be used with caution since only certain types of facilities are require d 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 manufactur ers in 1977 was 911,000 metric tons.

4.2 IMPORT/EXPORT
Imports of carbon disulfide have fallen at a fair ly 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 co ntinued to decline to 450 metric tons in 1983 and then rose to 1,400 metric tons in 1984 (Mannsvi lle 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 ab ility to solubilize fats, rubbers, phospho rus, 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 re placed by another chemical. Carbon disulfide’s fat solvent properties also made it i ndispensable 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 appl ications including the following: vulcanization and manufacture ofCARBON DISULFIDE 124 4. PRODUCTION, IMPORT, USE, AND DISPOSAL rubber and rubber accessories; production of resins, xanthates, thiocyanates, plywood adhesives, and flotation agents; solvent and sp inning-solution applications prim arily in the manufacture of rayon; polymerization inhibition of vinyl chloride; conversion and proc essing of hydrocarbons; petroleumwell cleaning; brightening of precious metals in el ectroplating; 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 wast e 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 developm ent restrainer in photography and lithography, and as a solvent to remove printing on recycled plastics (Timmerman 1978).
Carbon disulfide’s most important industrial use, how ever, has been in the manufacture of regenerated cellulose rayon by the viscose proc ess (viscose rayon) and of cell ophane (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 greate st fraction of carbon disulfide production (Mannsville Chemical Pr oducts Corp. 1985). Since 1989, the consumption of carbon disulfide in the production of carbon tetrachlo ride has increased to 38%, while the rayon industry’s consumption has dropped to 34% (HSDB 1995).
Another principal industrial use fo r carbon disulfide has been as a feedstock for carbon tetrachloride production (Mannsville Chemical Products Cor p. 1985; NIOSH 1977; Timmerman 1978). While only 10% of U.S. carbon disulfide production was us ed to produce carbon tetrachloride in 1960, this increased to 32% in 1974, largely b ecause of a rapid incr ease 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 disu lfide produced was used to manufacture carbon tetr achloride (HSDB 1995).
In the food industry, carbon disulfide has been used to protec t fresh fruit from insects and fungus during shipping, in adhesives for food packaging, and in the solvent extraction of gr owth inhibitors (Timmerman 1978).CARBON DISULFIDE 125 4. PRODUCTION, IMPORT, USE, AND DISPOSAL In agriculture, carbon disulfide has been widely used as a fumigant to contro l 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). Car bon disulfide is used extensively in research laboratory chemical synthetic s methods (Dunn and Rudolf 1989).

In 1989, the estimated distribution of carbon disulfid e utilization was as follows: 34% of production went to manufacture viscose rayon, 6% to produce cellophane, 38% to pr oduce carbon tetrachloride, 7% to produce rubber chemicals, and 15% to produ ce pesticides and to so lubilize 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 fo r which the demand has declined and for which alternate production processe s may be found (HSDB 1995; Mannsville Chemical Products Corp. 1985; Timmerman 1978). Unless subs titutes for carbon disulf ide are found, its use levels may depend largely on relative import and e xport 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 flamma ble liquid that bums to produce carbon dioxide and sulfur dioxide. Therefore, it is a good candidate for controlled inci neration, provided that a su lfur dioxide scrubber is used. Some methods proposed by the EPA (HSDB 1995) include liquid injec tion 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 inci neration at a temperature range of 450-980°C. Carbon disulfide can be removed from waste water by air strippi ng (HSDB 1995). Adsorption to activated coal with hydrogen sulfide in the absence of free oxygen yields a process that canregenerate large percentages of sulfur for reuse (HSDB 1995). It is not recomme nded 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 EP A 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 disu lfide in the environment is related to its use as an industrial solvent and chemical intermediate. Releases from industrial processes are al most 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 be en detected at generally low levels in ambient air, surface water, groundw ater, drinking water, food products, and human milk. Concentrations in environmental media are greate st near source areas (e.g., industrial point sources, oceans and marshes, volcanoes).

Inhalation of carbon disulfide in wo rkplace 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 l east 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 disulfid e. As more sites are evaluated by EPA, this number may change. The frequency of these sites w ithin 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 A m endments and Reauthorization Act (SARA), Section 313, Toxics Release Inventory (TR I 93 1995), an esti m ated tot a l 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 es timated 2,805 pounds that were released through underground injection. The TRI data must be viewed with caution, however, si nce 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 sour ces of carbon disulfide, includi ng wetlands (Hines et al. 1993), oceans (Chin and Davis 1993), and mi crobial activity in soils (Banwart and Bremner 1975; Kanda et al. 1995). The quantity of carbon disulfide emitted fr om such natural sources as volcanic and geothermal activity is not known but is thought to be small comp ared 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 cross link rubber during the vulcanization process may account for the carbon disulfide re leased from ground tire treads in laboratory experiments (Pos and Berresheim 1993). Automotive tire wear has been s uggested as a potential source of atmospheric carbon disulfide. Currently, th e largest single use of car bon disulfide is in the viscose rayon industry. For every kg of viscos e 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 de gradation 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 se wage treatment plant (Ruby et al. 1987).

Point sources of carbon disulfide incl ude 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 po llution sources in the nor theastern United States (Cooper and Saltzman 1993).
According to TR I 93 (1995), an esti m ated total of 93,271,722 pounds of carbon disulfide, am ounting to 99.9% of the total environmental release, was discharged to the air from manufacturing and processing facilities in the United States in 1993 (TR I 93 1995) (see Tabl e 5-l). The data listed in TRI should be used with caution si nce only certain types of f acilities are required to report.CARBON DISULFIDE 132 5. POTENTIAL FOR HUMAN EXPOSURE Carbon disulfide has been detected in the magmatic gas over volcanoes, duri ng the aging of roasted coffee, during the pressure cooking of grain-water mi xtures, as a volatile constituent in the vapor of burning cigarettes, and in the vapo r 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 disulf ide were consistently detected insamples collected from the same area using a slightly modified procedure (Hines et al. 1993). Ba sed on their measurements and

assum ptions in the study of sulfur e m issions f r om a North Carolina salt m arsh, Aneja et al. (1980) esti m ated that carbon disulfide produced by m arshes (0.022 g sulfur/m 2 per year) contributes less than 0.07% of biogenic sulfur and less th an 8% to the stratospheric aero sol 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 severa l plant/soil systems using a flux chamber. The study was designed so that emissions fr om 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 system atic investigation could accurately measure the contributions of a number of sulf ur compounds under varying conditions.

5.2.2 Water
According to TRI, an esti m ated total of at least 34,169 pounds of carbon disulfide, am ounting to 0.04% of the total environmental release, was discharged to water from manu facturing and processing facilities in the United States in 1993 (TR I 93 1995) (see Table 5-l). In addition, an esti m ated total of 226,215 pounds, am ounting to 0.24% of the total envi r onm ental release, was discharged to publiclyCARBON DISULFIDE 133 5. POTENTIAL FOR HUMAN EXPOSURE
owned treatment works. The TRI data should be used with caution sin ce 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 μ g/L in groundwater samples collected from only 1 of 19 municipal solid waste landfills ex amined 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 cons tructed in a surficial a quifer 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 disu lfide was found in six of the effl uents at concentrations less than 10 pg/L and in two of the effluents at l0-100 μ g/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 fo r which testing was done (Hwang et al. 1995).

5.2.3 Soil
According to TRI, an estimated to tal of at least 8 pounds of carbon disulfide was discharged to soils from manufacturing and proces sing 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 regardi ng releases of carbon disulfide to so ils. Fain et al. (1987) reported 0.9 mg/L carbon disulfide (dry weight basis) in a typical refineryoily 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 th e environment as a result of industrial activity are expected to be primarily to the atmosphere. Any carbon disulfide re leased to surface waters in effluent streams is expected to partition rapidly to th e atmosphere as a result of the hi gh ratio of vapor pressure to the solubility (Henry’s law constant = 1.01x10 -2 atm • m 3 /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 disu lfide from water onto sediments, it is not expected to be removed si gnificantly from the aquatic phase through adsorption. The low K oc value, calculated from water solubilitydata, 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 adsorp tion studies, they classi fied carbon disulfide as a mobile solvent exhibiting a low tendency to be re tained by soils. Carbon disu lfide released to soils in spills should rapidly volatilize to the atmos phere, but a portion of the compound remaining on soil surfaces could be available for transport into groundw ater since it does not have much affinity for soil particles. Farwell et al . (1979) indicated that ca rbon disulfide volatilizes fr om 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 2.94X10 3 ) were calculated from solubility and K ow , (log K owis 2.16) data. The calculated values, 6.8 and 25.8 respectively fo r solubility and K owdata, indicate that carbon disulfide will not significantly bi oaccumulate 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 hydr oxyl radicals in the troposphere to produce carbonyl sulfide (Cox and Sheppard 1980). The lifetime of car bon disulfide in the troposphere, assuming a reaction rate constant of 4.3x10 -13 cm 3 molecule -3 , is =73 days (uncertain); other es timates (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 labor atory were identified as carbon monoxide, carbonyl sulfide, sulfur dioxide, and a polymer th at 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. EP A (1978a) stated that th e information available indicated that carbon disulfide is relatively persistent in the atmo sphere. For the atmospheric oxidation of carbon disulfide to sulfur dioxide, car-bony1 sulfide, and car bon monoxide, the half-life was estimated to be about 12 days.
According to Wine et al. (1981), electronically ex cited 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 yiel d 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 suggest ed to occur by a hydroxyl radical reaction, or an oxygen atom reaction but not by dissoci ation (Khalil and Rasmussen 1984).

Based on the estimates of a lifetim e in the troposphere for carbon di sulfide on the order of weeks and the troposphere to stratosphere turnover time on th e order of years, very little tropospheric carbon disulfide is expected to be trans ported 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 hydroly sis 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 volatili zation 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 withits volatilization from surface waters.

5.3.2.3 Sediment and Soil

No data were found in the avai lable literature on the biodegrad ation of carbon disulfide in soil. However, since the chemical is rapidly volatili zed (high Henry’s law cons tant) and probably highly mobile in soil (low K oc ), it is unlikely that it remains inthe 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). Oxid ation of carbon disulfide by a Thiobacillus species isolated from so il 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 tr illion (ppt) in 61 rural samples and at 65 ppt in 88 urban/suburban air samples collected by Brodz insky and Singh (1983). Carr oll (1985) sampled air in the vicinity of San Juan, Puerto Rico; Al bany, 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 di sulfide. 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 mars h, about 100 ppt above a freshwater marsh, andCARBON 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 Pa cific 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 A tlantic (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 con centrations three to four times higher than upwind (background) levels (Marquardt 1987). The maximum concentration of carbon disulfide measured in samples from ei ght solid waste composting facilities was 150 μ g/m 3 (0.05 ppm) (Eitzer 1995).

Breath and air collected atsites in and around New York City we re measured for carbon disulfide by Phillips (1992). The group tested consisted of f our 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 de tected 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 bl ood 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 of f the coast of Ireland showed carbon disulfide present at every location, with the high est 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 andCARBON DISULFIDE 140 5. POTENTIAL FOR HUMAN EXPOSURE Sonzogni (1986) reported on an anal ytical survey of municipal and private groundwater sources in Wisconsin in which carbon disulfide was found in tw o private wells at con centrations lower than 830 μ g/L (the published health advisory level). Car bon disulfide was also f ound in borings on the site of a landfill in Jacksonville, Flor ida (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 μ g/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, meta l, and plastic manufacturing plants are adjacent to the lake (the highest level detect ed was 3.9 mg/L). Carbon disulfide was also found in the Niagara River at 25 μ g/L. Kaiser and Comba (1983) measured levels as high as 25 μ g/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 so ils. 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 disu lfide 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 disu lfide in dried legumes. In a study of fumigant residues in foods , Daft (1987) reported finding car bon 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 tetr athiocarbonate may be converted to carbon disulfide after appl ication 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 sp ecies emitted in oil shale off-gases were measured (Sklarew et al. 1984). The c oncentration of carbon disulfide ranged from 8 to 28 ppm. TheyCARBON DISULFIDE 141 5. POTENTIAL FOR HUMAN EXPOSURE concluded that strategies for the use of oil shal e 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) identi fied carbon disulfide at low levels (less than 1 μ g/L) in fire gas emissions from the combustion of wool. Exposures at this level do not usually re sult in significant body concentration of carbon disulfide.

5.5 GENERAL POPULATION AN D OCCUPATIONAL EXPOSURE
Exposure to carbon disulfide is pr imarily confined to occupationa l 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 disu lfide outside the workplace or th e effects on the general population. Teisinger and Soucek (1949) reported that, in spite of consider able variation among individuals, absorption seems to be proportional to the concentr ation of carbon disulfide in inhaled air. Assuming an inhalation intake of 20 m 3 air/day, and concentrations in urban and rural air of 65 ppt and 41 ppt, respectively, the average da ily intake of carbon disu lfide 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 con centrations to result inmeasurable uptake (WHO 1979). However, in a study that compared 70 childrenliving 400 meters from a factory discharging carbon disulfide into the atmosphe re with a control group of 30 ch ildren living 15 km from the factory, physical examinations did not show any he alth disorders in the exposed group even though urine concentrations of carbon di sulfide 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

co m pany were m onitored with charcoal tubes for carbon disulfide (Vanhoo rn e et al. 1991). The geometric mean for carbon disulfide ranged from 3.67 mg/m 3 (1.17 ppm) to 147.23 mg/m 3 (47.11 pp m ) (Vanhoo rn e et al. 1991). Eighty-nine perce nt of the job classificat ions studied exceeded the present TLV for carbon disulfide of 31 m g /m 3 (10 pp m ) (Vanhoo rn e et al. 1991). Typically, workers are simultaneously exposed to both carbon disulfide (4-l 12 mg/m 3 ) and hydrogen sulfide (0.2-8.9 m g/m 3 ) (Vanhoo rn e et al. 1995). Various studies throughout the world (see Table 5-4) indicate that there has been a re cent decline in personal exposure of workers in Western countries to carbon disulfide, but in the Far Ea st and Eastern Europe (Rigterink 1988) exposure to carbon disulfide of workers is still substantial.
According to the National Occupational Exposur e Survey (NOES) conducted by NIOSH from 1980 to 1983, an estimated 44,438 workers, including 4,881 wo men, were potentially exposed to carbon disulfide in the workplace in 1980. The NOES databa se 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 unspec ified levels in all eight samp les 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 μ g/L and found that carbon disulf ide was still present in the milk after a month or more away from the factory.

5.6 POPULATIONS WITH POTEN TIALLY HIGH EXPOSURES
Human exposure to carbon disulfide is expected to be highest among certainoccupational groups (e.g., rayon plant workers). In addition, members of th e general population living in the vicinity of industrial point emission sources are exposed to higher than bac kground 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 di sposal sites. No information was found regarding the number of people potentially expos ed in the vicinity of hazardous waste sites. However, since carbon disulfide has been found n ear 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 exposur e to carbon disulfide who lived close enough to the plant to be expose d to elevated levels at home as well, particularlyif that worker was in poor health from other causes (e.g., smoki ng, 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 avai lable. Where adequate information is not available, ATSDR, in conjunction w ith the NTP, is required to assure the initiation of a program of research designed to determin e the health effects (and techniques for developing methods to determine such healtheffects) 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 substanc e-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 rese arch 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; NIOS H 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; Ti mm e rm an 1978; TR I 93 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 uncerta in because of a long-term decline in the demand for viscose rayon and cellophane and restrictions on the use of fluoroc arbon propellants, it is expected that the demand for this chemical in many other specia lty 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 in formation is needed on the disposal of carbon disulfide. Current disposal methods include liquid injection incineration, rotary kiln incineration, fluidized be d incineration, and air stripping (HSDB 1995), however, data on the efficiency of these methods are lacking. This info rmation 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 Commun ity Right-to-Know Act of 1986, 42 U.S.C. Section 11023, industries are required to submit substance releas e 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 e nvironment as a result of industrial activity are expected to be primar ily to the atmosphere. Carbon disulf ide volatilizes from a variety of soils (Farwell et al. 1979). Carbon disulfide reacts w ith 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 environm ental conce rn (pH 4- 10 ), with a hydro l ysis half-life at pH 13 of about 1 year (EPA 1976). No data are availabl e concerning the biodegradation of carbon disulfide in soil. Concerted efforts should be made to meas ure the spatial and tempor al variations in the atmospheric levels of carbon disulfide in the vici nity of specific point or nonpoint sources. Although volatilization is the primary fate of carbon disulfide released to th e 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 disulf ide in surface and groundwater could be useful in determining the persistence of low levels of the compound in the e nvironment. Additional information on the transport and transformation of carbon disulfide in soils, partic ularly on biotransformation, would also be useful.CARBON DISULFIDE 146 5. POTENTIAL FOR HUMAN EXPOSURE Bioavailability from En vironmental Media. Carbon disulfide is absorb ed 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 fo llowing ingestion of contaminated soils and groundwater or foods grown with contaminat ed water. This information would be useful in determining the importance of these routes of exposure.

Food Chain Bioaccumulation. An estimated bioconcentration factor (BCF) of 2.94x10 3 was calculated from solubility and K owdata. Based on these data, car bon disulfide does not significantly bioaccumulate in aquatic organisms. Although it is generally accepted that carbon disulfide does not bioaccumulate because of its rapid metabolism (EPA1986b), the data are insufficient to determine the bioconcentration and biomagnification of carbon disu lfide at various levels in the food chain. This information would be particularly useful in determ ining 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 beenconducted (Bandy et al. 1993b; Brodzinsky and Singh 1983; Carroll 1985; Cooper and Saltzman 1993; Mar oulis and Bandy 1980; Marquardt 1987), but site specific concentration data for ambient air, drinking water, and biota, particul arly at hazardous waste sites, are lacking. These data woul d be helpful in estimating the e xposure 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, estim ates of human intake from various media would be helpful in assessing human exposure for carbon disu lfide for populations living near hazardous waste sites.
Reliable and current monitoring data for the leve ls 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 th e 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 ur ine, 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 elim ination of carbon disulfide, these fluid and breath levels do not correlate well with environmental levels, except for the urinary marker, 2-thiothiazolidine-4-carboxylic ac id. In addition, the interaction of carbon disulfide with other potential confounders may affect th e reliability of urinary metabol ites 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 popul ations living near hazardous waste sites.

Exposure Registries. No exposure registries for carbon disu lfide 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 informati on 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 th ese compounds in the general population.
The data generated as a result of the remedial i nvestigation/feasibility studies of the 200 NPL sites known to be contaminated with carbon disulfide s hould 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 analyt ical methods that are avai lable 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 identif y well-established methods that are used as the standard methods of analysis. Many of the analytical methods used fo r environmental samples are the methods approved by federal agencies and organizations such as EP A 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, an d/or to improve accuracy and precision.

6.1 BIOLOGICAL SAMPLES
A limited number of analytical techniques have b een 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 chromat ography (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 environm ental air with a detec t ion sen s itivity capab le of 7.61 x 1 0 -2 μ g/m 3 (2.44 x 10 -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 s ubsequent chromatography (Phillips 1992).
Gas chromatography equipped with a flame ionizati on detector (FID) and quadrupole MS have been employed for measuring carbon disulf ide concentrations in the breath of workers following exposure to carbon disulfide (Campbell et al. 1985; Wells and Koves 1974). The MS t echnique is rapid and requires no sample preparation (Campbell et al. 1985). A detection limit of 1.6 ppb (5 μ g/m 3 ) ofCARBON DISULFIDE 153 6. ANALYTICAL METHODS carbon disulfide in air was achieved using this t echnique. 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 μ g/rnL levels of free and acid-labile (chemically bound) carbon disulfid e 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 wo rkers exposed to carbon disulfide (Campbell et al. 1985). A detection limit of 15.2 μ g of carbon disulfide/L of blood was achieve d. 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 me tabolites in urine. Urinary 2-thiothiazolidine-4- carboxylic acid is the best availabl e indicator to assess the degree of occupational exposure to carbon disulfide (ACGIH 1994; Theinpont et al. 1990). Theinpont et al. (1990) describe d the isolation of this compound from urine prior to reverse phase high-p erformance liquid chromatography. It is based on liquid-liquid extraction with me thyl tertbutyl ether, followe d by affinity chromatography on organomercurial agarose gel. The detection limit of the procedure was 50 μ g 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-thiothiazo lidine-4-carboxylic acid in the ur ine 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 sensit ive, specific, and noni nvasive. A detection limit of 25 μ g of carbon disulfide/L of urine was obtained (L ee et al. 1995). The iodine -azide test has been used for the detection of metabolites of carbon disu lfide in the urine of humans and animals following exposure to carbon disulfide (Baselt 1980; Djur ic 1967; WHO 1979). This method is based on the measurement of the time to decolor iodine, as catalyzed by sulfur-contai ning metabolites of carbon disulfide most notably thiourea and dithiocarbamates. However, the iodine-azi de test is nonspecific and has relatively poor sensitivity for measuring the metabolites of carbon disulfide in the urineCARBON DISULFIDE 154 6. ANALYTICAL METHODS (Baselt 1980; Djuric 1967). TLC has also been empl oyed to detect 2-mercapto-2-thiazolin-5-one and thiocarbamide (metabolites of carbon disulfide) in the urine of work ers exposed to carbon disulfide (Pergal et al. 1972a, 1972b; WHO 1979). GC/MS is us ed to confirm 2-mercapto-2-thiazolin-5-one, thiocarbamide, and TTCA.

Carbon disulfide has also been detected in moth er’s milk using HRGC/MS and spectrophotometry (Cai and Bao 1981; Pellizzari et al. 1982). Sample pr eparation 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, precisi on, and recovery were not reported. For the spectrophotometric technique, sample preparati on 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 excelle nt and sensitivity is in the μ g range. Precision was not reported.

6.2 ENVIRONMENTAL SAMPLES
High-resolution GC equipped with an appropriate de tector is the most common analytical technique for measuring the concentrations of carbon disulfide in air and vari ous foods (e.g., grains, grain-based foods, fruits, and beverages). The choice of a par ticular 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 comple x mixtures or at very low concentrations, preconcentration of these samples prior to quantification is usuallynecessary (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 det ector (PID), or FPD has been us ed for measuring carbon disulfide after elution from the solid phase . Detection limits of low ppm leve ls 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 recomme nded GC/FPD (method 1600) for determining carbon disulfide in air. The range of quantification is 3-64 ppm fo r 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 (SF 6 ), and then detected by ECD. The ECD de tector 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 (Drexe l 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 measuri ng 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 chel ate whose concentration is related directly to carbon disulfide concentration (Kn eebone and Freiser 1975). Analysis of carbon disulfide in air for AAS quantification involves desorb ing 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 μ g of carbon disulfide/m 3 of air was obtained. Carbon disulfid e is usually isolated from various foods by liquid-liquid extraction and steam di stillation (AOAC 1984; Bi elorai 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 car bon 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 avai lable. Where adequate information is not available, ATSDR, in conjunction w ith the NTP, is required to assure the initiation of a program of research designed to determin e the health effects (and techniques for developing methods to determine such healtheffects) 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 substanc e-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 rese arch 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 io dine-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 b ackground levels in the population, as well as levels at which biological effects might occur. Analysis of th e parent compound is complicated by the chemical’s high volatility and short half-life in biological materials, making de tection of urinary metabolites a more reliable approach. Sensitiv e and selective methods of measur ing urinary metabolites of carbon disulfide exist, but further studies might be useful in correlating m easured levels of metabolites with carbon disulfide exposure levels and levels at which biological effects might occur.
No specific biomarkers of effect have been excl usively associated with carbon disulfide exposure. Some biological parameters, e.g., decreased ne rve 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 a ssociated 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 exposur e or effect other than the parent compound or its metabolites are available for carbon disulfide. Howe ver, the covalent cross-linking of erythrocyte spectrin by carbon disulfide may serve as a pote ntial biomarker (Valentin e 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 isotopical ly 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 car bon 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 beve rages (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 th e analytical method used to measure low ppm to ppb levels of volatile organic compounds (V OCs) 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 hea lth effects might begin to occur. NIOSH has recommended GC/FPD as the method (M ethod 1600) for measuring low levels of carbon disulfide in air. GC equipped w ith 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 app ear 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 appr opriate for measuring carbon disulfide in these media since it is a volatile compound.

6.3.2 On-going Studies
The Environmental Health Laboratory Sciences Di vision 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 lo w parts per trillion (ppt) range.CARBON DISULFIDE 161 

### 7. REGULATIONS AND ADVISORIES

Table 7-l summarizes internationa l, 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 ppmfor 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 ha s 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 (Hardi n et al. 1981). An inhalation re ference concentr ation (RfC) of 0.7 mg/m 3 (0.2 ppm) was also derived for carbon di sulfide (IRIS 1995). The RfC was based on a benchmark concentration (human-equivalent) of 19.7 mg/m 3 (6.3 ppm) divided by an uncertainty factor of 30 (Johnson et al. 1983).
The Clean Air Act regulates carbon disulfide for equi pment 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 Circui t 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).CARBON DISULFIDE 167 

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