Biomarkers carbon disulfide

Urine catecholamines may also serve as biomarkers of disulfoton exposure. No human data are available to support this, but limited animal data provide some evidence of this. Disulfoton exposure caused a 173% and 313% increase in urinary noradrenaline and adrenaline levels in female rats, respectively, within 72 hours of exposure (Brzezinski 1969). The major metabolite of catecholamine metabolism, HMMA, was also detected in the urine from rats given acute doses of disulfoton (Wysocka-Paruszewska 1971). Because organophosphates other than disulfoton can cause an accumulation of acetylcholine at nerve synapses, these chemical compounds may also cause a release of catecholamines from the adrenals and the nervous system. In addition, increased blood and urine catecholamines can be associated with overstimulation of the adrenal medulla and/or the sympathetic neurons by excitement/stress or sympathomimetic drugs, and other chemical compounds such as reserpine, carbon tetrachloride, carbon disulfide, DDT, and monoamine oxidase inhibitors (MAO) inhibitors (Brzezinski 1969). For these reasons, a change in catecholamine levels is not a specific indicator of disulfoton exposure. 

TTCA is commonly determined by chemical analysis of urine as a biomarker of exposure to carbon disulfide. Another metabolite of carbon disulfide that appears at levels of about 30% those of TTCA in workers exposed to carbon disulfide is 2-thioxothiazolidin-4-ylcarbonylglycine7 ... 

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. 

Higher cholesterol levels (correlated with exposure levels), higher blood creatinine levels, marked disturbances of the hepatic cytochrome P-450 content and of the associated microsomal monooxygenase system, as well as the inhibition of succinic-oxidase enzyme activity, may also be considered as nonspecific biomarkers of carbon disulfide exposure. More research, however, needs to be done in order to determine whether a direct correlation exists between these parameters and carbon disulfide exposure. 

The following paragraphs describe reasonably specific biomarkers for carbon disulfide exposure in humans that correlate with exposure levels to varying degrees. 

Because of these confounding factors, results of breath tests for carbon disulfide exposure do not correlate well with its environmental levels. However, one might be able to detect carbon disulfide exposure more reliably if measurements of carbon disulfide were made during a second slower elimination phase and if a more sensitive detection technique were used. A quadrupole mass spectrometer makes the measurement of carbon disulfide in exhaled breath much more sensitive, detecting exposure levels as low as 1 ppm. In an investigation by Campbell et al. (1985), the short-term elimination of carbon disulfide was studied measuring uptake that had taken place 1-2 hours before the test. Carbon disulfide levels in the breath were found to fluctuate, but the value of next-day tests measuring the slower elimination phase of carbon disulfide by the breath should be explored. Nevertheless, the use of exhaled carbon disulfide remains an equivocal biomarker of exposure. 

Some investigators have measured levels of carbon disulfide in urine as a biomarker of exposure, but this is probably optimal only for measuring high exposure levels (Beauchamp et al. 1983). Good correlation between urinary carbon disulfide levels and work exposure was not found in any studies. The measurements of excreted or "free" carbon disulfide may have been confounded by the presence of various thiometabolites or "bound" species. Moreover, the volatility of carbon disulfide and individual variations in urinary flow rate and metabolism may have confounded results in these studies (Djuric 1967). 

As new red blood cells must be made to replace the damaged spectrin, the crosslinking of this protein may serve as a longer term biomarker of carbon disulfide exposure. 

Measuring the total concentration of urinary thio compounds (including glutathione conjugates, mercapturic acids, and other sulfur-containing carbon disulfide metabolites) can serve as a good marker of exposure. The level of total thio compounds correlates with carbon disulfide exposure levels and is a more sensitive biomarker of exposure than the iodine-azide test (Beauchamp et al. 1983 Van Doom et al. 

McKee etal. 1943 WHO 1979). For the present, the biomarker that correlates best with exposure is measurement of metabolites in the urine. The iodine-azide and TTCA tests can be conducted to measure urinary levels of carbon disulfide metabolites as they have been shown to correlate with exposure (Baselt 1980 Beauchamp et al. 1983 Campbell et al. 1985 Lieben 1974 WHO 1986), with the TTCA test being more sensitive and specific than the iodine-azide test. 

The battery of biomarkers discussed here may be used as indicators of probable carbon disulfide exposure. However, the physiological effects of carbon disulfide poisoning are numerous and range from mild to severe. Their utilization as biomarkers of effect are confounded by their occurrence in response to other epidemiological, nutritional, and environmental factors. Their significance as biomarkers is further reduced by the fact that these effects occur with great variance in the cohort exposed population. 

The following are proposed as likely biomarkers of effect for carbon disulfide however, more information about their possible correlation with actual carbon disulfide exposure and their reliability and consistency is necessary before they can be utilized to indicate level or duration of exposure or predict potential health... 

Changes in lipid metabolism are the most obvious biomarkers of carbon disulfide s vasculopathic effects. Hypercholesterolemia (Toyama and Sakurai 1967) and high -lipoproteins in the blood (Prerovska and Drdkova 1967) have been observed by investigators following long-term occupational carbon disulfide... 

In exposed women, possible disruptions of the neurohormonal-endocrine balance necessary for normal ovarian and uterine cycles may lead to amenorrhea, abnormal menstrual cycles, spontaneous abortions, and even sterility (WHO 1979 Zielhuis et al. 1984). Serum thyroxine levels, which decrease following carbon disulfide exposure, have also been suggested as a biomarker (Cavalleri 1975). 

Higher plasma creatinine levels were observed among workers exposed to 4-18 ppm of ambient carbon disulfide. Creatinine level in plasma may be utilized as a nonspecific biomarker of short-term renal dysfunction (Hemberg et al. 1971). Another such biomarker of renal effects may be the blood sugar level. Higher than normal blood sugar levels in response to carbon disulfide exposure were observed in a chronic-duration human study (Hemberg et al. 1971) and an intermediate-duration dog study (Lewey et al. 1941). 

In studying the effects of carbon disulfide exposure on enzyme systems of carbohydrate metabolism, McKee et al. (1943) observed that the succinic-oxidase system was inhibited. They noted a 10% decrease in the activity of this system. Carbohydrate metabolism is crucial in proper neural function thus, succinic-oxidase activity may serve as an appropriate biomarker of nervous system effects (McKee et al. 1943). 

At the present time, the biomarkers that correlate best with exposure are metabolite levels in the urine (Baselt 1980 Beauchamp et al. 1983 Campbell et al. 1985 Lieben 1974 WHO 1986). The iodine-azide and the TTCA tests, which measure the presence of urinary carbon disulfide metabolites, have been shown to correlate well with actual exposure. However, the iodine-azide test is nonspecific (Dox et al. 1992). TTCA is produced in humans after exposure to Antabuse and in rats after exposure to Captan (Cox et al. 1992). Moreover, other investigations are necessary in order to determine whether the interaction of carbon disulfide with other substances (such as hydrogen sulfide, drugs, carbon tetrachloride, malathion, and alcohol), disease states, and variations in diet and in individual metabolism, as well as other factors, could confound the results of the iodine-azide test and the TTCA test for carbon disulfide exposure. Baseline urine, breath, and blood samples are necessary to correct for non-workplace exposures. For exposures around hazardous waste sites, the influence of workplace exposures must also be corrected for in this manner. 

Bao 1981 Campbell et al. 1985 Cox et al. 1992 Djuric 1967 Helasova 1969 Lieben 1974 McKee et al. 1943 NIOSH 1989 Pellizzari et al. 1982 Teisinger and Soucek 1949 WHO 1979). However, because of the rapid metabolism and elimination of carbon disulfide, these fluid and breath levels do not correlate well with environmental levels, except for the urinary marker, 2-thiothiazolidine-4-carboxylic acid. In addition, the interaction of carbon disulfide with other potential confounders may affect the reliability of urinary metabolites as biomarkers of exposure. Biomarkers may therefore be of limited utility in the quantitative assessment of human exposure to carbon disulfide at hazardous waste sites however, biomarkers may be useful in qualitatively establishing that possible exposure has occurred. 

The purpose of this chapter is to describe the analytical methods that are available for detecting, and/or measuring, and/or monitoring carbon disulfide, its metabolites, and other biomarkers of exposure and effect to carbon disulfide. The intent is not to provide an exhaustive list of analytical methods. Rather, the intention is to identify well-established methods that are used as the standard methods of analysis. Many of the analytical methods used for environmental samples are the methods approved by federal agencies and organizations such as EPA and the National Institute for Occupational Safety and Health (NIOSH). Other methods presented in this chapter are those that are approved by groups such as the Association of Official Analytical Chemists (AOAC) and the American Public Health Association (APHA). 

No specific biomarkers of effect have been exclusively associated with carbon disulfide exposure. Some biological parameters, e.g., decreased nerve conduction velocity and changes in lipid metabolism, have been tentatively linked to carbon disulfide exposure, but there are insufficient data with which to assess the analytical methods associated with measurement of these potential biomarkers. Further investigations into these potential biomarkers, in conjunction with improvements in their detection methods might aid in establishing reliable biomarkers of effect for carbon disulfide. 

At present, no specific biomarkers of exposure or effect other than the parent compound or its metabolites are available for carbon disulfide. However, the covalent cross-linking of erythrocyte spectrin by carbon disulfide may serve as a potential biomarker (Valentine 1993). There are no data to indicate whether a biomarker, if available, would be preferred over chemical analysis for monitoring exposure to carbon disulfide. 

Lee BL, Yang XF, New AL, et al. 1995. Liquid-chromatographic determination of urinary 2-thiothiazolidine-4-carboxylic acid, a biomarker of carbon-disulfide exposure. J Chromatogr B Biomed Appl 668 265-272. 

Keywords carbon disulfide workplace air external exposure assessment internal exposure assessment biomarkers... 

The assessment of internal exposure is made by testing biomarkers -metabolites of carbon disulfide in urine. The samples were collected in the end of the working shift. The results were re-calculated based on creatinine. The correction of the results vs. creatinine excretion is applied for reducing the confounding factors, respectively to eliminate the external and internal factors that are not associated with exposure to carbon disulfide. 

TABLE 3. Biomarkers for assessment of internal exposure to carbon disulfide 2-thiothiazolidin-4-carboxylic acid (TTCA) and iodine-azide test in urine collected at the end of the working shift. 

The comparative analysis of the data for external exposure and the biomonitoring results enable the study of the relationships between exposure level and deviations in applied biomarkers for prediction of the health risk at chronic exposure to carbon disulfide (Table 4). 

The results obtained categorically confirm the adequate choice of biomarkers for assessment of internal exposure. The determination of specific metabolites of carbon disulfide in urine can be widely applied, as the methods are specific and non-invasive. As mentioned above the only source of TTCA appearance is the inhaled carbon disulfide. It should be underlined that the high correlation between external and internal exposure proves the credibility of the used sampling strategy and implemented GC methods for determination of carbon disulfide concentrations in workplace... 

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