THC as Excreted THC-COOH 2.4.2. of Percentage Urinary

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26.06.2018

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  • THC as Excreted THC-COOH 2.4.2. of Percentage Urinary
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  • 1. Introduction
  • A percentage of the THC was radiolabeled; however, investigators were unable to .. Percentage of THC Excreted as Urinary THC-COOH. An average of. Terminal Elimination Half-Lives of THCCOOH.. Percentage THC Dose Excreted as Urinary THCCOOH . Cannabinoid Glucuronide. PercentageTHCDoseExcretedasUrinaryTHCCOOH. Percentage THC Dose Excreted as Urinary THCCOOH. An average of ± µg.

    THC as Excreted THC-COOH 2.4.2. of Percentage Urinary

    The same report also summarized the results of a survey of organic compounds in surface soils in background areas in the same municipalities, in which carbon disulfide was reportedly detected at three of 30 urban residential and parkland sites in Port Credit, Oakville and Burlington, at concentrations of 0.

    However, the latter results are of uncertain validity, as the reported levels were near the method detection limit 0. In , carbon disulfide was measured in sediment suspensions taken from Lake Ontario, near Burlington, Ontario, and in Harp Lake, near Huntsville, Ontario.

    Caron and Kramer , using a sulfur-specific gas chromatographic method, were able to detect 5. No information was identified in the literature regarding the levels of carbon disulfide in biota in Canada. No data were identified on the levels of carbon disulfide in Canadian foods.

    Carbon disulfide was previously registered as a fumigant for use on stored grain, but this registration was withdrawn in There are currently no registered food uses for carbon disulfide in Canada Warfield, For certain pesticides, such as dithiocarbamates, carbon disulfide is produced during their metabolism in plants and in soil. Carbon disulfide is also known to be a metabolite produced by plants from naturally occuring sulfur compounds Section 2.

    However, no information was accessed with which to quantitatively characterize the potential for exposure to carbon disulfide in Canada from these sources Ballantine, ; Moore The results of a number of food surveys from the United States in which the levels of carbon disulfide were determined have been published Heikes and Hopper, ; Daft, , , ; Heikes, A variety of sulfur compounds are components of tobacco smoke.

    Horton and Guerin analysed the mainstream smoke from seven samples of commercial and experimental cigarettes and a single cigar and marijuana cigarette. No data were identified on levels of carbon disulfide in biological materials from the general population in Canada. This provides support for the data on levels in environmental media, which indicate that humans have environmental exposure to carbon disulfide. The toxic mode of action of carbon disulfide varies from species to species.

    In microorganisms, carbon disulfide may interfere with the general metabolism of a nitrifier species or with the primary oxidative reactions. In higher life forms, it is suggested that metabolic reactions of carbon disulfide follow two distinctly different pathways: Acute toxicity is confined mainly to neurotoxic effects. The following sections present a summary of the most sensitive endpoints found for terrestrial and aquatic organisms.

    More extensive descriptions of environmental effects are provided in Environment Canada a. Mammals appear to have relatively high tolerance to short-term or acute exposure to carbon disulfide Crookes et al. While no tests on wild mammals were found in the literature, effects on laboratory mammals have been extensively studied.

    This was the most sensitive result identified from the literature see Section 2. Taylor and Selvidge studied the effects of gaseous carbon disulfide on bush beans Phaseolus vulgaris in a closed system, with three replicate exposures, and reported no effect on transpiration or photosynthesis at any of the measured concentrations tested 0. In a previous study to assess the internal flux of carbon disulfide and other gases from leaf surface to leaf interior, Taylor et al.

    This may account in part for its relatively low toxicity compared with that of other sulfur gases, since flux to the interior of a leaf is the major determinant of the ability of a compound to cause leaf injury.

    Few other studies on plants were identified in the literature; however, the effects on seeds from the use of carbon disulfide as a fumigant were examined by two separate investigators Kamel et al.

    The most sensitive species was seed of the wheat plant, Giza variety. In general, seeds with higher moisture content were more sensitive. Overall, it can be stated that a concentration of carbon disulfide of 2. It has been found that carbon disulfide fumigation affects all life stages of invertebrates with varying degrees of toxicity Crookes et al. The most sensitive test result was a 7-day LC 50 value of 1.

    Further studies in invertebrates are listed in Table A. In one 5-day study of the effects of carbon disulfide on the nitrification of ammonium in soils using sealed containers, Bremner and Bundy reported nearly complete inhibition of nitrification at nominal concentrations as low as 0. The ecological signif icance of this result is uncertain, however, because concentrations in test soils were not measured, and the effect nearly disappeared when the test duration was increased to 14 days.

    Van Leeuwen et al. Under controlled conditions in a sealed container to prevent evaporative loss, the most sensitive species was Daphnia magna , with a hour LC 50 , tested according to Organisation for Economic Cooperation and Development OECD test guideline , of 2. Further data are presented in Table A. Calculations were made to determine if carbon disulfide has the potential to contribute to depletion of stratospheric ozone, the formation of ground-level ozone or climate change Bunce, Since carbon disulfide is non-halogenated, its Ozone Depletion Potential ODP is 0, and it will therefore not contribute to the depletion of stratospheric ozone Bunce, The Photochemical Ozone Creation Potential POCP of carbon disulfide, relative to that of the reference compound, ethene, which has a value of , was conservatively estimated to be 35 Bunce, , based on the following formula:.

    Although this POCP is somewhat elevated, the magnitude of any effect will depend on the concentration of carbon disulfide in the atmosphere.

    Except in proximity to strong point sources, average annual concentrations of carbon disulfide in ambient air are low relative to typical annual concentrations reported by Dann and Summers for the volatile organic compounds with similar POCPs that contribute most to the formation of ground-level ozone.

    Therefore, the contribution of carbon disulfide to ground-level ozone formation is not expected to be significant. Worst-case calculations were made to determine if carbon disulfide has the potential to contribute to climate change Bunce, Quantitative data on infrared absorption strength are not available.

    Therefore, the worst-case calculations assumed the same infrared absorption strength as for a reference compound CFC Carbon disulfide may also have an indirect impact on climate change and stratospheric ozone depletion through its main atmospheric transformation product, carbonyl sulfide, but the magnitude of this impact is considered to be small Environment Canada, a.

    Owing to the relatively extensive database in humans, the epidemiological data have been emphasized in characterizing the hazard associated with exposure to carbon disulfide; information from studies in animals contributes primarily to assessment of biological plausibility and understanding of the mode of action.

    In several case reports, ingestion of approximately 18 g caused neurological signs, cyanosis, peripheral vascular collapse and hypothermia, followed by death due to central nervous system depression and respiratory paralysis within a few hours HSE, The majority of the available epidemiological studies are of workers in the viscose rayon industry, in which workers are exposed to airborne carbon disulfide, along with lesser quantities of hydrogen sulfide, at several stages during the process of manufacturing viscose rayon fibres.

    The following discussion is limited principally to studies in which information on the exposure levels associated with the effects observed in the study population was provided. Neurophysiological effects on both the peripheral and central nervous systems, as well as behavioural and neuropathological effects, have been reported in a number of cross-sectional studies of workers exposed to carbon disulfide in the viscose rayon industry.

    The most common observations are of effects on the peripheral nervous system, most often characterized by reduced conduction velocity in the motor and, in some instances, sensory nerves, and generally most pronounced in the more distal portions of the nervous system e.

    In exposed workers as a whole, there were significant reductions in motor nerve conduction velocities of the deep peroneal, posterior tibial and ulnar nerves and in slow motor fibre conduction velocities in the deep peroneal and ulnar nerves. Findings were comparable in workers who were currently exposed and in those removed from exposure for a number of years.

    Effects on peripheral nervous system conduction were also associated with lower exposures to carbon disulfide in a well-conducted study of white male workers in a U.

    Based on area samples, exposures were stable over more than 20 years prior to the study. In contrast to the findings for nerves in the legs, none of the neurophysiological variables in the ulnar nerve was associated with carbon disulfide exposure. In behavioural testing of this population, there were no remarkable findings in psychological, psychomotor, cognitive-perceptual or vision testing, although exposed workers reported symptoms of neurobehavioural ailments significantly more frequently Putz-Anderson et al.

    The authors questioned the significance of these results, based primarily on the lack of effects on other neurophysiological parameters and the lack of significant dose-response among exposed workers. However, it is considered that the changes observed by Reinhardt et al.

    While Reinhardt et al. In addition, the equivocal nature of the findings for the sural nerve is consistent with the general pattern of increased susceptibility of the longest and largest- diameter axons to the neurotoxic effects of carbon disulfide in exposed humans and animals Section 2.

    Finally, although there was no dose-response among the exposed workers, there was a significant dose-response when the control workers were included in the analysis.

    In contrast, there was little indication of effects on the peripheral nervous system in a small study of Italian viscose rayon workers who had been exposed to slightly lower carbon disulfide levels - i. In this study, motor nerve conduction velocity of the peroneal nerve was non-significantly slower in exposed workers than in well-matched controls. Based on needle electromyography and neurological examinations, five out of 50 exposed subjects had peripheral nerve impairment, compared with only two out of 50 controls.

    There were no significant differences in the results of neuropsychological testing of intelligence, performance and memory conducted on half of the subjects. In the subset of these studies in which subgroup analyses were conducted, there was an exposure-response relationship, with reductions in peroneal motor nerve conduction velocity among exposed workers being related to the exposure concentrations Gilioli et al. The results of sural nerve biopsy revealed ultrastructural changes similar to those in the peripheral nervous system of animals exposed to carbon disulfide axonal degeneration with disorganized neurofilaments Section 2.

    The evidence that such effects are associated with lower exposures is conflicting, although there were no remarkable differences in the results of extensive neurobehavioural testing in workers exposed to similar or slightly higher levels of carbon disulfide in several well-described studies Cirla and Graziano, ; Putz-Anderson et al.

    However, in all of these studies, the group sizes were fairly small, and there was often historical exposure to higher levels. Excess mortality from cardiovascular disease, most often ischemic heart disease, has been reported in a number of occupational cohorts exposed to carbon disulfide.

    In an early prospective study, Hernberg et al. There were also significant increases in indicators of cardiovascular morbidity non-fatal myocardial infarction, chest pain and of risk factors for coronary heart disease increased blood pressure. In a subsequent year follow-up Tolonen et al.

    Cardiovascular mortality was significantly greater in the most highly exposed workers in a cohort of male workers at a U. A significant trend between mortality from ischemic heart disease among long-term older workers and cumulative exposure score or exposure score over the last 2 years was observed.

    These patterns were not evident in workers who had left employment or those with less than 10 years of exposure. While there was concomitant exposure to hydrogen sulfide, the excess of mortality from ischemic heart disease was similar among workers with high-level exposure to carbon disulfide alone or to both compounds.

    Findings were similar in a larger cohort of 10 male workers employed for at least 1 year at one of four U. No data were presented on exposures to carbon disulfide or other chemicals, nor on other known risk factors for heart disease. In a historical cohort study of Dutch male viscose rayon workers, mortality from circulatory diseases was significantly increased among the workers exposed to carbon disulfide compared with the general population Swaen et al.

    Among these workers, mortality from cardiovascular diseases and ischemic heart disease was inversely related to cumulative exposure, although this was estimated from personal air samples collected late in the study period, and historical exposures were most likely higher.

    The risk for cardiovascular disease was reported to be most pronounced years after the first exposure. In contrast to the results of other studies Hernberg and Tolonen, ; Sweetnam et al. No information was available on other risk factors for heart disease, but there was no excess of cardiovascular diseases in unexposed workers, who were considered to be similar to the exposed workers in terms of lifestyle.

    Mancuso conducted a historical cohort study of more than males and females employed at a U. In the year follow-up, there was significant excess mortality from coronary heart disease among males deaths, SMR There were no quantitative exposure data, but the SMRs for coronary heart disease increased with increasing duration of exposure and were significantly increased in male workers employed for more than 10 years in those tasks for which exposure was considered high spinning and twisting, maintenance and mechanics.

    In females, findings were similar but less pronounced and generally not statistically significant. Results were similar among women but were based on few cases and were often not statistically significant. Exposures to carbon disulfide, although apparently heavy, were poorly characterized. Several other epidemiological studies of cardiovascular mortality among populations exposed to carbon disulfide in the workplace were identified, but each is considered to contribute less to the weight of evidence for this effect, as a consequence of one or more of small numbers of deaths, limited statistical power and poor characterization of exposure Lyle, ; Wilcosky and Tyroler, ; Liss and Finkelstein, , In a number of cross-sectional studies, associations have been reported between exposure to carbon disulfide and clinical measures that are established risk factors for heart disease, including blood pressure and serum cholesterol.

    In addition, there are reports of increases in overt manifestations of coronary heart disease, such as angina and coronary electrocardiographs, in workers exposed to carbon disulfide. In a well-conducted study, Egeland et al. There was no association between exposure and high-density lipoprotein cholesterol HDL-C , triglyceride, blood glucose or systolic blood pressure.

    The levels of LDL-C, total cholesterol and diastolic blood pressure were significantly greater in the high-exposure group than in the low-exposure workers.

    Patterns were generally similar in comparison with the unexposed workers. The results of area sampling indicated that exposures were stable for more than 20 years prior to the study. Similar results were reported in a study of Polish women exposed to levels of carbon disulfide in the same range i. Exposed women had significantly increased levels of total cholesterol and LDL-C and a significantly reduced level of HDL-C compared with a control group of female textile workers of similar age.

    Effects on these blood lipids were confined to women aged and to those with greater than 10 years of exposure. No subgroup analyses by exposure level were conducted. These findings are supported by two studies of viscose rayon workers Wronksa-Nofer and Laurman, ; Vanhoorne et al. However, it should be noted that there was no significant association between total cholesterol and exposure to similar levels of carbon disulfide in the prospective study by Hernberg et al.

    In contrast to the above studies, findings were negative in two investigations in which exposure levels were slightly less than those for the U. HDL-C and apoliprotein levels were associated with duration of employment in jobs with exposure, but this was also observed in the controls, and the authors suggested that this was the result of long-term shift work. There is also evidence from cross-sectional studies of overt toxicity to the cardiovascular system, most often reported as an increased frequency of angina or non-fatal myocardial infarction or of abnormal electrocardiograph Hernberg et al.

    However, the increases were often non-significant and were based on small numbers of cases, and there is no clear dose-response across studies although exposures were poorly characterized in most of these investigations. However, there appears to be considerable variation in the susceptibility to this effect among populations, and there is no clear evidence that exposure to lower levels of carbon disulfide is associated with retinopathy Albright et al.

    In addition, such effects are of uncertain clinical significance, although it has been suggested that they could possibly be early indicators of more serious damage to the ocular, vascular or nervous system Vanhoorne et al. The association of exposure to carbon disulfide with other effects on the eye has not been extensively investigated. In these populations, there were no other effects on measures of vision, including visual acuity, visual field, eye motility, depth perception and pupillary reaction Raitta et al.

    In those epidemiological studies in which mortality from non-cardiovascular causes was presented, there was no consistent excess of mortality from all cancers combined or from cancers at any specific site Lyle, ; Mancuso, ; Wilcosky et al. However, exposures were poorly characterized if at all , and the number of cancer deaths at any given site was small or modest in all of these studies, many of which were designed specifically to investigate the association between exposure to carbon disulfide and mortality from cardiovascular diseases.

    Semen quality, fertility and pregnancy outcomes were not associated with exposure of male viscose rayon workers to carbon disulfide in the better documented of the available studies Meyer, ; Selevan et al. Two early Finnish reports Hemminki et al.

    No reports of developmental effects associated with exposure to carbon disulfide were identified. There are a number of epidemiological investigations of the association between exposure to carbon disulfide and a variety of other effects, most often alterations in circulating levels of thyroid hormones Cirla et al. Most of the available studies in animals have addressed the effects of carbon disulfide on the nervous system.

    In general, the results of these studies provide neurophysiological, histopathological, neurochemical and behavioural support for the effects on the nervous system observed in workers exposed to carbon disulfide Section 2.

    In a number of these studies, this effect was accompanied in later stages by neurological impairment and atrophy of the hind limbs and was only partially reversible upon cessation of exposure. In rats exposed to carbon disulfide, hydrogen sulfide or both in approximate proportion to their concentrations in the workplace, reductions in peripheral nerve conduction velocity were observed only in those exposed to carbon disulfide, and there was no interaction between the compounds Gagnaire et al.

    However, it is noted that this endpoint was affected only at much higher levels i. The reductions in nerve conduction velocity observed in animal studies are accompanied by characteristic histopathological lesions in the axon. The distal portions of the largest and longest myelinated axons which are the most rapidly conducting axons are affected first.

    Structural changes proceed through the development of large axonal swellings composed of disorganized masses of neurofilaments proximal to the nodes of Ranvier, followed by axonal atrophy and Wallerian-like degeneration proximal and distal to the swellings, respectively.

    These features are characteristic of giant neurofilament axonopathies induced by other compounds, such as 2,5-hexanedione, the neurotoxic metabolite of hexane Graham et al. Neurobehavioural effects have been observed in a number of studies in rats. In those studies that included a recovery period, these neurobehavioural effects were reversible. This appeared to be the combined result of increased synthesis and decreased conversion of dopamine.

    The sequence of neurotoxic effects of carbon disulfide was elucidated in a recent collaborative study at the U. National Institute for Environmental Health Sciences. Chemical cross-linking of neurofilament proteins by a derivative of carbon disulfide is postulated to be the mechanism of its peripheral neurotoxicity [Section 2. Other early indicators were increased expression of nerve growth factor receptor mRNA in the sciatic nerve an indicator of alterations in the axon-Schwann cell relationship Toews et al.

    By 4 weeks, the neuromotor alterations progressed to the point where there were reductions in grip strength of the hind limbs and forelimbs Moser et al. Axonal swelling and degeneration Sills et al. The effect of carbon disulfide on lipid metabolism has been extensively studied. This appears to have resulted from increased hepatic synthesis and, perhaps, reduced degradation of cholesterol to bile acids Wronska-Nofer, , , ; Wronska-Nofer et al.

    There is only limited evidence of other effects induced by inhalation of carbon disulfide. While it has often been assumed that the cardiovascular effects of carbon disulfide are secondary to its arteriosclerotic effects, the results of several studies in rats suggest that these may be the result of a direct effect on the heart.

    No adequate cancer bioassays of carbon disulfide have been conducted. The data available are confined to a single screening study of lung tumour induction in mice Adkins et al. It is not possible to assess the carcinogenicity of carbon disulfide to animals based on this limited database.

    The results of in vitro studies have provided little evidence that ca rbon disulfide i s genotoxic. In several studies in bacteria, carbon disulfide did not induce point mutations in Salmonella typhimurium or in Escherichia coli, both with and without metabolic activation Hedenstedt et al.

    In human sperm exposed to carbon disulfide in vitro, there was a significant increase in the frequency of chromosomal aberrations and in the frequency of chromosomal breaks Le and Fu, In contrast, Vasil'eva reported that oral exposure to carbon disulfide induced chromosomal aberrations and polyploid cells in the bone marrow of female rats and in rat embryos exposed on days of gestation.

    It is difficult to assess the validity of these findings, as the reporting was brief e. There were no clear effects on sperm counts, circulating levels of reproductive hormones or testicular histology Tepe and Zenick, ; Zenick et al. This dose adversely affected maternal weight and weight gain and increased pup mortality, decreased pup viability and decreased live litter size, but development of pups was otherwise unaffected.

    The developmental toxicity of inhaled carbon disulfide in rats has been investigated in a number of studies. Behavioural effects, most often reduced exploratory activity in open field tests, were also reported at levels between 0. Exposure over two generations appeared to result in greatly increased sensitivity to the teratogenic effects of carbon disulfide, causing malformations at as little as 0.

    However, it is difficult to evaluate the validity of these findings. The studies are generally only briefly reported, and important information e. There is also some inconsistency in the findings; for example, Tabacova et al. Moreover, the results of subsequent studies, most of which are better reported, have generally failed to confirm the teratogenic findings reported by Tabacova and colleagues, although it should be noted that some of the studies conducted by these investigators differed somewhat in their design e.

    In another study Belisles et al. However, there is some weak support for the behavioural effects reported by Tabacova and colleagues Hinkova and Tabacova, ; Tabacova et al. Significant increases in visceral and skeletal malformations were also observed at the higher, maternally toxic, dose level PAI, However, it is difficult to assess the validity of these results, owing to mortality among the dams from causes that were apparently unrelated to the chemical exposure.

    The highest dose also induced significant increases in the frequency of malformed fetuses Jones-Price et al. Carbon disulfide can be metabolized in the liver by the cytochrome P monooxygenase system to an unstable oxygen intermediate that either spontaneously generates atomic sulfur, carbonyl sulfide and carbon dioxide or hydrolyzes to form atomic sulfur and monothiocarbonate, yielding carbonyl sulfide and carbon dioxide in breath and inorganic sulfates and organosulfur compounds in urine.

    Alternatively, dithiocarbamates are formed in humans and animals by reaction with amino acids; conjugation of carbon disulfide or carbonyl sulfide with endogenous glutathione forms TTCA and 2-oxythiazolidinecarboxylic acid, respectively, which are excreted in urine ATSDR, As reviewed by Graham et al.

    The adducts decompose to an electrophile isothiocyanate and isocyanate, respectively , which in turn reacts with protein nucleophiles on the neurofilaments to cause protein cross-linking. However, it is noted that, although the metabolites resulting from carbonyl sulfide have been identified, the production of protein cross-links via this pathway has not yet been demonstrated.

    Progressive cross-linking of the neurofilament occurs during its transport along the axon, and covalently cross-linked masses of neurofilaments may occlude axonal transport at the nodes of Ranvier, ultimately resulting in axonal swelling and degeneration.

    The environmental risk assessment of a PSL substance is based on the procedures outlined in Environment Canada a. Analysis of exposure pathways and subsequent identification of sensitive receptors are used to select environmental assessment endpoints e.

    If these quotients are less than one, it can be concluded that the substance poses no significant risk to the environment, and the risk assessment is completed. If, however, the quotient is greater than one for a particular assessment endpoint, then the risk assessment for that endpoint proceeds to an analysis where more realistic assumptions are used and the probability and magnitude of effects are considered.

    This latter approach involves a more thorough consideration of sources of variability and uncertainty in the risk analysis. In Canada, nearly all carbon disulfide is released to air.

    Therefore, terrestrial organisms living near industrial sources are chosen as assessment endpoints, as these organisms are the most likely to have the highest potential for exposure and effects. Despite the fact that nearly all releases of carbon disulfide are to the atmosphere, there are releases to water. Since aquatic organisms close to discharge points could also be affected, they are also selected as assessment endpoints. Toxicity test results are available for terrestrial plants, invertebrates and vertebrates, all of which can be exposed to carbon disulfide in the atmosphere.

    The most sensitive organism identified in these studies was the mouse, and effects data for this organism were used for the risk characterization for terrestrial organisms. Toxicity test results are available for algae, Daphnia, an amphibian and several fish species. The most sensitive organism identified in these tests was the invertebrate, Daphnia magna, and effects data for this species were used for the risk characterization for aquatic organisms.

    Aquatic invertebrates are key consumers in the aquatic food web and are themselves consumed by other species of invertebrates and by vertebrates.

    The CTV for terrestrial organisms is 6. Dividing this CTV by an application factor of to account for the conversion of an LC 50 to a long-term no-effects value, extrapolation from laboratory to field conditions and interspecies and intraspecies variations in sensitivity gives an ENEV of 6.

    Since this hyperconservative quotient is less than 1, it is very unlikely that carbon disulfide causes adverse effects on populations of terrestrial organisms in Canada. The conservative EEV for aquatic biota is 3.

    This value is believed to be conservative, because emissions of carbon disulfide to the environment have decreased significantly since the early s.

    The CTV is 2. Since this quotient is less than 1, it is unlikely that carbon disulfide causes adverse effects on populations of aquatic organisms in Canada. There are several sources of uncertainty in this assessment, the principal one being the lack of recent ambient concentration data in most Canadian media.

    The EEV for air, the principal environmental compartment of concern, was, however, based on monitoring data in areas where the largest Canadian releases occur. Furthermore, it represents a maximum value over a very short time period 8 minutes.

    It is very unlikely that environmental concentrations resulting from pulsed releases of carbon disulfide would be underestimated by this value. The EEV for air is furthermore supported by the modelling study of The and by monitoring data near other similar sources. It should also be noted that since the substance was first proposed as a priority for assessment, the majority of Canadian industrial users of carbon disulfide have either ceased operation or improved emission controls.

    Consequently, the ambient concentrations of carbon disulfide in the various environmental compartments near such industrial sources in Canada would likely be lower than the values presented in the literature. In the case of surface waters, for example, the values obtained for carbon disulfide from the literature are at least 12 years old; as most releases from industrial sources have decreased since then, these older values likely represent a conservative exposure scenario for surface water.

    Regarding effects of carbon disulfide on terrestrial and aquatic organisms, uncertainty surrounds the extrapolation from available acute toxicity data to prediction of long-term ecosystem effects. For wildlife, and especially small mammals, inhalation exposure in laboratory animals was used as a surrogate for actual exposure in the field. While the aquatic toxicit y data set included studies on organisms from a variety of ecological niches and taxa, there are no chronic studies available for invertebrates or fish.

    To account for these uncertainties, conservative application factors were used in the environmental risk analysis to derive ENEVs. Despite some data gaps regarding the environmental effects and exposure of carbon disulfide, the data available at this time are considered adequate to assess the environmental risk of carbon disulfide in Canada.

    The calculations shown in Section 2. The magnitude of this effect would depend upon the concentration of carbon disulfide in the atmosphere, and the concentration of carbon disulfide in Canadian air is very low relative to the concentrations of volatile organic compounds that are responsible for ozone formation. Consequently, the contribution of carbon disulfide to ground-level ozone formation is not expected to be significant. Based on the above, the atmospheric effects of carbon disulfide are not expected to be significant.

    It is proposed at this time that carbon disulfide not be considered "toxic" as defined under CEPA Paragraph 64 b. Data on levels of carbon disulfide in environmental media to serve as the basis for development of estimates of population exposure in Canada are limited to a small number of surveys of ambient air conducted at few locations in Canada or in the United States and limited Canadian surveys in drinking water and soil in which carbon disulfide was seldom detected.

    Meaningful probabilistic exposure assessment is precluded, therefore. In this section, mean deterministic estimates of environmental intake from air, water and soil by members of the general population of Canada have been derived. These are followed by consideration of mean estimates of potential airborne exposures by populations in the vicinity of point sources in Canada, based on the very limited available data. Point estimates of total daily intake of carbon disulfide by six age groups of the general population of Canada were developed Table 5 , primarily to determine the relative contributions from various media.

    These estimates indicate that intake from environmental exposure to carbon disulfide is virtually all from inhalation. That air is the principal route of exposure is supported by the results of the EQC and ChemCAN4 fugacity modelling, which indicate that virtually all of the carbon disulfide released to air industrial releases in Canada are almost entirely to air will tend to remain in that compartment.

    However, it is noted that the atmospheric concentrations predicted by the ChemCAN4 fugacity modelling are an order of magnitude or more lower than those measured in ambient air in a number of studies throughout the world. This may reflect the combined contribution of natural sources, local anthropogenic sources and advective inputs from outside of the region to the levels measured.

    Exposure from ingestion of drinking water and soil appears to be negligible in comparison with that from air. For smokers, it is estimated that cigarette smoking can increase the intake of carbon disulfide severalfold. Intake by cigarette smokers Phillips, ; Section 2. In calculating the mean, a value of one-half the detection limit 0.

    It is also known that concentrations of carbon disulfide in ambient air are elevated in the vicinity of some point sources in Canada Section 2. Based on the range of mean concentrations measured in the vicinity of natural gas processing 1.

    The data most relevant to hazard characterization are those from epidemiological studies of populations exposed to carbon disulfide in the workplace. In this section, the available data for those effects that are potentially critical i. While the epidemiological data regarding the association between exposure to carbon disulfide and damage to the retinal capillaries [ Section 2. The weight of evidence for the remaining categories of effects discussed in Sections 2.

    Effects on the nervous system, including neurophysiological, behavioural and pathological effects, were reported in a large number of cross-sectional studies of viscose rayon workers Section 2.

    The most common findings were reduced conduction velocity in the motor and sensory nerves, generally most pronounced in the more distal portions of the nervous system e. There are also a small number of reports of impaired performance on neuropsychological testing, most often on psychomotor tests of motor speed or dexterity, in workers exposed to relatively high levels of carbon disulfide.

    Hence, there is evidence of both consistency and specificity for these effects on the nervous system. In most instances when subgroups of the study populations were analysed separately, the reductions in nerve conduction velocities were most pronounced in those workers with exposure to the highest concentrations, those employed in tasks that were considered to entail the highest exposures or those with the greatest cumulative exposures Gilioli et al.

    In addition, effects on peripheral nerve conduction velocity were generally observed at lower levels than were other effects on the nervous system, particularly the psychomotor effects, both within and between studies Cassitto et al. Hence, there is evidence of a dose-response relationship for effects on peripheral nerve conduction velocity and other parts of the nervous system, both within and across studies. With respect to temporality, results are conflicting; although there is little information, reductions in nerve conduction velocity in workers who were removed from exposure for a number of years were less pronounced often non-significant than in workers who were currently exposed in some studies Hirata et al.

    However, the lack of temporality is not unexpected in light of the limited capacity of the peripheral nervous system to regenerate. The effects reported on the peripheral nervous system are supported by the results of studies of animals exposed subchronically or chronically by inhalation, in which nerve conduction velocity in the peripheral nerves or spinal cord was consistently reduced, accompanied by histopathological lesions and biochemical changes similar to those induced by certain other compounds that cause axonopathy e.

    Similar histopathological alterations, accompanied by clinical and neurophysiological signs of peripheral neuropathy, were also reported in a worker exposed to relatively high levels of carbon disulfide Chu et al.

    In several studies in rats, exposure to carbon disulfide also affected performance in neurobehavioural testing or altered levels of catecholamines in the brain or adrenals Section 2. Although impaired performance in certain behavioural tests was evident in animals at earlier time points and at lower levels than histopathological or neurophysiological effects, in contrast to the results of epidemiological studies, the changes observed [i.

    While the exact mechanism of action is not yet known, there is considerable evidence that the axonal degeneration that underlies the neuropathy may be the result of covalently cross-linked masses of neurofilaments occluding axonal transport at the nodes of Ranvier Section 2. Excess mortality from coronary heart disease has been observed in a number of cohorts of viscose rayon workers exposed to carbon disulfide. While there was inadequate account taken of factors known to affect heart disease e.

    The strength of the association was moderate to high, with relative risks ranging from 1. There was evidence of a dose-response relationship in most of the studies in which it was examined, although exposure was not well characterized in any of the investigations, and this was based principally on rather crude measures - i.

    The excesses were generally much less pronounced following elimination or reduction of exposure e. The results of cross-sectional studies of cardiovascular morbidity or of clinical measures known to be related to risk from heart disease are generally consistent with the reported excesses of mortality from coronary heart disease.

    In a number of cross-sectional studies, occupational exposure to carbon disulfide was associated with clinical changes that increase the risk of heart disease, including increases in blood pressure and in serum levels of total cholesterol and LDL-C and with decreases in serum levels of HDL-C. Potential confounders, such as age and smoking, were accounted for in most of these studies.

    In those studies where internal comparisons were made, these effects were related to the extent of exposure i. However, while these effects were fairly consistently absent in less exposed populations and present in moderately or heavily exposed populations, the available data are not entirely consistent in this regard.

    For example, increases in total cholesterol were observed in some studies Wronska-Nofer and Laurman, ; Vanhoorne et al. In the German workers studied by Drexler et al. Thus, exposure of occupational populations to carbon disulfide has been associated with increased risks for coronary heart disease at a number of levels of manifestation, including mortality, morbidity and risk factors, providing a coherent picture.

    There is little information relevant to temporality for effects other than mortality, although Toyama and Sakurai observed that an initial significant difference in total serum cholesterol in Japanese viscose rayon workers disappeared in a second survey, conducted after airborne concentrations had been reduced severalfold.

    The biological plausibility of these findings is supported by the results of studies in animals, in which chronic exposure of rats to high levels of airborne carbon disulfide consistently altered lipid metabolism, resulting in increased serum levels of cholesterol and other blood lipids and exacerbating the atherogenic effects of a lipid-rich diet Section 2.

    Hence, the traditional criteria for causality for associations observed in epidemiological studies are fulfilled, at least in part, for cardiovascular effects associated with exposure to carbon disulfide. The weight of evidence for effects on the nervous system, which meets most of the traditional criteria for causality in epidemiological studies including consistency, specificity, dose-response relationship, coherence and biological plausibility , is clearly the strongest from among the various types of effects observed in epidemiological studies that might have been considered critical.

    Further, while the effects on the nervous system do not appear to meet the criterion of temporality, this is expected, given the limited capability of the nervous system for regeneration.

    While the weight of evidence for effects on the cardiovascular system meets several of the criteria for causality, there are several inconsistencies in the dose-response across studies, and potential modes of action have not been as well elucidated as for the reductions in peripheral nerve conduction velocity.

    Further, there is a high background prevalence of heart disease, and it is affected by a number of other factors, with the result that the dose-response curve is shallow and variable, limiting the ability to detect a compound-related effect more than is the case for a specific effect such as nerve conduction velocity. Effects on the peripheral nerve conduction velocity have also been fairly consistently observed at concentrations that are lower than those at which other effects were observed, and, as noted in the next section, this effect also yields a lower benchmark concentration BMC than for cardiovascular risk factors.

    While the populations of viscose rayon workers in which effects on the nervous system were observed had concomitant exposure to carbon disulfide and hydrogen sulfide, the available evidence indicates that the effects on peripheral nerve conduction velocity were due to carbon disulfide alone. In these studies, concentrations of hydrogen sulfide were typically much less than concentrations of carbon disulfide.

    In addition, the results of a large number of studies in animals have confirmed that carbon disulfide reduces peripheral nerve conduction velocity and have documented the associated histopathological and ultrastructural changes in the axons of the peripheral nerves Section 2. In one study, motor tail nerve conduction velocity in rats was reduced by exposure to carbon disulfide but was not affected by hydrogen sulfide alone, nor did hydrogen sulfide modify the effect of carbon disulfide in combined exposures Gagnaire et al.

    Concentrations of carbon disulfide in the viscose rayon industry are known to have declined substantially over the several decades encompassed by the available epidemiological studies Price et al. In addition, it i s clear that exposures vary considerably between sites at a given workplace and between job titles Vanhoorne and Grosjean, Based principally on the results of studies that meet these criteria, effects on the nervous system that occurred at the lowest concentrations in humans were reductions in conduction velocity in the peripheral motor or sensory nerves, which were observed in several studies of viscose rayon workers with long-term exposure to carbon disulfide.

    There is also fairly consistent evidence of effects on the results of neurobehavioural testing in such populations, but such effects have not been observed at levels as low as those associated with alterations in peripheral nerve conduction velocity, and the exposure-response has been less well characterized. It is not possible at present to identify a quantitative relationship between a given decrease in nerve conduction velocity and an expected degree of loss of function.

    However, it is noted that nerve conduction velocity is a relatively crude indicator of effects of carbon disulfide on the nerves, because function is not impaired until axonal degeneration has actually occurred, in contrast to agents that produce demyelination or have a direct effect on conduction. An additional concern is that, although the effect is measured in the peripheral nervous system, because carbon disulfide produces a central-peripheral distal axonopathy, it is likely that the long axons of the central nervous system are also affected.

    Further, there is only limited capability for regeneration in the peripheral nervous system, and even less in the central nervous system. In short, while reduced nerve conduction velocity by itself may not produce an adverse health outcome, it is indicative of, and a precursor of, other changes that clearly are adverse; given the limited reversibility of this effect, a precautionary approach is warranted. Consequently, the critical effect for the characterization of exposure-response is defined as a statistically significant, compound-related decrease in peripheral nerve conduction velocity.

    However, in only one of the available epidemiological studies in which there was an association between exposure to carbon disulfide and reductions in peripheral nerve conduction velocity was the exposure of the study population adequately characterized to permit quantitative exposure-response analyses - i.

    In the remaining key studies, the analysis was limited to a comparison of exposed versus control workers Hirata et al.

    In addition, the design of the study by Johnson et al. Based on the results of the study by Johnson et al. All of the response variables in the data were of a continuous nature, thus complicating the BMC calculation.

    With continuous data, there is not usually a clear distinction between normal and adverse responses. Crump suggested a method for developing BMCs in such cases.

    This method involves directly defining an abnormal response by specifying a cut-off within the unexposed population that separates continuous responses into normal and abnormal categories. In other words, responses that are observed to be more extreme than the cut-off are considered abnormal. This effectively reduces the continuous endpoint to a quantal endpoint. The BMC is then chosen as the concentration at which the risk of an abnormal response is increased by a specified quantity. The mean observed response may then be modelled as a function of other confounding factors such as age, weight and height.

    This method of computing BMCs was applied to the data from the study of workers exposed to carbon disulfide by Johnson et al. The original study data 1 from the population studied by Johnson et al. The data file contained measurements on exposed and unexposed workers. The measurements consisted of indicators i. Following Johnson et al. These conditions can cause peripheral neuropathy and therefore potentially mask an exposure effect. Following Egeland et al. Stepwise regression was performed to determine which confounding variables including the three exposure measures -current, cumulative and average could be used to explain the response variables.

    For those responses showing a significant relationship with exposure, BMCs were calculated using the following procedure. First, the regression was obtained of exposure and all other significant confounders on the response:. For the purpose at hand, the response y is thought of as the mean response as a function of exposure.

    Next, the responses were discretized following the method of Crump , modified to use excess risk rather than additional risk.

    In this method, it is assumed that a proportion, P 0 , of the control group will be abnormal. This proportion is chosen to be small e. The probability of a response in the unexposed population being abnormal is given by. Note that this argument assumes that larger responses are adverse.

    Blood pressure is an example of a case where a larger response is adverse, since higher blood pressure levels are associated with an increased risk of heart disease. If smaller responses are more severe, such as with nerve conduction velocities, where slower velocities are detrimental, a similar argument would hold and equation 5 would be identical, except that M would be replaced by -M. Finally, BMCL, the lower bound on the BMC, was obtained using a standard formula in linear regression for the lower bound on an inverse prediction i.

    This formula can be found in, for example, Neter et al. BMCs computed on the basis of cumulative exposures were converted to a daily exposure in ppm by dividing by The stepwise regression indicated that, of the nervous system outcomes, maximum motor conduction velocity for the peroneal nerve and sensory conduction velocity for the sural nerve were significantly related to all three exposure measures.

    If given the choice, the stepwise model would choose average exposure for peroneal motor nerve conduction velocity and cumulative exposure for sural sensory nerve conduction velocity. Average exposure was chosen to model both outcomes, however, since the model including cumulative exposure fit the sural sensory nerve conduction velocity data nearly as well r 2 of 0.

    Sural distal latency was significantly related to current exposure; when one large outlier was removed a value of As a result, sural distal latency was not utilized for BMC calculation.

    Among the risk factors for heart disease, LDL-C was significantly related to current exposure. The variables selected for inclusion in the linear regression models by the stepwise procedure were age, height, race and average exposure for the maximum motor conduction velocity of the peroneal nerve; age, height, weight and average exposure for the sensory conduction velocity of the sural nerve; and age, current exposure, weight and height for LDL-C.

    For each of peroneal motor nerve conduction velocity, sural sensory nerve conduction velocity and LDL-C, the corresponding contributing variables were input into the linear regression in equation 1, and the resulting parameter estimates were obtained.

    BMC 05 s were calculated by applying equation 6 with M equal to either 0. The resulting values are presented in Table 6. For an abnormal response based on the 5th percentile of the control population i. While serum LDL-C was also significantly associated with exposure to carbon disulfide, it is noted that the weight of evidence for cardiovascular effects is not as great as for effects on the nervous system, and the BMC calculated for this endpoint was greater than those for the peroneal motor nerve conduction velocity, in any case [Table 6].

    The BMC 05 point estimates are quite similar to the lower bounds. While neurobehavioural endpoints in animals were consistently affected by lower concentrations of carbon disulfide in developing offspring Hinkova and Tabacova, ; Tabacova et al. This source of uncertainty is discussed further in Section 3.

    An additional uncertainty factor to account for less than lifetime exposure was not considered necessary, in light of the long duration of exposure for the population on which the TC is based mean of An uncertainty factor was also not incorporated for inadequacies in the available data for some other effect s e.

    A Tolerable Intake for oral exposure to carbon disulfide has not been derived, owing to the limitations of the available data. There are no epidemiological or controlled studies of humans exposed to carbon disulfide via the oral route. The data concerning the toxicity to animals, which are limited to the results of short-term investigations of specialized endpoints in small groups of rats or mice exposed to one or two dose levels and single well-conducted and well-reported developmental toxicity studies in rats and rabbits, are considered inadequate to support exposure-response analyses for oral exposure to carbon disulfide.

    The mean airborne concentrations of carbon disulfide used to estimate exposure of the general population of Canada are 0. Assuming that people spend on average 21 hours indoors and 3 hours outdoors each day EHD, , they would be exposed to a time-weighted average concentration of 0.

    This concentration is fold less than the TC derived above. The mean concentrations of carbon disulfide measured in air in limited available studies in the vicinity of point sources in Canada ranged from 1. These concentrations are 7- to fold less than the TC. There is a high degree of uncertainty inherent in the mean estimates of the intake of carbon disulfide in air, the likely principal medium of exposure, due to the paucity of monitoring data for both outdoor and indoor air.

    The estimated intakes from air are based on the results of a very small U. While the low levels measured in ambient air in this study are supported by other available data, all of the available studies are extremely limited, inasmuch as they were conducted at very few locations, for very short time periods and often using methods that were not sufficiently sensitive to reliably detect carbon disulfide at ambient levels.

    The same limitations apply to the extremely limited data that exist on the levels of carbon disulfide in the vicinity of point sources in Canada. Moreover, how the monitoring stations in these studies were situated with respect to the point of impingement of the point source emissions was not often reported, nor were the size and location of local human populations. Finally, there are very few data on levels of carbon disulfide in indoor air.

    There is also some uncertainty introduced by the lack of current, representative monitoring data for food. Although carbon disulfide is no longer registered for food applications in Canada and the results of fugacity modelling suggest that it does not accumulate to an appreciable degree in terrestrial plants and animals, it is known to be a soil and plant metabolite of some thiocarbamate pesticides applied to fruit crops.

    Carbon disulfide is also known to be a metabolite produced by plants and soil organisms from naturally occuring sulfur compounds. However, no information was accessed with which to quantitatively estimate the potential for exposure to carbon disulfide in Canada from these sources Ballantine, ; Moore, There is, however, a fair degree of certainty that drinking water and soil contribute only negligible amounts to the total exposure to carbon disulfide.

    Based on data from a limited survey of treated drinking water and a very small survey of soils from non-contaminated areas, even the upper range of estimated intakes via these media, calculated by assuming that carbon disulfide was present at the detection limit in samples in which it was not detected the vast majority , is orders of magnitude lower than those from indoor or outdoor ai r.

    Furthermore , these estimates are consistent with what is known concerning anthropogenic releases in Canada i. The overall degree of confidence in the population exposure estimates is, therefore, low, owing principally to the scarcity of data on levels of carbon disulfide in air, the principal medium of exposure.

    To a lesser extent, uncertainty arises from the lack of knowledge concerning the contribution of food to total environmental exposure, particularly the possible role of dithiocarbamate pesticides and naturally occuring sulfur compounds as a source of general population exposure. The degree of confidence in the available data regarding the effects of exposure to carbon disulfide is moderate. There is a fair degree of confidence in the results of the critical study by Johnson et al.

    Further, there is consistent support for the critical effect i. However, while the exposure characterization in the critical study was based on personal monitoring of a population for whom a large majority had had the same work assignment for the duration of their employment, it is noted that the personal monitoring was conducted only over a few days at the time of the study and on a minority of the study population.

    Further, in the exposure-response analyses in the original paper by Johnson et al. There is also additional uncertainty arising because the critical effect i. Moreover, it is likely that similar effects are occurring in the long axons of the central nervous system indeed, Hirata et al. Finally, there is considerable uncertainty introduced by the limitations of the available database, particularly with respect to the effects of carbon disulfide on neurobehavioural development.

    While the available data in animals consistently indicate that the developing offspring is more sensitive to the neurotoxicity of carbon disulfide than the adult there are no data regarding neurobehavioural effects in humans exposed in utero , the degree of the difference in sensitivity is not at all clear, as a consequence of the variety of endpoints that have been examined, the inconsistency in the concentrations that have been employed and the inadequate reporting in a number of the key studies.

    Consequently, these data are inadequate to serve as a basis for developing a TC. Although the confidence in these studies, which were conducted in one laboratory and were poorly reported in some cases, is low, research into the effects of carbon disulfide on neurobehavioural development is considered an important area for further work, given the very low effect levels reported in some of these studies.

    In particular, while there are a number of developmental studies [ Section 2. While the available data concerning other effects of exposure to carbon disulfide e. CEPA 64 a: Based on available data, it has been concluded that carbon disulfide is not entering the environment in a quantity or concentration or under conditions that have or may have an immediate or long-term harmful effect on the environment or its biological diversity.

    Therefore, carbon disulfide is not considered to be "toxic" as defined in Paragraph 64 a of CEPA CEPA 64 b: Based on available data, it has been concluded that carbon disulfide is not entering the environment in a quantity or concentration or under conditions that constitute or may constitute a danger to the environment on which life depends. Therefore, carbon disulfide is not considered to be "toxic" as defined in Paragraph 64 b of CEPA CEPA 64 c: Based on available data, it has been concluded that carbon disulfide is not entering the environment in a quantity or concentration or under conditions that constitute or may constitute a danger in Canada to human life or health.

    Therefore, carbon disulfide is not considered to be "toxic" as defined in Paragraph 64 c of CEPA Based on critical assessment of relevant information, carbon disulfide is not considered to be "toxic" as defined in Section 64 of CEPA Since carbon disulfide is not considered to be "toxic" as defined in Section 64 of CEPA investigation of options to reduce exposure under CEPA is not considered a priority at this time.

    However, this is based upon current use patterns; thus, future releases of this compound should continue to be monitored to ensure that exposure does not increase to any significant extent.

    Available data indicate that anthropogenic releases of carbon disulfide into the environment in Canada at present are virtually all from the processing of gas and oil. Identification of organic compounds in effluents from industrial sources. Policy review of solution gas flaring and conservation in Alberta. Health effects of occupational exposures to carbon disulfide.

    Toxicological profile for carbon disulfide update. Behavioural effects, most often reduced exploratory activity in open field tests, were also reported at levels between 0. Exposure over two generations appeared to result in greatly increased sensitivity to the teratogenic effects of carbon disulfide, causing malformations at as little as 0. However, it is difficult to evaluate the validity of these findings.

    The studies are generally only briefly reported, and important information e. There is also some inconsistency in the findings; for example, Tabacova et al.

    Moreover, the results of subsequent studies, most of which are better reported, have generally failed to confirm the teratogenic findings reported by Tabacova and colleagues, although it should be noted that some of the studies conducted by these investigators differed somewhat in their design e.

    In another study Belisles et al. However, there is some weak support for the behavioural effects reported by Tabacova and colleagues Hinkova and Tabacova, ; Tabacova et al.

    Significant increases in visceral and skeletal malformations were also observed at the higher, maternally toxic, dose level PAI, However, it is difficult to assess the validity of these results, owing to mortality among the dams from causes that were apparently unrelated to the chemical exposure.

    The highest dose also induced significant increases in the frequency of malformed fetuses Jones-Price et al. Carbon disulfide can be metabolized in the liver by the cytochrome P monooxygenase system to an unstable oxygen intermediate that either spontaneously generates atomic sulfur, carbonyl sulfide and carbon dioxide or hydrolyzes to form atomic sulfur and monothiocarbonate, yielding carbonyl sulfide and carbon dioxide in breath and inorganic sulfates and organosulfur compounds in urine.

    Alternatively, dithiocarbamates are formed in humans and animals by reaction with amino acids; conjugation of carbon disulfide or carbonyl sulfide with endogenous glutathione forms TTCA and 2-oxythiazolidinecarboxylic acid, respectively, which are excreted in urine ATSDR, As reviewed by Graham et al.

    The adducts decompose to an electrophile isothiocyanate and isocyanate, respectively , which in turn reacts with protein nucleophiles on the neurofilaments to cause protein cross-linking. However, it is noted that, although the metabolites resulting from carbonyl sulfide have been identified, the production of protein cross-links via this pathway has not yet been demonstrated.

    Progressive cross-linking of the neurofilament occurs during its transport along the axon, and covalently cross-linked masses of neurofilaments may occlude axonal transport at the nodes of Ranvier, ultimately resulting in axonal swelling and degeneration. The environmental risk assessment of a PSL substance is based on the procedures outlined in Environment Canada a. Analysis of exposure pathways and subsequent identification of sensitive receptors are used to select environmental assessment endpoints e.

    If these quotients are less than one, it can be concluded that the substance poses no significant risk to the environment, and the risk assessment is completed. If, however, the quotient is greater than one for a particular assessment endpoint, then the risk assessment for that endpoint proceeds to an analysis where more realistic assumptions are used and the probability and magnitude of effects are considered. This latter approach involves a more thorough consideration of sources of variability and uncertainty in the risk analysis.

    In Canada, nearly all carbon disulfide is released to air. Therefore, terrestrial organisms living near industrial sources are chosen as assessment endpoints, as these organisms are the most likely to have the highest potential for exposure and effects. Despite the fact that nearly all releases of carbon disulfide are to the atmosphere, there are releases to water.

    Since aquatic organisms close to discharge points could also be affected, they are also selected as assessment endpoints. Toxicity test results are available for terrestrial plants, invertebrates and vertebrates, all of which can be exposed to carbon disulfide in the atmosphere.

    The most sensitive organism identified in these studies was the mouse, and effects data for this organism were used for the risk characterization for terrestrial organisms.

    Toxicity test results are available for algae, Daphnia, an amphibian and several fish species. The most sensitive organism identified in these tests was the invertebrate, Daphnia magna, and effects data for this species were used for the risk characterization for aquatic organisms. Aquatic invertebrates are key consumers in the aquatic food web and are themselves consumed by other species of invertebrates and by vertebrates.

    The CTV for terrestrial organisms is 6. Dividing this CTV by an application factor of to account for the conversion of an LC 50 to a long-term no-effects value, extrapolation from laboratory to field conditions and interspecies and intraspecies variations in sensitivity gives an ENEV of 6. Since this hyperconservative quotient is less than 1, it is very unlikely that carbon disulfide causes adverse effects on populations of terrestrial organisms in Canada.

    The conservative EEV for aquatic biota is 3. This value is believed to be conservative, because emissions of carbon disulfide to the environment have decreased significantly since the early s.

    The CTV is 2. Since this quotient is less than 1, it is unlikely that carbon disulfide causes adverse effects on populations of aquatic organisms in Canada. There are several sources of uncertainty in this assessment, the principal one being the lack of recent ambient concentration data in most Canadian media. The EEV for air, the principal environmental compartment of concern, was, however, based on monitoring data in areas where the largest Canadian releases occur.

    Furthermore, it represents a maximum value over a very short time period 8 minutes. It is very unlikely that environmental concentrations resulting from pulsed releases of carbon disulfide would be underestimated by this value.

    The EEV for air is furthermore supported by the modelling study of The and by monitoring data near other similar sources. It should also be noted that since the substance was first proposed as a priority for assessment, the majority of Canadian industrial users of carbon disulfide have either ceased operation or improved emission controls.

    Consequently, the ambient concentrations of carbon disulfide in the various environmental compartments near such industrial sources in Canada would likely be lower than the values presented in the literature.

    In the case of surface waters, for example, the values obtained for carbon disulfide from the literature are at least 12 years old; as most releases from industrial sources have decreased since then, these older values likely represent a conservative exposure scenario for surface water. Regarding effects of carbon disulfide on terrestrial and aquatic organisms, uncertainty surrounds the extrapolation from available acute toxicity data to prediction of long-term ecosystem effects.

    For wildlife, and especially small mammals, inhalation exposure in laboratory animals was used as a surrogate for actual exposure in the field. While the aquatic toxicit y data set included studies on organisms from a variety of ecological niches and taxa, there are no chronic studies available for invertebrates or fish. To account for these uncertainties, conservative application factors were used in the environmental risk analysis to derive ENEVs. Despite some data gaps regarding the environmental effects and exposure of carbon disulfide, the data available at this time are considered adequate to assess the environmental risk of carbon disulfide in Canada.

    The calculations shown in Section 2. The magnitude of this effect would depend upon the concentration of carbon disulfide in the atmosphere, and the concentration of carbon disulfide in Canadian air is very low relative to the concentrations of volatile organic compounds that are responsible for ozone formation. Consequently, the contribution of carbon disulfide to ground-level ozone formation is not expected to be significant.

    Based on the above, the atmospheric effects of carbon disulfide are not expected to be significant. It is proposed at this time that carbon disulfide not be considered "toxic" as defined under CEPA Paragraph 64 b. Data on levels of carbon disulfide in environmental media to serve as the basis for development of estimates of population exposure in Canada are limited to a small number of surveys of ambient air conducted at few locations in Canada or in the United States and limited Canadian surveys in drinking water and soil in which carbon disulfide was seldom detected.

    Meaningful probabilistic exposure assessment is precluded, therefore. In this section, mean deterministic estimates of environmental intake from air, water and soil by members of the general population of Canada have been derived. These are followed by consideration of mean estimates of potential airborne exposures by populations in the vicinity of point sources in Canada, based on the very limited available data.

    Point estimates of total daily intake of carbon disulfide by six age groups of the general population of Canada were developed Table 5 , primarily to determine the relative contributions from various media. These estimates indicate that intake from environmental exposure to carbon disulfide is virtually all from inhalation.

    That air is the principal route of exposure is supported by the results of the EQC and ChemCAN4 fugacity modelling, which indicate that virtually all of the carbon disulfide released to air industrial releases in Canada are almost entirely to air will tend to remain in that compartment. However, it is noted that the atmospheric concentrations predicted by the ChemCAN4 fugacity modelling are an order of magnitude or more lower than those measured in ambient air in a number of studies throughout the world.

    This may reflect the combined contribution of natural sources, local anthropogenic sources and advective inputs from outside of the region to the levels measured. Exposure from ingestion of drinking water and soil appears to be negligible in comparison with that from air. For smokers, it is estimated that cigarette smoking can increase the intake of carbon disulfide severalfold. Intake by cigarette smokers Phillips, ; Section 2.

    In calculating the mean, a value of one-half the detection limit 0. It is also known that concentrations of carbon disulfide in ambient air are elevated in the vicinity of some point sources in Canada Section 2.

    Based on the range of mean concentrations measured in the vicinity of natural gas processing 1. The data most relevant to hazard characterization are those from epidemiological studies of populations exposed to carbon disulfide in the workplace.

    In this section, the available data for those effects that are potentially critical i. While the epidemiological data regarding the association between exposure to carbon disulfide and damage to the retinal capillaries [ Section 2.

    The weight of evidence for the remaining categories of effects discussed in Sections 2. Effects on the nervous system, including neurophysiological, behavioural and pathological effects, were reported in a large number of cross-sectional studies of viscose rayon workers Section 2. The most common findings were reduced conduction velocity in the motor and sensory nerves, generally most pronounced in the more distal portions of the nervous system e.

    There are also a small number of reports of impaired performance on neuropsychological testing, most often on psychomotor tests of motor speed or dexterity, in workers exposed to relatively high levels of carbon disulfide.

    Hence, there is evidence of both consistency and specificity for these effects on the nervous system. In most instances when subgroups of the study populations were analysed separately, the reductions in nerve conduction velocities were most pronounced in those workers with exposure to the highest concentrations, those employed in tasks that were considered to entail the highest exposures or those with the greatest cumulative exposures Gilioli et al.

    In addition, effects on peripheral nerve conduction velocity were generally observed at lower levels than were other effects on the nervous system, particularly the psychomotor effects, both within and between studies Cassitto et al. Hence, there is evidence of a dose-response relationship for effects on peripheral nerve conduction velocity and other parts of the nervous system, both within and across studies. With respect to temporality, results are conflicting; although there is little information, reductions in nerve conduction velocity in workers who were removed from exposure for a number of years were less pronounced often non-significant than in workers who were currently exposed in some studies Hirata et al.

    However, the lack of temporality is not unexpected in light of the limited capacity of the peripheral nervous system to regenerate. The effects reported on the peripheral nervous system are supported by the results of studies of animals exposed subchronically or chronically by inhalation, in which nerve conduction velocity in the peripheral nerves or spinal cord was consistently reduced, accompanied by histopathological lesions and biochemical changes similar to those induced by certain other compounds that cause axonopathy e.

    Similar histopathological alterations, accompanied by clinical and neurophysiological signs of peripheral neuropathy, were also reported in a worker exposed to relatively high levels of carbon disulfide Chu et al. In several studies in rats, exposure to carbon disulfide also affected performance in neurobehavioural testing or altered levels of catecholamines in the brain or adrenals Section 2.

    Although impaired performance in certain behavioural tests was evident in animals at earlier time points and at lower levels than histopathological or neurophysiological effects, in contrast to the results of epidemiological studies, the changes observed [i. While the exact mechanism of action is not yet known, there is considerable evidence that the axonal degeneration that underlies the neuropathy may be the result of covalently cross-linked masses of neurofilaments occluding axonal transport at the nodes of Ranvier Section 2.

    Excess mortality from coronary heart disease has been observed in a number of cohorts of viscose rayon workers exposed to carbon disulfide. While there was inadequate account taken of factors known to affect heart disease e. The strength of the association was moderate to high, with relative risks ranging from 1.

    There was evidence of a dose-response relationship in most of the studies in which it was examined, although exposure was not well characterized in any of the investigations, and this was based principally on rather crude measures - i. The excesses were generally much less pronounced following elimination or reduction of exposure e.

    The results of cross-sectional studies of cardiovascular morbidity or of clinical measures known to be related to risk from heart disease are generally consistent with the reported excesses of mortality from coronary heart disease. In a number of cross-sectional studies, occupational exposure to carbon disulfide was associated with clinical changes that increase the risk of heart disease, including increases in blood pressure and in serum levels of total cholesterol and LDL-C and with decreases in serum levels of HDL-C.

    Potential confounders, such as age and smoking, were accounted for in most of these studies. In those studies where internal comparisons were made, these effects were related to the extent of exposure i. However, while these effects were fairly consistently absent in less exposed populations and present in moderately or heavily exposed populations, the available data are not entirely consistent in this regard. For example, increases in total cholesterol were observed in some studies Wronska-Nofer and Laurman, ; Vanhoorne et al.

    In the German workers studied by Drexler et al. Thus, exposure of occupational populations to carbon disulfide has been associated with increased risks for coronary heart disease at a number of levels of manifestation, including mortality, morbidity and risk factors, providing a coherent picture.

    There is little information relevant to temporality for effects other than mortality, although Toyama and Sakurai observed that an initial significant difference in total serum cholesterol in Japanese viscose rayon workers disappeared in a second survey, conducted after airborne concentrations had been reduced severalfold.

    The biological plausibility of these findings is supported by the results of studies in animals, in which chronic exposure of rats to high levels of airborne carbon disulfide consistently altered lipid metabolism, resulting in increased serum levels of cholesterol and other blood lipids and exacerbating the atherogenic effects of a lipid-rich diet Section 2.

    Hence, the traditional criteria for causality for associations observed in epidemiological studies are fulfilled, at least in part, for cardiovascular effects associated with exposure to carbon disulfide. The weight of evidence for effects on the nervous system, which meets most of the traditional criteria for causality in epidemiological studies including consistency, specificity, dose-response relationship, coherence and biological plausibility , is clearly the strongest from among the various types of effects observed in epidemiological studies that might have been considered critical.

    Further, while the effects on the nervous system do not appear to meet the criterion of temporality, this is expected, given the limited capability of the nervous system for regeneration. While the weight of evidence for effects on the cardiovascular system meets several of the criteria for causality, there are several inconsistencies in the dose-response across studies, and potential modes of action have not been as well elucidated as for the reductions in peripheral nerve conduction velocity.

    Further, there is a high background prevalence of heart disease, and it is affected by a number of other factors, with the result that the dose-response curve is shallow and variable, limiting the ability to detect a compound-related effect more than is the case for a specific effect such as nerve conduction velocity.

    Effects on the peripheral nerve conduction velocity have also been fairly consistently observed at concentrations that are lower than those at which other effects were observed, and, as noted in the next section, this effect also yields a lower benchmark concentration BMC than for cardiovascular risk factors.

    While the populations of viscose rayon workers in which effects on the nervous system were observed had concomitant exposure to carbon disulfide and hydrogen sulfide, the available evidence indicates that the effects on peripheral nerve conduction velocity were due to carbon disulfide alone. In these studies, concentrations of hydrogen sulfide were typically much less than concentrations of carbon disulfide.

    In addition, the results of a large number of studies in animals have confirmed that carbon disulfide reduces peripheral nerve conduction velocity and have documented the associated histopathological and ultrastructural changes in the axons of the peripheral nerves Section 2. In one study, motor tail nerve conduction velocity in rats was reduced by exposure to carbon disulfide but was not affected by hydrogen sulfide alone, nor did hydrogen sulfide modify the effect of carbon disulfide in combined exposures Gagnaire et al.

    Concentrations of carbon disulfide in the viscose rayon industry are known to have declined substantially over the several decades encompassed by the available epidemiological studies Price et al. In addition, it i s clear that exposures vary considerably between sites at a given workplace and between job titles Vanhoorne and Grosjean, Based principally on the results of studies that meet these criteria, effects on the nervous system that occurred at the lowest concentrations in humans were reductions in conduction velocity in the peripheral motor or sensory nerves, which were observed in several studies of viscose rayon workers with long-term exposure to carbon disulfide.

    There is also fairly consistent evidence of effects on the results of neurobehavioural testing in such populations, but such effects have not been observed at levels as low as those associated with alterations in peripheral nerve conduction velocity, and the exposure-response has been less well characterized. It is not possible at present to identify a quantitative relationship between a given decrease in nerve conduction velocity and an expected degree of loss of function.

    However, it is noted that nerve conduction velocity is a relatively crude indicator of effects of carbon disulfide on the nerves, because function is not impaired until axonal degeneration has actually occurred, in contrast to agents that produce demyelination or have a direct effect on conduction. An additional concern is that, although the effect is measured in the peripheral nervous system, because carbon disulfide produces a central-peripheral distal axonopathy, it is likely that the long axons of the central nervous system are also affected.

    Further, there is only limited capability for regeneration in the peripheral nervous system, and even less in the central nervous system.

    In short, while reduced nerve conduction velocity by itself may not produce an adverse health outcome, it is indicative of, and a precursor of, other changes that clearly are adverse; given the limited reversibility of this effect, a precautionary approach is warranted. Consequently, the critical effect for the characterization of exposure-response is defined as a statistically significant, compound-related decrease in peripheral nerve conduction velocity.

    However, in only one of the available epidemiological studies in which there was an association between exposure to carbon disulfide and reductions in peripheral nerve conduction velocity was the exposure of the study population adequately characterized to permit quantitative exposure-response analyses - i.

    In the remaining key studies, the analysis was limited to a comparison of exposed versus control workers Hirata et al. In addition, the design of the study by Johnson et al. Based on the results of the study by Johnson et al. All of the response variables in the data were of a continuous nature, thus complicating the BMC calculation.

    With continuous data, there is not usually a clear distinction between normal and adverse responses. Crump suggested a method for developing BMCs in such cases. This method involves directly defining an abnormal response by specifying a cut-off within the unexposed population that separates continuous responses into normal and abnormal categories.

    In other words, responses that are observed to be more extreme than the cut-off are considered abnormal. This effectively reduces the continuous endpoint to a quantal endpoint. The BMC is then chosen as the concentration at which the risk of an abnormal response is increased by a specified quantity. The mean observed response may then be modelled as a function of other confounding factors such as age, weight and height.

    This method of computing BMCs was applied to the data from the study of workers exposed to carbon disulfide by Johnson et al. The original study data 1 from the population studied by Johnson et al. The data file contained measurements on exposed and unexposed workers. The measurements consisted of indicators i. Following Johnson et al. These conditions can cause peripheral neuropathy and therefore potentially mask an exposure effect.

    Following Egeland et al. Stepwise regression was performed to determine which confounding variables including the three exposure measures -current, cumulative and average could be used to explain the response variables. For those responses showing a significant relationship with exposure, BMCs were calculated using the following procedure.

    First, the regression was obtained of exposure and all other significant confounders on the response:. For the purpose at hand, the response y is thought of as the mean response as a function of exposure. Next, the responses were discretized following the method of Crump , modified to use excess risk rather than additional risk.

    In this method, it is assumed that a proportion, P 0 , of the control group will be abnormal. This proportion is chosen to be small e. The probability of a response in the unexposed population being abnormal is given by. Note that this argument assumes that larger responses are adverse. Blood pressure is an example of a case where a larger response is adverse, since higher blood pressure levels are associated with an increased risk of heart disease.

    If smaller responses are more severe, such as with nerve conduction velocities, where slower velocities are detrimental, a similar argument would hold and equation 5 would be identical, except that M would be replaced by -M. Finally, BMCL, the lower bound on the BMC, was obtained using a standard formula in linear regression for the lower bound on an inverse prediction i.

    This formula can be found in, for example, Neter et al. BMCs computed on the basis of cumulative exposures were converted to a daily exposure in ppm by dividing by The stepwise regression indicated that, of the nervous system outcomes, maximum motor conduction velocity for the peroneal nerve and sensory conduction velocity for the sural nerve were significantly related to all three exposure measures. If given the choice, the stepwise model would choose average exposure for peroneal motor nerve conduction velocity and cumulative exposure for sural sensory nerve conduction velocity.

    Average exposure was chosen to model both outcomes, however, since the model including cumulative exposure fit the sural sensory nerve conduction velocity data nearly as well r 2 of 0. Sural distal latency was significantly related to current exposure; when one large outlier was removed a value of As a result, sural distal latency was not utilized for BMC calculation.

    Among the risk factors for heart disease, LDL-C was significantly related to current exposure. The variables selected for inclusion in the linear regression models by the stepwise procedure were age, height, race and average exposure for the maximum motor conduction velocity of the peroneal nerve; age, height, weight and average exposure for the sensory conduction velocity of the sural nerve; and age, current exposure, weight and height for LDL-C.

    For each of peroneal motor nerve conduction velocity, sural sensory nerve conduction velocity and LDL-C, the corresponding contributing variables were input into the linear regression in equation 1, and the resulting parameter estimates were obtained. BMC 05 s were calculated by applying equation 6 with M equal to either 0. The resulting values are presented in Table 6.

    For an abnormal response based on the 5th percentile of the control population i. While serum LDL-C was also significantly associated with exposure to carbon disulfide, it is noted that the weight of evidence for cardiovascular effects is not as great as for effects on the nervous system, and the BMC calculated for this endpoint was greater than those for the peroneal motor nerve conduction velocity, in any case [Table 6]. The BMC 05 point estimates are quite similar to the lower bounds.

    While neurobehavioural endpoints in animals were consistently affected by lower concentrations of carbon disulfide in developing offspring Hinkova and Tabacova, ; Tabacova et al. This source of uncertainty is discussed further in Section 3. An additional uncertainty factor to account for less than lifetime exposure was not considered necessary, in light of the long duration of exposure for the population on which the TC is based mean of An uncertainty factor was also not incorporated for inadequacies in the available data for some other effect s e.

    A Tolerable Intake for oral exposure to carbon disulfide has not been derived, owing to the limitations of the available data. There are no epidemiological or controlled studies of humans exposed to carbon disulfide via the oral route. The data concerning the toxicity to animals, which are limited to the results of short-term investigations of specialized endpoints in small groups of rats or mice exposed to one or two dose levels and single well-conducted and well-reported developmental toxicity studies in rats and rabbits, are considered inadequate to support exposure-response analyses for oral exposure to carbon disulfide.

    The mean airborne concentrations of carbon disulfide used to estimate exposure of the general population of Canada are 0. Assuming that people spend on average 21 hours indoors and 3 hours outdoors each day EHD, , they would be exposed to a time-weighted average concentration of 0. This concentration is fold less than the TC derived above. The mean concentrations of carbon disulfide measured in air in limited available studies in the vicinity of point sources in Canada ranged from 1.

    These concentrations are 7- to fold less than the TC. There is a high degree of uncertainty inherent in the mean estimates of the intake of carbon disulfide in air, the likely principal medium of exposure, due to the paucity of monitoring data for both outdoor and indoor air.

    The estimated intakes from air are based on the results of a very small U. While the low levels measured in ambient air in this study are supported by other available data, all of the available studies are extremely limited, inasmuch as they were conducted at very few locations, for very short time periods and often using methods that were not sufficiently sensitive to reliably detect carbon disulfide at ambient levels.

    The same limitations apply to the extremely limited data that exist on the levels of carbon disulfide in the vicinity of point sources in Canada. Moreover, how the monitoring stations in these studies were situated with respect to the point of impingement of the point source emissions was not often reported, nor were the size and location of local human populations.

    Finally, there are very few data on levels of carbon disulfide in indoor air. There is also some uncertainty introduced by the lack of current, representative monitoring data for food. Although carbon disulfide is no longer registered for food applications in Canada and the results of fugacity modelling suggest that it does not accumulate to an appreciable degree in terrestrial plants and animals, it is known to be a soil and plant metabolite of some thiocarbamate pesticides applied to fruit crops.

    Carbon disulfide is also known to be a metabolite produced by plants and soil organisms from naturally occuring sulfur compounds. However, no information was accessed with which to quantitatively estimate the potential for exposure to carbon disulfide in Canada from these sources Ballantine, ; Moore, There is, however, a fair degree of certainty that drinking water and soil contribute only negligible amounts to the total exposure to carbon disulfide.

    Based on data from a limited survey of treated drinking water and a very small survey of soils from non-contaminated areas, even the upper range of estimated intakes via these media, calculated by assuming that carbon disulfide was present at the detection limit in samples in which it was not detected the vast majority , is orders of magnitude lower than those from indoor or outdoor ai r.

    Furthermore , these estimates are consistent with what is known concerning anthropogenic releases in Canada i. The overall degree of confidence in the population exposure estimates is, therefore, low, owing principally to the scarcity of data on levels of carbon disulfide in air, the principal medium of exposure.

    To a lesser extent, uncertainty arises from the lack of knowledge concerning the contribution of food to total environmental exposure, particularly the possible role of dithiocarbamate pesticides and naturally occuring sulfur compounds as a source of general population exposure. The degree of confidence in the available data regarding the effects of exposure to carbon disulfide is moderate.

    There is a fair degree of confidence in the results of the critical study by Johnson et al. Further, there is consistent support for the critical effect i.

    However, while the exposure characterization in the critical study was based on personal monitoring of a population for whom a large majority had had the same work assignment for the duration of their employment, it is noted that the personal monitoring was conducted only over a few days at the time of the study and on a minority of the study population.

    Further, in the exposure-response analyses in the original paper by Johnson et al. There is also additional uncertainty arising because the critical effect i. Moreover, it is likely that similar effects are occurring in the long axons of the central nervous system indeed, Hirata et al.

    Finally, there is considerable uncertainty introduced by the limitations of the available database, particularly with respect to the effects of carbon disulfide on neurobehavioural development. While the available data in animals consistently indicate that the developing offspring is more sensitive to the neurotoxicity of carbon disulfide than the adult there are no data regarding neurobehavioural effects in humans exposed in utero , the degree of the difference in sensitivity is not at all clear, as a consequence of the variety of endpoints that have been examined, the inconsistency in the concentrations that have been employed and the inadequate reporting in a number of the key studies.

    Consequently, these data are inadequate to serve as a basis for developing a TC. Although the confidence in these studies, which were conducted in one laboratory and were poorly reported in some cases, is low, research into the effects of carbon disulfide on neurobehavioural development is considered an important area for further work, given the very low effect levels reported in some of these studies.

    In particular, while there are a number of developmental studies [ Section 2. While the available data concerning other effects of exposure to carbon disulfide e.

    CEPA 64 a: Based on available data, it has been concluded that carbon disulfide is not entering the environment in a quantity or concentration or under conditions that have or may have an immediate or long-term harmful effect on the environment or its biological diversity.

    Therefore, carbon disulfide is not considered to be "toxic" as defined in Paragraph 64 a of CEPA CEPA 64 b: Based on available data, it has been concluded that carbon disulfide is not entering the environment in a quantity or concentration or under conditions that constitute or may constitute a danger to the environment on which life depends. Therefore, carbon disulfide is not considered to be "toxic" as defined in Paragraph 64 b of CEPA CEPA 64 c: Based on available data, it has been concluded that carbon disulfide is not entering the environment in a quantity or concentration or under conditions that constitute or may constitute a danger in Canada to human life or health.

    Therefore, carbon disulfide is not considered to be "toxic" as defined in Paragraph 64 c of CEPA Based on critical assessment of relevant information, carbon disulfide is not considered to be "toxic" as defined in Section 64 of CEPA Since carbon disulfide is not considered to be "toxic" as defined in Section 64 of CEPA investigation of options to reduce exposure under CEPA is not considered a priority at this time.

    However, this is based upon current use patterns; thus, future releases of this compound should continue to be monitored to ensure that exposure does not increase to any significant extent. Available data indicate that anthropogenic releases of carbon disulfide into the environment in Canada at present are virtually all from the processing of gas and oil. Identification of organic compounds in effluents from industrial sources.

    Policy review of solution gas flaring and conservation in Alberta. Health effects of occupational exposures to carbon disulfide.

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    Stimulation of dopamine-b-hydroxylase in rat adrenals by repeated exposures to carbon disulphide. Carbon disulphide exposure affects the response of rat adrenal medulla to hypothermia and hypoglycaemia. Formation of volatile sulfides in freshwater environments.

    Subjective and objective behavioural alterations in carbon disulphide workers. Proceedings of a symposium, Prague, September , Excerpta Medica Foundation, Amsterdam. The evaluation of the health state of the workers occupationally exposed to low concentration of carbon disulphide CS 2.

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    Determination of fumigants and related chemicals in fatty and nonfatty foods. De Bacquer and M. Neuropsychological effects of occupational exposures to carbon disulfide and hydrogen sulfide. Pathways analysis using fugacity modeling of carbon disulfide for the second Priority Substances List. Carbon disulfide is not mutagenic in bacteria or Drosophila. Risk factors for coronary heart diseases in workers in the viscose industry.

    Cardiovascular function in workers in the viscose industry. Effects of exposure to carbon disulphide on low density lipoprotein cholesterol concentration and diastolic blood pressure.

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    Alberta Environmental Protection, Edmonton, Alberta. The influence of simultaneous exposure to carbon disulfide and hydrogen sulfide on the peripheral nerve toxicity and metabolism of carbon disulfide in rats. Preparation for human study of pesticide applicators: Toxicity and teratogenic effects in the frog embryo.

    Effect of carbon disulfide on liver function in vivo and in the isolated perfused liver. Study of neurological and neurophysiological impairment in carbon disulphide workers.

    Effect of repeated inhalation of vapors of industrial solvents on animal behaviour. Evaluation of nine solvent vapors on pole-climb performance in rats.

    Behavioural response of rats during inhalation of trichloroethylene and carbon disulphide vapours. The medical and hygienic prevention of carbon disulphide poisoning in Japan. Studies on chronic carbon disulfide poisoning. Pathogenesis of retinal microaneurysms due to carbon disulfide, with special reference to a subclinical defect of carbohydrate metabolism. The morphology of carbon disulphide neurotoxicity. Pathogenetic studies of hexane and carbon disulfide neurotoxicity.

    Psychological picture of manifest and latent carbon disulphide poisoning. Psychological tests as indicators of excessive exposure to carbon disulfide. Testing of selected workplace chemicals for teratogenic potential. Salmonella mutagenicity test results for chemicals. Canadian Environmental Protection Act. Human health risk assessment for Priority Substances.

    Mutagenicity and metabolism studies on 12 thiuram and dithiocarbamate compounds used as accelerators in the Swedish rubber industry. Purge and trap method for determination of volatile hydrocarbons and carbon disulfide in table-ready foods. Purge and trap method for determination of fumigants in whole grains, milled grain products, and intermediate grain-based foods.

    Community study of spontaneous abortions: Spontaneous abortions among female chemical workers in Finland. Epidemiology of coronary heart disease among viscose rayon workers. Coronary heart disease among workers exposed to carbon disulphide. Blood lipids, glucose tolerance and plasma creatinine in workers exposed to carbon disulphide.

    Excess mortality from coronary heart disease in viscose rayon workers exposed to carbon disulphide. Carbon disulfide neurotoxicity in rats: Electrophysiological examination of caudal tail nerve compound action potentials and nerve conduction velocity.

    Open field exploration in two successive generations of rats treated with carbon disulphide throughout gestation. Changes in auditory brainstem response in rats chronically exposed to carbon disulfide. A cross-sectional study on the brainstem auditory evoked potential among workers exposed to carbon disulphide. A cross-sectional study on nerve conduction velocities among workers exposed to carbon disulphide. Effects of carbon disulfide on cardiovascular function after acute and subacute exposure of rats.

    Subacute carbon disulfide exposure modifies adrenergic cardiovascular actions in rats. Quantitative determination of sulfur compounds in the gas phase of cigarette smoke.

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    Histochemically demonstrable non-specific cholinesterase as an indicator of peripheral nerve lesion in carbon-disulphide-induced polyneuropathy.

    Histochemical and electron microscopic observations on the myoneural junctions of rats with carbon disulfide induced polyneuropathy. Volatile contaminants in the Welland River watershed. Volatile halocarbon contaminants in the Niagara River and in Lake Ontario. Quantitative evaluation of ECG components of workers exposed to carbon disulfide.

    The phytotoxic effect of carbon bisulfide, methyl bromide, and hydrogen phosphide on the germination of seeds of certain field crops. A fluorescein angiographic study on carbon disulphide retinopathy among workers in viscose rayon factories. Role of decomposition products in sodium methyldithiocarbamate-induced immunotoxicity. Sources of atmospheric carbonyl sulfide and carbon disulfide. Carbon disulfide in sea water and the marine atmosphere over the North Atlantic.

    Carbon disulfide exposure attenuates adrenergic inotropic response in rats. Conduction velocity in the peripheral nerves of rats with chronic carbon disulphide neuropathy.

    The effects of long-term occupational exposure to carbon disulphide on serum lipids. Effects of exposure to carbon disulfide CS 2 on electrocardiographic features of ischemic heart disease among viscose rayon factory workers.

    Human sperm chromosome analysis - study on human sperm chromosome mutagens induced by carbon disulfide.

    Emissions of marine biogenic sulfur to the atmosphere. Characteristics of the background air quality. Lewis Publishers, Chelsea, Michigan. Air quality of an area proximal to anthropogenic emissions. Behavioural effects of prenatal exposure to carbon disulphide and to Aromatol in rats. Effects of paternal occupational exposure on spontaneous abortions. Mortality among workers exposed to carbon disulfide. Eight years of experience with experimental CS 2 polyneuropathy in rats.

    Mortality of the cohort of employees in a viscose factory up to 31 December Evaluating the multimedia fate of organic chemicals: Mortality in the US rayon industry.

    Effects of diethyldithiocarbamate and carbon disulphide on brain tyrosine. Epidemiological study of workers employed in the viscose rayon industry. Biochemical and morphological investigations on nervous tissue of rats inhaling carbon disulphide. Application of effective born relative permitivity functions for the evaluation of polarity effect of solutes on the octanol-water partition coefficient.

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    A benchmark concentration for carbon disulfide: A review of carbon disulfide exposure data and the association between carbon disulfide exposure and ischemic heart disease mortality.

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    Trace gas trends and their potential role in climate change.

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    Intramuscular heroin. Intravenous heroin. comes from the limited urinary excretion data from controlled clinical studies. . 15,8 mg THC, varieerden de THCCOOH waarden in de eerste urine van 5,5 ng/ml . cannabis is no longer required, the percentage of cannabis is probably. Terminal Elimination Half-Lives of THC-COOH Percentage of THC Excreted as Urinary THC-COOH Cannabinoid-Glucuronide Conjugates The description of the endocannabinoid system follows in chapter . THC is excreted both in urine and feces as metabolites. main metabolite found in urine is the THC-COOH glucuronide, which, normalised to the . another clinical study, the analgesic potency of THC in cancer pain was compared with codeine.

    1. Introduction



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