Gasoline vapor exposures. Part II. Evaluation of the nephrotoxicity of the major C4/C5 hydrocarbon components

Analysis of workplace exposures to gasoline vapors revealed that C4 and C5 hydrocarbons constitute anywhere from 67 to 74% by weight of a typical vapor. Furthermore, it was found that n-butane, isobutane, n-pentane, and isopentane together comprise greater than 90% of all the C4/C5 vapor components and approximately 61 to 67% by weight of the total vapor. Accordingly, a 21-day inhalation toxicity study of a blend consisting of 25% (w/w) each of these four hydrocarbons was conducted using rats to assess the potential for these major gasoline vapor components to induce kidney damage. No evidence of the kidney lesions typically associated with hydrocarbon-induced nephropathy was observed in rats exposed at up to 11 800 mg/m3 (4437 ppm) of the blend.     

Respiratory effects of intermittent exposure to ozone of rats

Intermittent exposures of rats to ozone (O₃) of 1 and 0.5 ppm were performed. Flow resistance of the lungs left in situ in the chest cavity opened after the sacrifice was measured at different levels of elastic pressure, and it was shown that daily 3-hr exposures to 1 ppm O₃ for 30 consecutive days mainly produced increased resistance of more-central airways, while daily 6-hr exposures to 0.5 ppm O₃ for 60 consecutive days mainly increased the resistance of peripheral airways. Morphological changes of the lungs caused by both exposures were in general similar in nature, but differences in secretion were noticed: it was more evident in larger to middle-sized bronchi in the animals intermittently exposed to 1 ppm O₃, but more evident in the peripheral airway region in the animals intermittently exposed to 0.5 ppm O₃. No change in the pulmonary static volume-pressure curve, indicative of the altered retractive forces of alveoli, was observed in both exposures, although a slight reduction in lung distensibility was suggested.     

Service station attendants' exposure to benzene and gasoline vapors.

Service station attendants' exposure to benzene, based on 85 TWA results at 7 stations, were well below 1 ppm except one exposure of 2.08 ppm. Short term exposures were 1.21 ppm or less over 15 minutes. Attendants' TWA exposures to total gasoline vapor were 114 ppm or less, with measured 15 minute exposures no higher than 100 ppm during actual filling operations. One station had vapor recovery nozzles; exposures here were below the detectable level (0.01 ppm benzene) on 10% more days than the next lowest station. Still, the magnitude of overall exposures and the degree of reduction indicate that vapor recovery is not needed to control exposures. Some attendants had consistently higher exposures than others. This is felt to be due to work practices, such as standing close to the fill opening, plus local wind conditions around the car as it is filled with gasoline.     

Hydrocarbon nephropathy in male rats: identification of the nephrotoxic components of unleaded gasoline

Previous subchronic and/or chronic inhalation studies of unleaded gasoline and a variety of petroleum naphthas, solvents, and distillates have shown that these complex materials are capable of inducing a distinctive nephropathy which appears limited to male rats. Therefore a series of gavage screening studies using male F-344 rats was conducted on components of gasoline to more clearly identify the major contributors to this nephrotoxicity. The dosing regimen consisted of 20 doses administered once daily, 5 days per wk for 4 wk. Tested were 15 pure hydrocarbon compounds typically found in unleaded gasoline boiling range, 4 naphtha streams representative of those commonly used to blend gasolines and 3 distillation fractions covering the less volatile portions of gasoline. The results revealed that the alkane (paraffin) components were primarily responsible for the nephrotoxic activity seen in unleaded gasoline, with a positive structure-activity response relating the degree of alkane branching to the potency of the nephrotoxic response. In addition, the nephrotoxic activity observed with the naphtha streams and distillation fraction correlated well with the proportion of branched alkanes contained in each.     

Concentrations of Hydrocarbons in Tissues as a Measure of Toxicity

Mice and rats were exposed of vapors of butane, butadiene, isoprene, isobutylene, hexenes, and styrene. The concentrations of hydrocarbons in tissues after exposure were determined by gas liquid chromatography. Lethal concentration (LC₅₀) values for two- and four-hour exposures, and the corresponding LC₅₀ in brain tissues were determined for several hydrocarbons. The hydrocarbon concentration found in the brain correlated with the degree of central nervous system depression and narcosis. Mixtures of butane and isobutylene had a potentiating effect in 10 of 12 experiments, and an additive effect in two experiments.     

Absence of carcinogenic activity in Fischer rats and B6C3F1 mice following 103-week inhalation exposures to toluene

Toluene, methylbenzene, is used to back-blend gasoline, as a chemical intermediate, and as a solvent; more than 7 million tonnes are produced each year in the United States. Following 14-15-week toxicity studies to estimate appropriate exposure concentrations for the carcinogenesis bioassays, toxicology and carcinogenesis studies of toluene (>99% pure) were conducted by whole-body inhalation exposures of F344/N rats and B6C3F1 mice of each sex for 15 months or two years. Toluene levels were 0 (chamber controls), 600, and 1,200 ppm for rats and 0, 120, 600, and 1200 ppm for mice. Exposures were 6.5 hr/day 5 days/wk. Genetic toxicology studies using Salmonella typhimurium, mouse L5178Y lymphoma cells, and Chinese hamster ovary cells were negative. No chemically related neoplasm was found in male rats, and one nasal, two kidney, and two forestomach neoplasms observed in female rats were considered not to be associated with the toluene exposure. For mice, no biologically important increase was observed for any nonneoplastic or neoplastic lesion. Studies by others had reported carcinogenicity of toluene, especially for total malignant tumors.     

Gasoline vapor exposures at a high volume service station

Gasoline vapor concentrations were measured at a high volume service station for one week in May, 1983, for service station attendants, self-service customers and for various area locations. To facilitate the retention of highly volatile, low-molecular weight gasoline vapor components, 100/50 mg charcoal adsorption tubes were used with flow rates of 100 cc/min for long-term exposure samples and 900 cc/min for short-term exposures. Methylene chloride was selected as the desorption solvent. Desorbed hydrocarbons were analyzed and quantitated by capillary column gas chromatography using a flame ionization detector and a 0-100 degrees C temperature program. The data proved that the predominant ambient air hydrocarbons are those of C4 and C5 compounds. Monitoring results showed that the total gasoline vapor TWA exposures for service station attendants ranged from 0.6 to 4.8 ppm with a geometric mean of 1.5 ppm. Short-term personal samples collected while refueling ranged from not detectable to 38.8 ppm with a geometric mean of 5.8 ppm.     

Absence of Carcinogenic Activity in Fischer Rats and B6C3F1 Mice Following 103-Week Inhalation Exposures to Toluene

Abstract

Toluene, methylbenzene, is used to back-blend gasoline, as a chemical intermediate, and as a solvent; more than 7 million tonnes are produced each year in the United States. Following 14–15-week toxicity studies to estimate appropriate exposure concentrations for the carcinogenesis bioassays, toxicology and carcinogenesis studies of toluene (>99% pure) were conducted by whole-body inhalation exposures of F344/N rats and B6C3F1 mice of each sex for 15 months or two years. Toluene levelswere 0 (chamber controls), 600, and 1,200 ppm for rats and 0, 120, 600, and 1200 ppm for mice. Exposures were 6.5 hr/day 5 days/wk. Genetic toxicology studies using Salmonella typhimurium, mouse L5178Y lymphoma cells, and Chinese hamster ovary cells were negative. No chemically related neoplasm was found in male rats, and one nasal, two kidney, and two forestomach neoplasms observed in female rats were considered not to be associated with the toluene exposure. For mice, no biologically important increase was observed for any nonneoplastic or neoplastic lesion. Studies by others had reported carcinogenicity of toluene, especially for total malignant tumors.     

Assessing total exposures to gasoline vapor using the source exposure model.

Recent developments in source apportionment modeling of volatile organic compounds (VOCs) include receptor modeling (RM) applications to "total" (indoor and outdoor) exposure assessment for source of VOC. Source fingerprints are available for major VOC sources such as gasoline vapor, automobile exhaust, refinery emissions, cleaning solvent vapors, printing inks, and waste-water treatment facilities. The relative proportion of each VOC species in the source fingerprint enables the RM method, through a least squares analysis, to identify each source's presence and quantify its contribution to ambient air concentrations. Sampling periods and locations may be selected to represent microenvironmental exposures. Receptor modeling has direct applicability to determining the relative contribution of gasoline vapors to VOC exposures in the general population.     

Acute and repetitive human exposure to isobutane.

Eight adult volunteers of both sexes were exposed to isobutane in a controlled-environment chamber for the purpose of monitoring their physiological responses to a series of gas concentrations ranging from 250 to 1,000 ppm. First, the response to exposure periods of 1 min, 2 min, 1 h, 2 h, and 8 h were studied. There being no untoward responses to these acute exposures, the eight volunteers were exposed repetitively to isobutane at concentrations of 500 ppm, 1, 2 or 8 h per day, five days per week for two weeks. Then exposures to two mixtures of isobutane and propane for 1, 2 or 8 h per day for two days were studied. During the investigation all subjects were kept under comprehensive medical surveillance. No untoward subjective responses or abnormal physiological responses occurred during or following these exposures. Special emphasis was placed on evaluating the cardiac and pulmonary response to these exposures through the use of continuous ECG telemetry and serial computerized spirometric measurements. The following serial laboratory studies were unaltered by the exposures: complete blood count, urinalysis, serum alkaline phosphatase, SGOT, LDH, serum bilirubin, blood sugar, serum clacium, serum phosphorus, BUN, spontaneous electroencephalogram, visual evoked response, a battery of cognitive tests, and an ACTH stimulation test.     

Exposure of the deck crew to carcinogenic agents on oil product tankers

Work on deck on eight oil product tankers was examined. The purpose was to evaluate the need for improvement of the working environment to reduce the risk of occupational cancer. Benzene, polyaromatic hydrocarbons (PAHs) and organic lead compounds were sampled, and the crew answered a questionnaire on acute health effects. By area monitoring, benzene was generally found to be in the range from the detection limit, of 0.01 ppm, up to 1.15 ppm, but one tanker which loaded gasoline with the hatches open had levels up to 55 ppm. Personal monitoring showed exposure levels in the range 0.01–1.15 ppm. The PAH-levels and the levels of organic lead were low. No seamen were observed using respiratory protective equipment. Central nervous system symptoms were reported by the crew with the highest exposures to benzene although benzene may not be the only cause. The exposure to benzene and other hydrocarbons on the deck of oil product tankers ought to be reduced.     

Gas and vapor exposure assessment methods

Developing methods for making exposure assessment measurements for gases and vapors is a well-developed, active research field. Industry, academia, and government agencies have worked in this field for several decades, resulting in many sampling and analytical methods for gases and vapors for use in occupational, environmental, and indoor air applications. Consensus groups such as the International Standards Organization (ISO) and the American Society for Testing and Materials (ASTM) have contributed to the standard (methods) bank as well. There is much being done and much remaining to be done in methods development for gases and vapors. Additionally, consideration is now being given to issues like exposure to mixtures (noise and solvent vapors), mixed exposures (asphalt, diesel exhaust), and ethical acceptability--areas that before were, for a variety of reasons, largely ignored. This presentation focuses on method availability for exposure assessment, on research opportunities relative to gas and vapor analytical methods, and on avenues for accomplishing such work, and discusses some of the newer considerations for developing methods for exposure assessment.     

A control technology evaluation of state-of-the-art,perchloroethylene dry-cleaning machines

NIOSH researchers evaluated the ability of fifth-generation dry-cleaning machines to control occupational exposure to perchloroethylene (PERC). Use of these machines is mandated in some countries; however, less than 1 percent of all U.S. shops have them. A study was conducted at a U.S. dry-cleaning shop where two fifth-generation machines were used. Both machines had a refrigerated condenser as a primary control and a carbon adsorber as a secondary control to recover PERC vapors during the dry cycle. These machines were designed to lower the PERC concentration in the cylinder at the end of the dry cycle to below 290 ppm. A single-beam infrared photometer continuously monitors the PERC concentration in the machine cylinder, and a door interlock prevents opening until the concentration is below 290 ppm. Personal breathing zone air samples were measured for the machine operator and presser. The operator had time-weighted average (TWA) PERC exposures that were less than 2 ppm. Highest exposures occurred during loading and unloading the machine and when performing routine machine maintenance. All presser samples were below the limit of detection. Real-time video exposure monitoring showed that the operator had peak exposures near 160 ppm during loading and unloading the machine (below the OSHA maximum of 300 ppm). This exposure (160 ppm) is an order of magnitude lower than exposures with more traditional machines that are widely used in the United States. The evaluated machines were very effective at reducing TWA PERC exposures as well as peak exposures that occur during machine loading and unloading. State-of-the-art dry-cleaning machines equipped with refrigerated condensers, carbon adsorbers, drum monitors, and door interlocks can provide substantially better protection than more traditional machines that are widely used in the United States.     

Adaptation and evaluation of a personal electronic nose for selective multivapor analysis

The evaluation of a commercial, belt-mountable "electronic nose" modified for the rapid recognition and quantification of individual solvent vapors and simple vapor mixtures at low ppm concentrations is described. Marketed under the name VaporLab this direct-reading instrument was designed for qualitative determinations of the presence or absence of selected individual vapors and was adapted in this study for quantitative determinations of vapors and vapor-mixture components. Vapor samples are concentrated on a small adsorbent bed and then thermally desorbed for analysis by an array of four polymer-coated surface acoustic wave sensors. Tests were performed with 13 organic solvent vapors individually and in selected binary, ternary, and quaternary mixtures at concentrations ranging from 0.1 to 12 times the respective American Conference of Governmental Industrial Hygienists' (ACGIH) threshold limit value (TLV). Pattern recognition analyses yielded a library of response patterns to which subsequent actual and virtual (i.e., Monte-Carlo simulated) samples were compared to assess performance. Limits of detection >0.025 x TLV are achieved (based on the most sensitive sensors) for 0.25 L of preconcentrated air samples collected over a 2-min period. Individual vapors from different functional group classes can be recognized, quantified, and discriminated from other vapors with little error, and discrimination of the components of binary mixtures is possible where the component vapor response patterns are sufficiently different. Within-class individual vapor and binary-mixture discriminations are more difficult and most ternary and higher-order mixtures could not be analyzed with acceptable accuracy. Changes in ambient humidity have no effect on responses and changes in temperature lead to well-behaved and compensable changes in responses. Tests of fluctuating concentrations demonstrate the capability for accurately tracking short-term variations in exposure. Overall, results suggest that this instrument could serve effectively as a personal exposure monitor in previously characterized occupational environments with proper revisions in design.     

Gasoline and vapor exposures in service station and leaking underground storage tank scenarios.

Exposure to gasoline and gasoline vapors from service station operations and leaking underground storage tanks is a major health concern. Six scenarios for human exposure were examined, based primarily on measured air and water concentrations of total hydrocarbons, benzene, xylenes, and toluene. Calculated mean and upper limit lifetime exposures provide a tool for assisting public health officials in assessing and managing gasoline-related health risks.     

Biological monitoring of workers exposed to ethylbenzene and co-exposed to xylene

OBJECTIVE: Ethylbenzene is an important constituent of widely used solvent mixtures in industry. The objective of the present study was to provide information about biological monitoring of occupational exposure to ethylbenzene, and to review the biological limit values corresponding to the threshold limit value of ethylbenzene. METHODS: A total of 20 male workers who had been exposed to a mixture of ethylbenzene and xylene, through painting and solvent mixing with commercial xylene in a metal industry, were recruited into this study. Environmental and biological monitoring were performed during an entire week. The urinary metabolites monitored were mandelic acid for ethylbenzene and methylhippuric acid for xylene. Correlations were analyzed between urinary metabolites and environmental exposure for ethylbenzene and xylene. The interaction effects of a binary exposure to ethylbenzene and xylene were also investigated using a physiologically based pharmacokinetic (PBPK) model. RESULTS: The average environmental concentration of organic solvents was 12.77 ppm for xylene, and 3.42 ppm for ethylbenzene. A significant correlation (R2 = 0.503) was found between environmental xylene and urinary methylhippuric acid. Urinary level of methylhippuric acid corresponding to 100 ppm of xylene was 1.96 g/g creatinine in the worker study, whereas it was calculated as 1.55 g/g creatinine by the PBPK model. Urinary level of mandelic acid corresponding to 100 ppm of ethylbenzene was found to be 0.7 g/g creatinine. PBPK results showed that the metabolism of ethylbenzene was highly depressed by co-exposure to high concentrations of xylene leading to a non-linear behavior. CONCLUSIONS: At low exposures, both methylhippuric acid and mandelic acid can be used as indicators of commercial xylene exposures. However at higher concentrations mandelic acid cannot be recommended as a biological indicator due to the saturation of mandelic acid produced by the co-exposure to xylene.     

Toxicokinetics of human exposure to methyl tertiary-butyl ether (MTBE) following short-term controlled exposures.

Methyl tertiary-butyl ether (MTBE) is an oxygenated compound added to gasoline to improve air quality as part of the US Federal Clean Air Act. Due to the increasing and widespread use of MTBE and suspected health effects, a controlled, short-term MTBE inhalation exposure kinetics study was conducted using breath and blood analyses to evaluate the metabolic kinetics of MTBE and its metabolite, tertiary-butyl alcohol (TBA), in the human body. In order to simulate common exposure situations such as gasoline pumping, subjects were exposed to vapors from MTBE in gasoline rather than pure MTBE. Six subjects (three females, three males) were exposed to 1.7 ppm of MTBE generated by vaporizing 15 LV% MTBE gasoline mixture for 15 min. The mean percentage of MTBE absorbed was 65.8 +/- 5.6% following exposures to MTBE. The mean accumulated percentages expired through inhalation for 1 and 8 h after exposure for all subjects were 40.1% and 69.4%, respectively. The three elimination half-lives of the triphasic exponential breath decay curves for the first compartment was 1-4 min, for the second compartment 9-53 min, and for the third compartment 2-8 h. The half-lives data set for the breath second and blood first compartments suggested that the second breath compartment rather than the first breath compartment is associated with a blood compartment. Possible locations for the very short breath half-life observed are in the lungs or mucous membranes. The third compartment calculated for the blood data represent the vessel poor tissues or adipose tissues. A strong correlation between blood MTBE and breath MTBE was found with mean blood-to-breath ratio of 23.5. The peak blood TBA levels occurred after the MTBE peak concentration and reached the highest levels around 2-4 h after exposures. Following the exposures, immediate increases in MTBE urinary excretion rates were observed with lags in the TBA excretion rate. The TBA concentrations reached their highest levels around 6-8 h, and then gradually returned to background levels around 20 h after exposure. Approximately 0.7-1.5% of the inhaled MTBE dose was excreted as unchange urinary MTBE, and 1-3% was excreted as unconjugated urinary TBA within 24 h after exposure.     

An apparatus for generation of vapors from liquids of low volatility for use in inhalation toxicity studies

While it is usually a simple matter to perform inhalation exposures to vapors from low-boiling liquids, inhalation exposures to vapors of high-boiling liquids present problems, especially the risk of decomposing the test substance by use of excessive heat. This work describes a device for the volatilization of high-boiling liquids, in a manner suitable for conducting inhalation exposures, without requiring heat input, which avoids this difficulty. The device is based on counter-current volatilization employing a multi-plate high efficiency distillation column. The column is thermostated below ambient temperature, which increases stability of operation and flexibility of application.     

Benzene toxicokinetics in humans: exposure of bone marrow to metabolites.

A three compartment physiologically based toxicokinetic model was fitted to human data on benzene disposition. Two separate groups of model parameter derivations were obtained, depending on which data sets were being fitted. The model was then used to simulate five environmental or occupational exposures. Predicted values of the total bone marrow exposure to benzene and cumulative quantity of metabolites produced by the bone marrow were generated for each scenario. The relation between cumulative quantity of metabolites produced by the bone marrow and continuous benzene exposure was also investigated in detail for simulated inhalation exposure concentrations ranging from 0.0039 ppm to 150 ppm. At the level of environmental exposures, no dose rate effect was found for either model. The occupational exposures led to only slight dose rate effects. A 32 ppm exposure for 15 minutes predicted consistently higher values than a 1 ppm exposure for eight hours for the total exposure of bone marrow to benzene and the cumulative quantity of metabolites produced by the bone marrow. The general relation between the cumulative quantity of metabolites produced by the bone marrow and the inhalation concentration of benzene is not linear. An inflection point exists in some cases leading to a slightly S shaped curve. At environmental levels (0.0039-10 ppm) the curve bends upward, and it saturates at high experimental exposures (greater than 100 ppm).     

Renal cell cancer and occupational exposure to chemical agents

A case-referent study of occupational risk indicators of renal cell adenocarcinoma was conducted. Each incident case in Finland in 1977-1978 was matched with two population referents. Lifelong job histories were collected and translated into indicators of industry, occupation, and occupational exposures. The analyses of 338 sets of cases and referents revealed elevated risks for a history of employment in white-collar occupations; the printing industry; the chemical industry; the manufacturing of metal products; mail, telephone, and telegraph services; and iron and metalware work. A decreased risk was observed for male farmers. An elevated risk and an exposure-response relationship were found for gasoline exposure. The excess risk was highest at a latency period of approximately 30 years. The findings support the hypothesis that exposure to some constituent(s) of gasoline increases the incidence of renal adenocarcinoma in humans. Suggestions of elevated risks appeared for exposures to inorganic lead, cadmium, and nonchlorinated solvents.