Chemical exposure levels in printing workers with cholangiocarcinoma.

OBJECTIVE: This study aimed to identify chemicals used by printing workers with cholangiocarcinoma, as well as the levels of exposure to the chemicals. METHODS: Information necessary to identify chemicals used by printing workers with cholangiocarcinoma and to estimate chemical exposure concentrations was obtained from the Ministry of Health, Labour and Welfare, Japan. Working environment concentrations of the chemicals in the printing rooms were estimated using a well-mixed model, and exposure concentrations during the ink removal operation were estimated using a near-field and far-field model. Shift time- weighted averages (TWA) of exposure concentrations were also calculated. RESULTS: Two workers from each of three small printing plants examined suffered from cholangiocarcinoma, and all six of these workers had been exposed to 1,2-dichloropropane (1,2-DCP) for 10-16 years. The estimated working environment concentrations of 1,2-DCP in the printing rooms were 17-180 ppm and estimated exposure concentrations during the ink removal operation were 150-620 ppm. Shift TWA values were estimated to be 62-240 ppm. Four of the six workers had also been exposed to dichloromethane (DCM) at estimated working environment concentrations of 0-98 ppm and estimated exposure concentrations during the ink removal operation of 0-560 ppm. Shift TWA values were estimated to be 0-180 ppm. Other chlorinated organic solvents (1,1,1-trichloroethane, 1,1-dichloro-1-fluoroethane) and petroleum solvents (gasoline, naphtha, mineral spirit, mineral oil, kerosene) were also used in the ink removal operation. CONCLUSIONS: All six printing workers with cholangiocarcinoma were exposed to very high levels of 1,2-DCP for a long term.

Human biomonitoring as a pragmatic tool to support health risk management of chemicals--examples under the EU REACH programme.

REACH requires health risk management for workers and the general population and introduced the concept of Derived No-Effect Level (DNEL). DNELs must be derived for all substances that are classified as health hazards. As with analogues to other health-risk based guidance values, such as reference doses (RfDs) and tolerable daily intakes (TDIs), risk to health is considered negligible if the actual exposure is less than the DNEL. Exposure assessment is relatively simple for occupational situations but more complex for the general public, in which exposure may occur via multiple pathways, routes, and media. For such complex or partially defined exposure scenarios, human biomonitoring gives a snapshot of internal or absorbed dose of a chemical and is often the most reliable exposure assessment methodology as it integrates exposures from all routes. For human risk management human biomonitoring data can be interpreted using the recently developed concept of Biomonitoring Equivalents (BE). Basically, a BE translates an established reference value into a biomarker concentration using toxicokinetic data. If the results of an exposure assessment using human biomonitoring indicate that the levels measured are below the DNEL-based BE (BE(DNEL)), it would indicate that the combined exposure via all potential exposure routes is unlikely to pose a risk to human health and that health risk management measures might not be needed. Hence, BEs do not challenge existing risk assessments but rather build upon them to help risk management, the ultimate goal of any risk assessment. A challenge in implementing this approach forms the limited availability of toxicokinetic information for many substances. However, methodologies such as generic physiologically-based toxicokinetic models, which allow estimation of biomarker concentrations based on physicochemical properties, are being developed for less data-rich chemicals. Use of BE by regulatory authorities will allow initial screening of population exposure to chemicals to identify those chemicals requiring more detailed risk and exposure assessment, assisting in priority setting and ultimately leading to improved product stewardship and risk management.

[A couple suffering acute respiratory illness due to waterproofing spray exposure].

The patients were a 28-year-old man and a his 27-year-old wife. The husband smoked a cigarette immediately after using a waterproofing spray, and developed fever, cough, and dyspnea 15 min later. The wife had nausea 2 hours later. Nine hours later, the husband visited a local clinic, and was referred to our hospital because of hypoxemia. In addition, chest CT showed ill-defined areas of increased density, predominantly in the bilateral upper lung fields, with interlobular septal thickening, and he was hospitalized. Although the wife was asymptomatic at the time of examination, she had chest CT findings similar to those of her husband, and was also hospitalized. After admission, the husband received steroid pulse therapy and oxygen inhalation for his symptoms and hypoxemia, with return of arterial blood gas analysis results to normal on the third day. The wife had no symptoms or hypoxemia during her hospital stay. Their chest CT findings improved on the seventh day after admission, and they were discharged. Thus, it appears that the couple suffered from acute respiratory illness due to waterproofing spray exposure, and probably heat degradation products from cigarette smoking caused the husband to have severe symptoms.

Cognitive impairment and olfactory panic from occupational exposure to VOCs.

BACKGROUND: A Canadian government clerical worker in her early thirties developed frontal lobe dysfunction from inhalation of volatile organic compounds off-gassed during an office renovation. METHODS: Pulmonary function, bronchial provocation, allergy testing, and a brain (SPECT) scan were performed. RESULTS: SPECT scanning showed frontotemporal hypoperfusion and neuropsychologic testing revealed deficits in verbal learning and poor organizational memory. CONCLUSIONS: A significant component of this worker's impairment was the development of "olfactory panic," a debilitating aversion to odor accompanied by symptoms of panic. The Ontario Workplace Safety and Insurance Appeals Tribunal granted entitlement for her cognitive difficulties and olfactory panic as a result of her toxic exposure.

Chlorinated hydrocarbon solvents.

Chlorinated hydrocarbon solvents, such as trichloroethylene and 1,1,1-trichloroethane, have been used widely in many industries because of their ready ability to dissolve oils, greases, and other materials, their low acute toxicity, and their non-flammability. Although these materials share certain toxicologic, functional, and chemical similarities, important differences exist. These differences largely explain why certain solvents, once common, are no longer in use and why others have become more widely used over time. This article reviews the properties, toxicologic effects of interest, workplace limits, and use history of the most common chlorinated hydrocarbon solvents.

Inhaled drugs of abuse enhance serotonin-3 receptor function.

Despite the prevalence of their use, little is currently known of the molecular mechanisms of action of inhaled drugs of abuse. Recent studies have shown effects on NMDA, GABA(A) and glycine receptors in vitro, suggesting that inhalants may exert at least some of their pharmacological effects on ligand-gated ion channels. Enhancement of serotonin-3 receptor function has been shown to play a role in the reinforcing properties of drugs of abuse. We tested the hypothesis that the commonly abused inhaled agents 1,1,1-trichloroethane, trichloroethylene, and toluene enhance serotonin-3 receptor function. All three inhalants significantly and reversibly potentiated, in a dose-dependent manner, serotonin-activated currents mediated by mouse serotonin-3A receptors expressed in Xenopus oocytes. Our findings add the serotonin-3 receptor to the growing list of molecular targets commonly affected by both inhalants and classic CNS depressants such as ethanol and the volatile anesthetics.

In silico toxicology: simulating interaction thresholds for human exposure to mixtures of trichloroethylene, tetrachloroethylene, and 1,1,1-trichloroethane.

In this study, we integrated our understanding of biochemistry, physiology, and metabolism of three commonly used organic solvents with computer simulation to present a new approach that we call "in silico" toxicology. Thus, we developed an interactive physiologically based pharmacokinetic (PBPK) model to predict the individual kinetics of trichloroethylene (TCE), perchloroethylene (PERC), and methylchloroform (MC) in humans exposed to differently constituted chemical mixtures of the three solvents. Model structure and parameterization originate from the literature. We calibrated the single-compound PBPK models using published data and described metabolic interactions within the chemical mixture using kinetic constants estimated in rats. The mixture model was used to explore the general pharmacokinetic profile of two common biomarkers of exposure, peak TCE blood levels and total amount of TCE metabolites generated, in rats and humans. Assuming that a 10% change in the biomarkers corresponds to a significant health effect, we calculated interaction thresholds for binary and ternary mixtures of TCE, PERC, and MC. Increases in the TCE blood levels led to higher availability of the parent compound for glutathione conjugation, a metabolic pathway associated with kidney toxicity/carcinogenicity. The simulated change in production rates of toxic conjugative metabolites exceeded 17% for a corresponding 10% increase in TCE blood concentration, indicating a nonlinear risk increase due to combined exposures to TCE. Evaluation of metabolic interactions and their thresholds illustrates a unique application of PBPK modeling in risk assessment of occupational exposures to chemical mixtures.

Two cases of chlorinated hydrocarbon-associated myocardial ischemia.

Chlorinated hydrocarbons are well known to produce ventricular arrhythmias because of myocardial sensitization to endogenous catecholamines, but cases of myocardial ischemia have not been described frequently. We report 2 cases of myocardial ischemia after exposure to chlorinated hydrocarbons. The first patient developed an asymptomatic myocardial infarction after inhalation of 1,1,1-trichloroethane at work. It is believed that 1,1,1-trichloroethane produced a coronary spasm that was sufficient to cause myocardial necrosis in the presence of coronary vessels already compromised by atherosclerosis. The second patient developed a reversible symptomatic myocardial ischemia of 4 h duration after chloral hydrate overdose. The evolution in both patients was favorable. Exposure to chlorinated hydrocarbons can be associated with myocardial ischemia particularly if the coronary circulation is already compromised.

Organic solvents and cancer.

Epidemiologic evidence on the relationship between organic solvents and cancer is reviewed. In the 1980s, more than a million persons were potentially exposed to some specific solvents in the United States; in Canada, 40 percent of male cancer patients in Montreal had experienced exposure to solvents; in the Finnish population, one percent was regularly exposed. There is evidence for increased risks of cancer following exposure to: trichloroethylene (for the liver and biliary tract and for non-Hodgkin's lymphomas); tetrachloroethylene (for the esophagus and cervix--although confounding by smoking, alcohol, and sexual habits cannot be excluded--and non-Hodgkin's lymphoma); and carbon tetrachloride (lymphohematopoietic malignancies). An excess risk of liver and biliary tract cancers was suggested in the cohort with the high exposure to methylene chloride, but not found in the other cohorts where an excess risk of pancreatic cancer was suggested. 1,1,1-trichloroethane has been used widely, but only a few studies have been done suggesting a risk of multiple myeloma. A causal association between exposure to benzene and an increased risk of leukemia is well-established, as well as a suggested risk of lung and nasopharynx cancer in a Chinese cohort. Increased risks of various gastrointestinal cancers have been suggested following exposure to toluene. Two informative studies indicated an increased risk of lung cancer, not supported by other studies. Increased risks of lymphohematopoietic malignancies have been reported in some studies of persons exposed to toluene or xylene, but not in the two most informative studies on toluene. Occupation as a painter has consistently been associated with a 40 percent increased risk of lung cancer. (With the mixed exposures, however, it is not possible to identify the specific causative agent[s].) A large number of studies of workers exposed to styrene have evidenced no consistent excess risk of all lymphohematopoietic malignancies, although the most sensitive study suggested an excess risk of leukemia among workers with a high exposure.

Use of computational models to reconstruct and predict trichloroethylene exposure.

In this study, a type frequently encountered by ATSDR, groundwater and surface-water contamination have occurred near the Gratuity Road site in the town of Groton, Massachusetts. A petitioned public health assessment for the Gratuity Road site identified the primary contaminants as trichloro-ethylene (TCE), 1,1,1-trichloroethane (TCA), hexavalent chromium (Cr+6), chromium (Cr), and lead (Pb) (ATSDR 1992). The health assessment also indicated that off-site residential groundwater wells had been contaminated with TCE and TCA. Because direct measures of historical exposure to TCE are unavailable for the Gratuity Road site, computational models were used to reconstruct and predict exposure to TCE. These computational models included environmental transport and exposure models. For the environmental transport models, numerical methods were used to approximate the equations of groundwater flow and contaminant transport. Results of using environmental transport models provided us with the spatial and temporal database necessary to conduct an exposure analysis. This database indicated that groundwater concentrations of TCE typically exceeded EPA's MCL of 5 ppb for TCE. The study demonstrated that although a hazardous waste site can be remediated, nearby populations may experience significant exposure because of historical contamination, which will not be captured by remediation activities. The exposure analysis used simulated concentrations of TCE predicted by environmental transport models. These concentrations were used to compare exposure to TCE from inhalation in a one-compartment model shower with exposure from ingestion of domestic water contaminated by TCE. The exposure model indicated that exposure to TCE by the inhalation route during showering is nearly identical to exposure by ingestion of domestic water supplies contaminated with TCE. As a result, entry by inhalation route is as important as entry by ingestion route when conducting exposure analyses of contamination from volatile organic compounds such as TCE.

Acute effects of 1,1,1-trichloroethane inhalation on the human central nervous system.

The object of this study was to examine the immediate nervous effects of variable 1,1,1-trichloroethane (TCE) exposure combined with physical exercise. The effects on the quantitative electroencephalography (EEG), visual evoked potentials (VEP) and body sway were analyzed. Nine male volunteers were exposed to either a stable or a fluctuating exposure pattern with the same time-weighted average concentration of 200 ppm (8.1 mumol/l). In both cases, the subjects engaged in physical exercise during the exposures. Exercise alone induced an increase in the dominant alpha frequency in the EEG and, after an initial drop, an increase in the alpha percentage with a concomitant decrease in theta, whereas delta and beta bands remained unaffected. By contrast, exposure to TCI and exercise did not affect the alpha, theta or delta activities but induced changes in beta during the morning recordings at peak exposure to TCE. The body sway tended to decrease slightly during the fluctuating TCE exposure, and the later peaks in VEPs showed slight prolongations. Overall, no deleterious effects of exposure were noted.