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.

Liver disease associated with exposure to 1,1,1-trichloroethane.

1,1,1-trichloroethane is a halogenated hydrocarbon solvent commonly used in industry because of its supposed lack of hepatotoxicity. Nonetheless, animal studies performed by several independent groups have shown the solvent to induce fat deposition, vacuolar degeneration, and centrilobular necrosis, changes similar to those seen after exposure to carbon tetrachloride, albeit of a much reduced magnitude, in animals exposed to the agent. Four patients with fatty liver disease whose work entailed substantial exposure to this agent were seen at the University of Pittsburgh (Pa). Based on this clinical experience, we believe that 1,1,1-trichloroethane should be reconsidered as an agent with potential hepatotoxicity in man.

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.

Sleep apnoea and organic solvent exposure.

Fifteen patients referred for the evaluation of possible organic solvent encephalopathy were studied by clinical polysomnography. Seven had more than 30 apnoeas per night and an apnoea index of higher than 5, thus fulfilling the commonly used criteria of the sleep apnoea syndrome. Another group of eight workers exposed to trichlorethane, examined without prior knowledge of their individual symptoms, showed a significantly elevated number of sleep apnoeas compared with nine controls. The results indicate that organic solvent exposure can cause sleep apnoea.

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.

Comparison of unconditioned reflex and conditioned avoidance tests in rats exposed by inhalation to carbon monoxide, 1,1,1-trichloroethane, toluene or ethanol.

The sensitivity of unconditioned reflex and conditioned avoidance tests in evaluating behavioral toxicity was compared. Male rats were exposed by inhalation up to four hours to 0, 200, 400, 800 or 1600 ppm carbon monoxide (CO); 0, 1500, 3000, 6000 or 12,000 ppm 1,1,1-trichloroethane; 0, 800, 1600, 3200, or 6400 ppm toluene; or 0, 4000, 8000, 16,000 or 32,000 ppm ethanol. Animals were tested for behavioral changes at one-half, one, two and four hours during exposure and eighteen hours after exposure ended. In unconditioned reflex testing the presence or absence of specific unconditioned reflexes (such as corneal, placing, grasping and righting reflexes) and simple behavior patterns including locomotor activity and coordination were observed. The conditioned reflex task consisted of shock avoidance by lever press following simultaneous light and sound stimuli. Rats began to fail unconditioned reflex tests at 800 ppm CO, 3000 ppm trichloroethane, 800 ppm toluene and 8000 ppm ethanol. Decrements in conditioned avoidance were observed at 800 ppm CO, 6000 ppm trichloroethane, 3200 ppm toluene and 8000 ppm ethanol. Neither test was consistently more sensitive than the other in detecting behavioral changes. For both methods, the concentrations at which changes were detected in rats were two to tenfold higher than those reported for human effects.

Skin pathology following epicutaneous exposure to seven organic solvents.

1,1,1,-Trichloroethane, benzene, trichloroethylene, tetrachloroethylene, dibromoethane, 1,2-dichloroethane, and 1,1,2,2-tetrachloroethane were applied to the skin of guinea-pigs for histopathological studies. Biopsies taken at different times of exposure showed the presence of karyopyknosis for all solvents tested; 1,1,1-trichloroethane, benzene, trichloroethylene, and tetrachloroethylene showed karyolysis; 1,1,1-trichloroethane, benzene, trichloroethylene, tetrachloroethylene, and dichloroethane induced spongiosis. All solvents, except 1,1,2,2-tetrachloroethane, produced junctional separation. Pseudoeosinophilic infiltration occurred for all solvents, except for 1,2-dichloroethane. The results are discussed in terms of occupational hazards and in relation to parallel studies on blood uptake and systemic toxicity at epicutaneous administration.

Peripheral sensory neuropathy associated with 1,1,1-trichloroethane.

A case is described of peripheral sensory neuropathy in a woman who had daily exposure to 1,1,1-trichloroethane, used as a degreasing agent. Although previous reviews of the health effects of 1,1,1-trichloroethane have not indicated long-term neurotoxicity, there are recent animal studies that suggest chronic central neurotoxic effects and previous case reports of peripheral neuropathy in three exposed workers in one plant. Our case provides additional evidence that 1,1,1-trichloroethane exposure may be associated with peripheral sensory neuropathy. Reporting of similar cases is encouraged and investigation of the neurotoxic effects of 1,1,1-trichloroethane is recommended.

Hydrogeologic assessment of exposure to solvent-contaminated drinking water: pregnancy outcomes in relation to exposure.

We recently concluded that exposure to solvent-contaminated drinking water was an unlikely explanation for observed excesses of adverse pregnancy outcomes during 1980-1981 in the Los Paseos neighborhood of Santa Clara County, California, because these excesses were not observed in an adjacent exposed area. The validity of this conclusion depends on the assumption that the two areas had comparable exposure. Using quantitative methods to model movement of the solvent leak plume and water flow within the distribution system, we estimated that women with adverse outcomes were no more likely to have received contaminated water than women with normal live births. These results strengthen the conclusion that exposures to water from the contaminated well were not responsible for the excess of adverse outcomes observed in the Los Paseos area.

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.

[The use of 1,1,1-trichloroethane (methylchloroform) in industrial operations: the neurotoxicity risk]. / Utilizzo di 1,1,1-tricloroetano (metilcloroformio) in lavorazioni industriali: il rischio neurotossicità.

1,1,1-Trichloroethane (1,1,1-TE) is a widely used organic solvent which is thought to be relatively safe. The present review is mainly focused on the neurotoxic effects of 1,1,1-TE. Concentrations above 350 ppm are considered capable of negatively conditioning the performance of the exposed person, in particular reaction time and manual abilities. Peripheral neuropathies have also been described. More recently the potential neurotoxicity of 1,1,1-TE has been underscored by animal studies investigating the effects of this substance in neurobehavioral tests and on neurochemical parameters. 1,1,1-TE alters the motor activity in small laboratory rodents. In fixed interval responding in mice, the effects of 1,1,1-TE are qualitatively similar to those of other volatile (ethanol) and non volatile (benzodiazepines and barbiturates) CNS depressants. In addition, in drug discrimination procedures 1,1,1-TE shares discriminative stimulus properties with barbiturates, toluene, halotane, and oxazepam indicating that this solvent has behavioral effects in common with central nervous system depressant drugs. From a neurochemical point of view long-term exposure to 1,1,1-TE induces astrogliosis in the cerebral cortex of gerbils as indicated by an increased concentration of glial fibrillary acidic protein. In addition low dose inhalation of 1,1,1-TE for 3 months decreases DNA concentrations in several brain regions of the gerbil. 1,1,1-TE affects also brain concentrations of cAMP and cGMP as well as calcium ion control, possibly through an action on voltage-dependent calcium channels. It has been also suggested that intermediate metabolites of 1,1,1-TE may give origin to condensation products with dopamine, ultimately impairing dopaminergic transmission. Some of the neurochemical effects of 1,1,1-TE are shared by other chlorinated organic solvents as well as by CNS depressants. The literature analyzed indicates that 1,1,1-TE may exert significant neurotoxic effects suggesting that more caution in its use is needed and that attention should be paid to the possibility of an additive effect of 1,1,1-TE and CNS depressants (ethanol, barbiturates, benzodiazepines and other volatile solvents) giving origin to severe neurotoxicity.

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.