Timing of sample collection for biological monitoring of occupational exposure.

The timing of sample collections for the biological monitoring of occupational exposure profoundly affects the resulting data. Sampling time with respect to the day in the working week and the end of exposure is crucial for measurements of rapidly excreted indicators of exposure. Owing to the cumulation of slowly excreted exposure indicators, timing of sample collection with respect to the duration of employment is essential. The steady state is established within a week, if the exposure indicator is excreted rapidly (with a half-life shorter than 45 h), or within months or years, if it is excreted slowly. In this study, exposure indicators are characterized by the elimination half-life. A monocompartmental model is used to calculate the biological levels at steady state and the duration of occupational exposure needed to reach the apparent steady state.

Exposure limits for unconventional shifts: toxicokinetic and toxicodynamic considerations.

Adjustment factors (AF) for inhalation exposure to chemical agents during unconventional work schedules were derived on toxicokinetic bases. AFs depend on the half-life of the agent and on the work schedule. Because they are grossly affected by cumulation, AFs were calculated for steady-state conditions. They were based on the following measures of chemical body burden: (1) end-of-shift biological level as used previously by other investigators; and (2) areas under the curves, AUCexp, AUCday, and AUCweek, which correlate with average biological levels during the shift, work day, and work week, respectively. The dependence of AFs on the half-life was studied on 50 possible work schedules using agents with a half-life of 1 hr to 2 years. Based on the data, simple equations suitable for field conditions were derived for determination of AFs. Since AFs based on individual measures of body burden are not the same, the pharmacodynamics of the toxic endpoint should be considered when selecting the measure of body burden and the half-life for AF determination.

Extrapolation of physiological parameters for physiologically based simulation models.

Masses of organs and fluids, pulmonary ventilation and cardiac output and its distribution are the basic input data used in physiologically based pharmacokinetic models. Since these parameters are rarely measured in pharmacokinetic studies, the values found in reference books or extrapolated to meet the specific exposure conditions are used in the models. In this review of the extrapolation of pertinent physiological parameters, power equations for scaling across mammals, adjustments to body build (lean body mass) and physical activity of humans and their significance for risk assessment of human exposure to solvents using animal data are assessed.

Relevance of occupational skin exposure.

Dermal exposure gains in significance by the same token as permissible occupational inhalation exposures are lowered. The contribution of dermal absorption to the total dose absorbed during occupational exposure is apparent when dermal and pulmonary uptake rates are compared. Development of an experimental data base for evaluation and control of dermal exposure is hindered by: lack of suitable methods for measurement of dermal absorption in humans; interspecies differences in skin permeability; regional differences in absorption rates due to non-homogeneity of skin composition and perfusion rates over the body; possible skin damage induced by the chemical or dispersant; and exposure conditions in the workplace. In the absence of sufficient human data, theoretical models can provide satisfactory information on dermal absorption. It is advocated that the current practice of using acute dermal toxicity (LD50) as a criterion for warning on the potential of significant dermal absorption be replaced by a criterion based on comparison of the dermal penetration rate with the pulmonary uptake rate at inhalation exposures permissible in the workplace.

Application of toxicokinetic models to establish biological exposure indicators.

This article is a critical review of the application of toxicokinetic models to the biological monitoring of occupational exposure to industrial chemicals. The experimentally based toxicokinetic models are used to determine the elimination half-lives, the metabolic clearance, the elimination rate constants and the volume of distribution. The physiologically based multicompartmental simulation models, which describe the uptake, distribution and elimination of inhaled or percutaneously adsorbed organic solvents, contributed to the understanding of the transport of the xenobiotics in the body. They are used for describing and predicting the dependence of concentrations of indicators of exposure in biological specimens on the extent of exposure and time (duration of exposure and sampling time), and for depicting the contribution of various biological and exposure factors to differences in biological response to the exposure. In biological monitoring, toxicokinetic models are used for matching biological concentrations and body burden of indicators of exposure with extent of inhalation or dermal exposure, and for predicting half-lives. They lay the grounds for the strategy used in collecting biological specimens and controlling external and internal factors which alter the biological concentrations and possibly increase the health risk from the exposure. Elimination half-lives are used as guidelines in selecting the appropriate indicators of exposure, in designing the procedure for the collection of biological specimens, and in interpreting the measured data. Predictive models are needed for heavy metals, particulates and compounds undergoing binding to constituents of tissues.

Dermal absorption potential of industrial chemicals: criteria for skin notation.

A dermal penetration rate (flux), predicted from physical properties of 132 chemicals, is suggested as an index of the dermal absorption potential of industrial chemicals. The prediction is designed for organic nonelectrolytes. Two reference values are recommended as criteria for skin notation: 1) dermal absorption potential, which relates to dermal absorption raising the dose of nonvolatile chemicals or biological levels of volatile chemicals 30% above those observed during inhalation exposure to TLV-TWA only--dermal absorption of chemicals belonging to this category should be considered when data obtained by biological monitoring are interpreted; and 2) dermal toxicity potential, which relates to dermal absorption that triples biological levels as compared with levels observed during inhalation exposure to TLV-TWA only. Chemicals belonging in this category should carry a skin notation. The toxicity criteria may not be valid for chemicals whose TLVs are based on preventing irritation and discomfort.

Hepatic protection from chemical injury by isoflurane.

Isoflurane inhibits oxidative metabolism of halothane. Because hepatotoxicity of chemicals may be associated with their metabolism, whether isoflurane can protect the liver against chemical injury was investigated. Hepatic injury was produced in female F344 rats by a 30-minute exposure to 250 ppm of carbon tetrachloride. In this and all other parts of the study, the inspired oxygen concentration was maintained at 21%. The injury was accompanied by elevated activity of liver enzymes in serum (SGOT, SGPT, and SDH), enlarged liver, fatty infiltration of the liver, and vacuolar degeneration of hepatocytes. These signs of toxicity were partly or completely suppressed by concurrent exposure to subanesthetic concentrations of isoflurane (0.2 or 0.038%, respectively). The protective effect was concentration-dependent. Enflurane was protective, but less so than isoflurane. Nitrous oxide and fentanyl had no protective effect.

Solubility properties in biological media 9: prediction of solubility and partition of organic nonelectrolytes in blood and tissues from solvatochromic parameters.

Solubilities in and partition among human blood, brain, lung, kidney, muscle, and fat tissue are well correlated by linear solvation energy relationships of the form: XYZ = XYZo + mVI/100 + s pi + b beta m where XYZ is the logarithm of the solubility property, VI is the intrinsic (van der Waals') molar volume, pi and beta are the solvatochromic parameters that measure solute dipolarity/polarizability and hydrogen-bond acceptor basicity, respectively, and the subscript m indicates that for self-associating compounds, the parameter applies to the non-self-associated "monomer" solute. The equation for log K(brain--blood) indicates that increasing molar volume favors, whereas increasing dipolarity and hydrogen-bond acceptor basicity oppose, solute transfer from blood into brain.

Determination and prediction of tissue-gas partition coefficients.

The head space method for determination of tissue-gas partition coefficients was modified to make it suitable for determination of tissue-gas partition coefficients of water soluble solvents. The method was used to determine tissue-gas partition coefficients of acetone, 2-butanone, methanol, ethanol, 1-propanol, 2-propanol and isobutanol for six representative tissues (muscle, kidney, lung, white and gray matter of brain, and adipose tissue). Blood-gas partition coefficients and distribution between plasma and erythrocytes were also determined. Relation between tissue-blood and fat-blood partition coefficients of 35 hydrophilic and hydrophobic substances of different chemical structure is described by linear correlation equations which can be used for prediction of tissue-gas partition coefficients of any chemical for which blood-gas and fat-gas partition coefficients are known. The correlation equations are based on all currently available data.

Transient inhibitory effect of isoflurane upon oxidative halothane metabolism.

The duration of inhibition of halothane oxidative metabolism by isoflurane was studied in rats exposed for 2 hr to an anesthetic concentration of isoflurane (0.6% inspired), followed by a 2-hr exposure to a subanesthetic concentration of halothane (0.06% inspired), starting either 0.5, 4, or 24 hr after the end of the isoflurane exposure. Other rats were exposed to halothane, isoflurane, or a mixture of both. Tissue levels of total nonvolatile fluorine were used as a measure of oxidative metabolism of halothane and hepatic levels of 1,1,1-trifluoro-2-chloroethane and 1,1-difluoro-2-chloroethylene as a measure of reductive metabolism of halothane. Isoflurane administered simultaneously with or 30 min prior to halothane significantly inhibited oxidative metabolism of halothane, but this inhibition was transient and was no longer apparent when halothane was administered 4 or 24 hr after the end of isoflurane anesthesia. The reductive metabolism of halothane was unaffected. This study suggests that isoflurane may transiently modify the action of some drugs administered during the perianesthesia period by inhibiting their oxidative metabolism. Differences in elimination kinetics of nonvolatile fluorine-containing metabolites after isoflurane and halothane exposure suggest the presence of an unidentified isoflurane metabolite.

Toxicokinetics of organic solvents.

Organic solvents, because of their small molecules and large solubility in fat, water, or both, are expected to be readily absorbed through the skin or by inhalation. Toxicokinetic models (empirical, pharmacokinetic, and simulation) are used to describe the time course of their absorption and elimination. Special attention is given in this review to simulation models in which rate constants are derived from physiological parameters of the exposed subject (alveolar ventilation, tissue perfusion, body build) and from physicochemical properties of the inhaled chemical (partition coefficient, metabolic clearance). Such a simulation model is used to gain insight into the uptake, distribution, and elimination of inhaled vapors of organic solvents. Large differences between kinetic patterns of hydrophobic and hydrophilic solvents are indicated by the effects of biosolubility, metabolic clearance, changes in physiological parameters, exposure duration, and concentration fluctuation on the uptake, distribution, and elimination of solvents. Because kinetics is the basis for interindividual and intraindividual differences in pulmonary uptake and bioavailability and in the development of toxic effects, simulation models have practical application in the biological exposure monitoring and medical surveillance of exposed workers.

Inhibitory effect of isoflurane upon oxidative metabolism of halothane.

The effect of isoflurane upon halothane metabolism was studied in rats exposed to mixtures of subanesthetic concentrations of isoflurane (0.015-0.32%) and halothane (0.062%). The extent of halothane metabolism was determined from concentrations of halothane and its metabolites (total nonvolatile fluorine, 1,1,1-trifluoro-2-chloroethane and 1,1-difluoro-2-chloroethylene) in tissues of rats. At the end of exposures lasting 3 hr, distribution of halothane in tissues indicated that the bioavailability of halothane in liver was unaffected by exposure to isoflurane. Isoflurane, however, significantly inhibited the oxidative metabolism of halothane, as indicated by reduced concentrations of total nonvolatile fluorine in tissues. The inhibition is concentration-dependent. Isoflurane enhances the reductive metabolism of halothane, as indicated by increased concentrations of volatile metabolites in liver. Exposure to nitrous oxide (2.2-50%) had no effect on halothane metabolism. The mechanism of the inhibitory effect remains to be explained.

Effects of biosolubility on pulmonary uptake and disposition of gases and vapors of lipophilic chemicals.

Since statistical analysis proved the intercorrelation of tissue-gas partition coefficients of chemicals with similar chemical structures, bioavailability is controlled by one parameter dependent on the physicochemical properties of the chemicals and two constants distinguishing the tissues. Oil-gas partition coefficients are suggested to describe the biosolubility of volatile halogenated aliphatic chemicals. Tissue-gas partition coefficients derived from oil-gas partition coefficients were substituted in a pharmacokinetic model in order to study the effect of biosolubility on uptake, distribution, and elimination of inhaled chemicals. The simulation was focused on occupational exposures (8 h/day, 5 days/wk). Desaturation curves for all tissues show three exponential decays. The analysis of the simulation data indicates three patterns in behavior of inhaled vapors and gases in the body. Tissue uptake of poorly soluble chemicals (oil-gas partition coefficient less than 10) is flow limited at the beginning of exposure, but the partial pressures of such chemicals in the body equilibrate very rapidly with ambient air. Increased pulmonary uptake compensates for metabolic clearance. The rapid response of tissue concentrations to changes in exposure concentrations indicates that the toxic effect can easily be induced by short-term increase of exposure concentration, and that emergence from the reversible effect is rapid when exposure ceases. Tissue uptake of chemicals with oil-gas partition coefficients between 10 and 10(4) is flow limited during the entire 8-h exposure. Tissue concentrations increase slowly. Pulmonary uptake, being restricted by alveolar ventilation, compensates at steady state only for the amount of chemical removed by metabolic clearance. Therefore, tissue concentrations at steady state are lower than biosolubility. Accumulation during occupational exposure is obvious. Dumping of inhaled chemicals in adipose tissue protects the target organ from the occasional short-term increases in the exposure concentration. Tissue uptake of highly soluble chemicals (oil-gas partition coefficients greater than 10(4)) is limited by alveolar ventilation and exposure concentration. The rising and declining of tissue concentrations is very slow, half-times being in the magnitude of months and years. Metabolism reduces the half-time significantly. A lagging acute toxic effect can develop as the chemical accumulates in the body; the effect is most likely to persist long after the termination of the exposure.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of exposure concentrations on distribution of halothane metabolites in the body.

The effect of exposure concentration on halothane metabolism was studied in rats exposed to subanesthetic concentrations of halothane in air. Concentrations of halothane, total nonvolatile fluorine, and volatile metabolites (CF3CH2Cl and CF2 = CHCl) were determined in liver, kidneys, muscles, and brains excised at the end of a 3-hr exposure. It was observed that concentrations of all halothane metabolites in tissues rose less than exposure concentrations, that nonvolatile fluorine was present in all tissues in approximately the same concentrations, and that concentrations of volatile metabolites in liver were much higher than in any other tissues. A simulation model was used to support the following conclusions. Metabolism of halothane by all metabolic pathways is flow limited at small exposure concentrations and is capacity limited at high exposure concentrations. Volatile metabolites formed in livers are efficiently removed from circulation by pulmonary clearance, but trifluoroacetic acid is accumulated in the body. Halothane is most susceptible to biodegradation to trifluoroacetic acid, but this pathway is saturated at very small exposure concentrations. Susceptibility to biodegradation of volatile metabolites is small, but the pathways are not saturated even at anesthetic concentrations. The contribution of each of the three metabolites to total metabolic clearance depends on exposure concentrations. Trifluoroacetic acid was the major metabolite during exposure to small halothane concentrations; formation of more toxic, volatile metabolites increased during exposure to high concentrations. Postmortem formation of metabolites was studied in order to prevent its interference with tissue analysis. The method for determination of volatile metabolites is described.

Predictable "individual differences" in uptake and excretion of gases and lipid soluble vapours simulation study.

A five-compartment pharmacokinetic model with two excretory pathways, exhalation and metabolism, based on first order kinetics is used to outline the effect of body build, pulmonary ventilation, and lipid content in blood on uptake, distribution, and clearance of low solubility gases and lipid soluble vapours during and after exposure. The model shows the extent that individual differences have on altering uptake and distribution, with consequent changes in blood concentration, rate of excretion, and toxicity, even when variations in these parameters are within physiological ranges. The model is also used to describe the concentration variation of inhaled substances in tissues of subjects exposed to concentrations with permitted excursions. During the same course of exposure, the tissue concentrations of low solubility gases fluctuate much more than tissue concentrations of lipid soluble vapours. The fluctuation is reduced by metabolism of inhaled substance. These conclusions are recommended for consideration whenever evaluating the effect of excursions above the threshold limit values used in the control of industrial exposures (by excursion factors).

Uptake and clearance of inhalation anesthetics in man.

The uptake, distribution, and clearance of inhaled vapors is governed by rules of partial pressure equilibration in a multicompartmental system. Since halogenated anesthetic agents are not soluble in water, biotransformation is their only clearance pathway during anesthesia. When apparent steady state is reached, the rate of overall metabolism can be determined from the pulmonary uptake rate. As a result of metabolism, pulmonary uptake increases but the concentration of inhaled vapor in blood and tissues decreases, and only a fraction of uptake is exhaled following anesthesia. Uptake and pulmonary clearance of five halogenated anesthetic agents were studied in 45 surgical patients. The susceptibility to biotransformation increases in the following order: isoflurane, enflurane, halothane, fluroxene, methoxyflurane.

Glutathione depletion following inhalation anesthesia.

Glutathione depletion following inhalation of halogenated anesthetics was investigated as a possible mechanism of toxic reactions associated with anesthesia. Concentrations of reduced glutathione were measured in the blood, liver, lung and kidney of the mouse after anesthesia with enflurane, fluroxene, halothane, isoflurane, methoxyflurane, or trichloroethylene. The anesthetic had no effect on glutathione concentrations in tissues except when fluroxene was used. After two hours of fluroxene anesthesia, glutathione in liver, lung, kidney, and blood was depleted by 93, 85, 85, and 61 per cent, respectively. The depletion was dose-dependent and was more extensive in animals anesthetized after phenobarbital pretreatment. Glutathione was also depleted in livers and lungs of rats anesthetized with fluroxene (60 and 38 per cent, respectively). In blood of rhesus monkeys anesthetized with fluroxene, glutathione was depleted by only 13 per cent. Extents of glutathione depletion are related to fluroxene toxicities in the three species studied.