Dermal absorption of neat liquid solvents on brief exposures in volunteers.

The dermal absorption of liquid 1,1,1-trichloroethane (111TRI), trichloroethene (TRI), tetrachloroethene (TETRA), toluene (TOL), and m-xylene (XYL) was studied in volunteers. The solvents were applied for 3 min on the volar forearm over an area of 27 cm2. An inhalation exposure with a known input rate served as a reference exposure. Using the linear system dynamics method, permeation rates were calculated from exhaled air concentration courses measured after both inhalation and dermal exposure. The permeation time courses of the solvents showed two different patterns. TRI, TOL, and 111TRI in three subjects showed fast increase in permeation, reaching maximal permeation rates a few minutes after initiation of exposure. Slower permeation was seen in the other three subjects exposed to 111TRI and in all subjects exposed to TETRA and XYL with the time of maximal permeation rates of 15-25 min. These differences in the permeation may partly be explained by the irritation of the skin observed in all subjects showing fast permeation kinetics. The flux into the skin averaged over the exposure period amounted to 56, 430, 69, 223, and 46 nmol/cm2/min for 111TRI, TRI, TETRA, TOL, and XYL, respectively. Comparing the dermal uptake with the respiratory uptake at the TLV, all solvents showed substantial skin absorption, although at present only TOL has a skin indication in the American Conference of Governmental Industrial Hygienists threshold limit value list.

Effect of coexposure to methyl ethyl ketone (MEK) on n-hexane toxicokinetics in human volunteers.

In order to study the effects of methyl ethyl ketone (MEK) on the toxicokinetics of n-hexane and, in particular, the formation of 2,5-hexanedione from n-hexane in humans, volunteers were exposed to n-hexane (approx. 60 ppm, 2.4 microM in the inhaled air) with or without simultaneous inhalatory coexposure to MEK for 15.5 min. The concentration-time course of n-hexane (in exhaled alveolar air) and its neurotoxic metabolite, 2,5-hexanedione (in serum), were studied. The concentration-time courses obtained after exposure to n-hexane alone were compared with those obtained after coexposure to 200 or 300 ppm MEK in the same volunteer on the same day. No effect of MEK was observed on the concentration-time course of exhaled n-hexane. The concentration-time course of the metabolite, 2,5-hexanedione, revealed a decrease in the rate of formation of 2,5-hexanedione (about three-fold) after coexposure to MEK. Furthermore, the time to reach the peak concentration was increased from 18 to 30 min after the start of exposure. These changes in the concentration-time course of 2,5-hexanedione caused by MEK are most likely the result of inhibition of the biotransformation of one of the intermediate steps in the conversion of n-hexane to 2,5-hexanedione. These results indicate that the interaction of n-hexane and MEK leads to a decreased concentration of the neurotoxic metabolite 2,5-hexanedione (after short-term, acute exposure).

Determination of 2,5-hexanedione, a metabolite of n-hexane, in urine: evaluation and application of three analytical methods.

Three methods for the determination of 2,5-hexanedione (2,5-HD) in urine were compared in order to assess their applicability for toxicokinetic studies and biological monitoring of occupational exposure to n-hexane. Two of them were based on derivatization, followed by gas chromatography and electron-capture detection. Of these two, one is a modification of the other, already published, method. The third one involves direct extraction of 2,5-HD followed by gas chromatography and flame-ionization detection. To determine 2,5-HD in urine of workers occupationally exposed to n-hexane, the most straightforward method, direct extraction of 2,5-HD from urine, has been proven to be the most suitable. However, in case of very low concentrations of 2,5-HD in urine, or analysis of small samples of blood, e.g. in kinetic studies, it is necessary to use a more sensitive procedure. The sensitivity of the methods based on the derivatization of 2,5-HD followed by electron-capture detection, was, as expected, much higher in terms of analytical reliability. By using these methods, however, precautions are necessary to avoid a matrix effect.

Linear systems dynamics in toxicokinetic studies.

Linear systems dynamics are introduced to study kinetics particularly in experimental exposure to toxic agents and to extrapolate the experimental results to the field of occupational exposure. The relationship between the agent input (e.g. dose, external exposure) and the concentration-time curve [C(t)] in biological media plays a central part. When this relationship has been established the C(t) can be predicted or the dose as function of time can be estimated retrospectively on an individual basis. Linear systems dynamics offer a kinetic model-independent approach which means that no assumptions are required about compartments, bloodflows, partition coefficients, etc. The systems dynamics appear to be a powerful tool to predict the time courses of an agent or toxic metabolites in, for example, blood or a target organ on the basis of a short-term experimental exposure. The power of systems dynamics becomes obvious especially in the case of non-constant rates of inputs (dose) into systemic blood at, for example, dermal exposure. Also the systems approach appears to be suitable to determine the metabolic rate of entrance into the system blood as function of the parent agent or a second agent. The paper emphasizes the value of human exposure experiments under controlled conditions in order to verify the outcomes of physiologically based simulation models and to provide experimental data for these models.

Intra and interindividual variability in the kinetics of a poorly and highly metabolising solvent.

Human subjects were experimentally exposed three times simultaneously to tetrachloroethene (PER) and trichloroethene (TRI) under conditions of rest and exercise. In each subject the individual kinetics for both PER and TRI were determined three times by means of frequent sampling of alveolar air up to 70-500 and 20-310 hours respectively. For PER the following parameters were found: the weighted pulmonary clearance (Clpul) = 0.27-0.64 l/min, terminal half time (t1/2(z] = 54-250 hours, mean residence time (MRT) = 35-155 hours, and volume of distribution (Vdss) = 1100-3570 1. For TRI the apparent hepatic clearance (CLhep) = 0.5-1.7 l/min, weighted Clpul = 0.41-1.48 l/min, t1/2(z) = 13-55 hours, MRT = 2.3-22 hours, and the Vdss = 420-3100 1. The intra and intersubject variation in the kinetics were reflected in the predictions of the individual time course of the solvent in the blood at repeated exposure up to five weeks (eight hours a day, five days a week). For PER the intrasubject variation in the predicted concentrations on the Monday mornings was within 5-15% whereas the intersubject variation was about twofold. For TRI the intrasubject variation in the predicted morning concentrations was substantial (two to threefold), whereas the intersubject variation was about 10-fold. The intrasubject variation was probably caused mainly by the level of exercise during exposure. The Clhep was not greatly influenced by the level of exercise, whereas exercise during exposure increased the MRT. Exercise during exposure probably speeds up the process of distribution and, therefore, there is a lower concentration in the blood relative to the increased respiratory intake. As a consequence, despite the increased Clpul and the rather unchanged Clhep, pulmonary and metabolic excretion will be delayed and the MRT increased. The MRT is more suited to predict the individual cumulation of both PER and TRI than the terminal t1/2(z).

A method for the retrospective estimation of the individual respiratory intake of a highly and a poorly metabolising solvent during rest and physical exercise.

A method for the retrospective estimation of the individual respiratory intake was tested. The method is based on system dynamics. Subjects were exposed simultaneously to the poorly metabolising solvent tetrachloroethene (PER, perchloroethylene) and the highly metabolising trichloroethene (TRI) at rest, 30, and 65 watt physical exercise. The time courses of the alveolar concentration (Calv) of both PER and TRI were measured. A retrospective estimation of the individual intake of PER could be carried out up to 400 hours after exposure with 10-20% accuracy, irrespective of the level of exercise. The estimates of the intake of TRI are less accurate. The Calv in the 1-15 hours postexposure permits the estimation of the intake of TRI within a mean error of 25% for most subjects. For men the method may be applied up to 48 hours after exposure within 20% error. For women the intake estimates showed a poor accuracy with the use of Calv beyond the day of exposure.

Respiratory input in inhalation experiments.

The definition of the respiratory input in experimental human exposure to volatile solvents was examined on theoretical grounds. The respiratory rate of input may be defined as the rate of uptake that equals the inhaled minus exhaled amount per minute. In the present paper the rate of respiratory input is defined as the rate of the functional intake (RFI) which equals the product of the inhaled concentration (CI) and a functional alveolar ventilation (Va). The functional Va is a virtual alveolar volume per minute which equilibrates completely with the mixed venous blood. Human subjects were exposed simultaneously to tetrachloroethene (PER, perchloroethylene) and trichloroethene (TRI) in order to study the consequences of the application of both definitions. It is shown that when using the uptake as the respiratory input some misleading conclusions may be drawn on (a) the dependence of the metabolised fraction on the duration of exposure, (b) the dependence of the kinetic characteristic on the duration and route of administration, and (c) the changes of the rate of metabolism during exposure due to physical exercise. The respiratory input defined as the rate of functional intake (RFI) rejects these misleading conclusions.

Alveolar sampling and fast kinetics of tetrachloroethene in man. II. Fast kinetics.

Fast kinetic phenomena were studied in human subjects exposed to tetrachloroethene (perchloroethylene, PER). The duration of exposure ranged from one to 60 minutes and the concentration of PER in inhaled air ranged from 0.02 to 0.40 mmol/m3. The PER concentration in mixed venous blood (pulmonary artery) was estimated by alveolar concentration (CAlv) measured after a residence time of 10 s. During exposure, stoppage of intake (breath holding up to 50 s) caused a decrease of CAlv down to about 60% of the CAlv at a residence time of 10 s. At the end of exposure, stoppage of intake (breathing fresh air) caused a decrease of CAlv with t1/2 = 15-25 s; after two to four minutes, the decrease slowed down abruptly and the concentration remained more or less constant for about one to three minutes. After this stationary level, the decrease of CAlv continued but at a slower rate. During and after exposure, the decrease of CAlv seems to be caused by large differences in the circulation times of blood flowing through rapid, well perfused tissues and slower, well perfused tissues which may explain the stationary level. From this point of view, the vessel rich group in a compartment model must be split up in order to predict tissue and organ concentrations during peak environmental concentrations.

Alveolar sampling and fast kinetics of tetrachloroethene in man. I. Alveolar sampling.

Human subjects were exposed to tetrachloroethene (perchloroethylene, PER). The duration of exposure ranged from one to 60 minutes and the concentration of PER in inhaled air ranged from 0.02 to 0.40 mmol/m3. Alveolar air was sampled after several residence times (t*) in the lung. Both during and after exposure, the concentration of PER in alveolar air (C Alv) as a function of the residence time was studied to estimate the concentration in the pulmonary artery (C Ven: mixed venous blood) and in the pulmonary vein (C Art: arterial blood). During exposure C Alv decreased as function of t*. At t* = 10 s C Alv was 70-75% of the value presented at t* = 5 s; this decrease approximates an exponential curve. C Alv seemed to stabilise at t* = 10-12 s, whereas it decreased more rapidly at t* greater than 12 s; this decrease continued up to at least t* = 55 s when C Alv was about 40% of the value it represented at t* = 5 s. In the postexposure period C Alv increased as function of t* from 5 to 10 s. Both during and after exposure, no difference was observed between C Alv at t* = 10 s and C Alv in the exhaled part of the expiratory reserve volume. A simple gas exchange model showed that the decrease or increase of C Alv at t* less than 10 s could be explained by either absorption or excretion by mixed venous blood. C Alv at t* = 10-12 s provided a valid estimate of C Ven. To estimate C Art, its fluctuating character due to the discontinuous breathing with a breathing frequency had to be taken into account. It is shown that C Alv during normal breathing (t* = 5 s) provides a reasonable estimate of the time weighted concentration in arterial blood.