A. C. Monster

Kinetics of tetrachloroethylene in volunteers; influence of exposure concentration and work load.

SummarySix male volunteers were exposed for 4 h to 72 ppm tetrachloroethylene (PERC) at rest, to 144 ppm PERC at rest, and to 142 ppm PERC at rest combined with work load (2 times 30 min, 100 W). Minute volume and concentrations in exhaled air were measured to estimate the uptake. Concentrations of PERC and trichloroacetic acid (TCA) were determined in blood. Exhaled air was analysed for PERC; urine for TCA.The uptake/min decreased in the course of the exposure to 60 % of the initial uptake. The total uptake was influenced more by (lean) body mass than by respiratory minute volume or adipose tissue. During work load the uptake and minute volume increased to 3 fold the value at rest. In the post exposure period the quotient of the bloodconcentrations and exhaled air concentrations of PERC remained nearly constant at 23. Following exposure about 80–100 % of the uptake was excreted unchanged by the lungs, whereas till 70 h after exposure the amount of TCA excreted in urine represented about 1 % of the uptake.

Pharmacokinetics of trichloroethylene in volunteers, influence of workload and exposure concentration

SummaryFour male volunteers inhaled for 4 h 70 and 140 ppm trichloroethylene (TRI) at rest and also at rest combined with exercise. To estimate the amount retained in the body (dose), minute volume and concentration in exhaled air were determined. Concentrations of TRI, trichloroethanol (TCE) and trichloroacetic acid (TCA) were determined in blood. Exhaled air was analysed for TRI and TCE; urine for TCE and TCA.During more than 60 h after exposure the concentration of TRI and TCE in blood and exhaled air were proportional to the dose, but the interindividual variation was large; workload increased the dose, but no influence was found on the distribution and metabolism. The total recovery was 67%; 10% as TRI by the lungs and in urine 39% as TCE and 18% as TCA.

Difference in uptake, elimination, and metabolism in exposure to trichloroethylene, 1,1,1-trichloroethane and tetrachloroethylene

SummaryThe relatively high and almost constant absorption/min of trichloroethylene (TRI) is explained by the relatively high partition coefficient between blood and air (λb/g = 15) combined with the rapid metabolism (75 %). Tetrachloroethylene (PERC) has about the same λb/g as TRI, but the metabolism is insignificant (2 %); therefore, the amount taken up/min decreases in the course of exposure. The λb/g (5) for 1,1,1-trichloroethane (MC) is smaller, the metabolism is insignificant (3.5 %), therefore the capacity of the body to absorb MC is relatively small and in consequence the uptake/min decreases fast in the course of exposure. Due to the lower λb/g the excretion of MC after exposure is much faster than of PERC. As a result of the metabolism of TRI only a relatively small amount of TRI absorbed is excreted by the lungs after exposure.

Dermal absorption of vaporous and liquid 2-methoxyethanol and 2-ethoxyethanol in volunteers.

OBJECTIVES: To estimate dermal absorption of vaporous and liquid 2-methoxyethanol (ME) and 2-ethoxyethanol (EE) in volunteers. METHODS: Five volunteers (two men and three women) were dermally exposed to vaporised and liquid ME and EE. Dermal exposure on an area of about 1000 cm2 (forearm and hand) to vapours of ME and EE (4000 mg/m3 ME and 3700 mg/m3 EE) lasted for 45 minutes. Duration of exposure to liquid ME and EE on an area of 27 cm2 (forearm) was 15 minutes. Dermal uptake was assessed by measurement of the main metabolites in urinary methoxyacetic acid (MAA) and ethoxyacetic acid (EAA). For each volunteer, excretion of metabolites was compared with a reference inhalatory exposure. RESULTS: Mean (SD) absorption rates of ME and EE vapour were 36 (11) and 19 (6) cm/h respectively. The mean (SD) absorption rates of the liquid ME and EE amounted to 2.9 (2.0) and 0.7 (0.3) mg/cm2.h. CONCLUSIONS: Vaporised and liquid ME and EE are readily absorbed through the skin. In the combined inhalatory and dermal exposure when whole body surface is exposed to vapour, the uptake through the skin is estimated to be 55% of the total uptake of ME and 42% of EE. Dermal uptake resulting from skin contact of both hands and forearms (about 2000 cm2) with liquid ME and EE for 60 minutes would exceed inhalatory uptake of the eight hour occupational exposure limit by 100 times at 16 mg/m3 of ME and 20 times at 19 mg/m3 of EE. The substantial skin uptake of ME and EE indicates that in assessing the health risks biological monitoring and use of biological exposure indices are preferable to environmental monitoring.

Kinetics of trichloroethylene in repeated exposure of volunteers.

SummaryFive male volunteers inhaled 70 ppm trichloroethylene (TRI) for 4 h on 5 consecutive days. TRI, trichloroethanol (TCE) and trichloroacetic acid (TCA) were measured, as far as present in exhaled air, blood, and urine. The uptake was 6.6 ± 0.4 mg/kg lean body mass in 4 h. The concentration of TRI in blood and exhaled air at 18 h after the 5th exposure was twice as high as at 18 h after the 1st exposure. The amount of TCE excreted per 24 h reached a level during the last exposure days, a diurnal rythm was evident. TCA in blood and urine increased during exposure days. Total recovery of the amount absorbed of TRI was 78%, 11% as TRI excreted unchanged by the lung, 43% as WE and 24% as TCA excreted in urine. Amounts of WE and TCE+TCA excreted in urine were related to lean body mass. Because of its small interindividual variation TCA in blood seems to be the most promising parameter for biological monitoring in repeated exposure.

Kinetics of 1,1,1-trichloroethane in volunteers; Influence of exposure concentration and work load

SummarySix male volunteers were exposed for 4 h to 70 ppm 1,1,1-trichloroethane (methylchloroform, MC) at rest, to 145 ppm. MC at rest, and to 142 ppm MC at rest combined with work load (2 times 30 min, 100 W). Minute volume and concentration in exhaled air were measured to estimate the uptake. MC and its metabolites trichloroethanol (TCE) and trichloroacetic acid (TCA) were determined as far as present in blood, exhaled air and urine. The uptake/min decreased in the course of exposure to 30 % of the initial uptake. The total uptake was more influenced by minute volume than by body weight or amount of adipose tissue. During work load the uptake increased to 2.3 fold and the minute volume to 3 fold the value at rest. In the post exposure period the quotients of the concentrations in blood and in exhaled air for MC and TCE remained nearly constant at 8.2 and 14,000, respectively. Following exposure about 60–80% of the amount taken up was excreted unchanged by the lungs, while until 70 h after exposure the amount of TCE and TCA excreted in urine represented about 2% and 0.5% of the uptake.

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.

Estimation of individual uptake of trichloroethylene, 1,1,1-trichloroethane and tetrachloroethylene from biological parameters.

SummaryThe results of single exposure studies with exposure to trichloroethylene, TRI, (Monster et al., 1976), to 1,1,1-trichloroethane, MC, (Monster et al., 1979b) and to tetrachloroethylene, PERC, (Monster et al., 1979c) were used to study the precision in estimating the individual uptake from measured biological parameters after exposure. With simple linear and multiple linear regression analysis the individual uptake of TRI, MC and PERC was estimated from the concentrations of solvents and metabolites in biological media (blood, urine, exhaled air) at 2 h and at 20 h after exposure. The best results are obtained by estimation from the concentrations in blood, particularly of the solvents themselves. Including results of simultaneously measured concentrations in exhaled air or urine did not improve the estimate.

Evaluation of biological monitoring parameters for occupational exposure to toluene

SummaryA survey was conducted in a rotogravure printing plant with inhalatory and percutaneous exposure to toluene. Workers (n=9) were followed for 2 consecutive days and the frequency and duration of skin contact with toluene were monitored. In order to assess percutaneous absorption an airstream helmet was worn during one day. Urine and exhaled air samples were collected simultaneously 5 times each day for toluene (urine and breath) and hippuric acid (urine). The mean (personal air sampling) exposure concentration was between 30 mg/m3 and 600mg/m3. The best biological monitoring parameter of external exposure (without a helmet) was the concentration toluene in exhaled air 8 h after work (r-0.99). While wearing the airstream helmet the relationship between external exposure (measured in the helmet) and concentrations in exhaled air and urine deviated from the preceding relations. This was likely the result of the high body burden and not of skin contact with toluene. Skin contact with toluene (usually by cleaning of the hands) was limited to 0–30 minutes a day, with an average of about 5 minutes. During experimental exposure (n=6) in which the hands were washed with toluene for 5 minutes the toluene in exhaled air (max after 1040 min) clearly demonstrated skin absorption of toluene. The next morning 0.1 mg/m3 toluene was still detectable; this was less than the concentration measured the next morning in exhaled air of workers: between 0.5 and 10mg/m3.

Metabolism of styrene in the human liver in vitro: interindividual variation and enantioselectivity

1. The interindividual variation and enantioselectivity of the in vitro styrene oxidation by cytochrome P450 have been investigated in 20 human microsomal liver samples. Liver samples were genotyped for the CYP2E1*6 and CYP2E1*5B alleles. 2. Kinetic analysis indicated the presence of at least two forms of styrene-metabolizing cytochrome P450. The enzyme constants for the high-affinity component were subject to appreciable interindividual variation, i.e. Vmax1 ranged from 0.39 to 3.20 nmol mg protein-1 min-1 (0.96±0.63) and Km1 ranged from 0.005 to 0.03 mM (0.011±0.006). Inhibition studies with chemical inhibitors of CYP2E1,CYP1A2, CYP2C8/9 and CYP3A4 demonstrated that CYP2E1 was the primary enzyme involved in the high-affinity component of styrene oxidation. No relationship between the interindividual variation in Vmax and Km1 and the genetic polymorphisms of the CYP2E1 gene was found. 3. Cytochrome P450-mediated oxidation of styrene demonstrated a moderate enantioselectivity, with an enantiomeric excess (ee) of (S)-styrene oxide of 15% (range 4−27%) at low styrene concentration and an ee of (R)-styrene oxide of 7% (range − 11 to - 22%) at high styrene concentration.This points towards the involvement of at least two cytochrome P450, with different enantioselectivities. 4. The data indicate that cytochrome P450-mediated styrene oxidation is subject to considerable interindividual variation, but only to a moderate product enantioselectivity.