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T R Auton

Publications and source records attributed to T R Auton.

25 records · Page 2Linked to original sources
PubMed1993

Modelling dermal pharmacokinetics using in vitro data. Part II. Fluazifop-butyl in man.

In a previous paper it was demonstrated that dermal absorption of the herbicide fluazifop-butyl in the rat could be modelled by combining a knowledge of the pharmacokinetics following intravenous and oral dosing with in vitro measurements of dermal absorption. This paper demonstrates the validation of a similar model for the dermal absorption of fluazifop-butyl in man. Pharmacokinetic parameters derived from an oral dosing study are combined in a mathematical model with in vitro measurements of dermal absorption of fluazifop-butyl. Model predictions of the rate and extent of dermal absorption of fluazifop-butyl are compared with the results of dermal absorption studies in human volunteers. Good agreement is found between the model predictions and the experimental measurements. These results have implications for improved risk assessment. The model provides a tool for risk assessment based on both internal dose (e.g. peak plasma concentration, plasma area under the curve) as well as total absorbed dose. However, further work is required to evaluate whether the same techniques are applicable to a wider range of compounds.

Administration, Cutaneous↗
PubMed1992

Human inhalation pharmacokinetics of chlorodifluoromethane (HCFC22).

Two groups of three male volunteers were exposed to atmospheric concentrations of either 327 or 1833 mg m-3 chlorodifluoromethane (HCFC22) for 4 h. Blood, urine and expired air samples were taken during and after the exposure period and analysed for HCFC22. Urine samples were also analysed for fluoride ion. During the exposure period, blood concentrations of HCFC22 approached a plateau, and the average peak blood concentrations of 0.25 and 1.36 micrograms cm-3 were proportional to dose. HCFC22 concentrations in expired air were similar to the exposure concentration during the exposure period. The ratio between venous blood and breath concentrations of HCFC22 towards the end of the exposure period was on average 0.77, which is consistent with in vitro estimates of the partition coefficient. In the post-exposure period, three phases for the elimination of HCFC22 were identified, with estimated half-lives of 0.005, 0.2 and 2.6h. HCFC22 was detected in urine samples taken in the post-exposure period, and the rate of decline was consistent with the terminal rate of elimination estimated from blood and breath measurements. On average 2.1% of the inhaled HCFC22 was recovered in breath within 26 h of exposure. This is consistent with the low solubility in blood and fat. Minimal changes in fluoride ion concentrations in urine following exposure indicate that HCFC22 is unlikely to be metabolised to a significant extent. Following inhalational exposure HCFC22 is poorly absorbed and is rapidly eliminated from the body. Possible biological monitoring strategies could be based on measurements of HCFC22 in urine or breath samples collected after the end of an exposure period.

Adult↗
PubMed1992

Pharmacokinetics of fluazifop-butyl in human volunteers. II: Dermal dosing.

1. The absorption of the herbicide fluazifop-butyl (f-b), has been determined from plasma and urine measurements in groups of six male volunteers following dermal administration of 2.5, 25 and 250 micrograms cm-2 from standardized formulations containing 0.05, 0.5 and 5.0% (w/v) fluazifop-butyl to a skin area of 800 cm2. 2. Urinary excretion rate of the principal metabolite fluazifop, following dosing with the 5% formulation, was described by a two-compartment pharmacokinetic model; the average elimination half-lives of initial and terminal phases were 18 h and approximately 70 h, respectively. For the other dose levels the elimination half-life was estimated to be 17 h; urine concentrations at later time points were too low to characterize a second compartment. 3. The estimated total fluazifop-butyl absorbed was 8.0, 3.4 and 1.6% of the applied dose for the 0.05, 0.5 and 5.0% formulations, respectively. 4. Up to 50% of the applied fluazifop-butyl was readily removed by skin washing and the majority of the remainder was transferred to clothing during the 24 h following application. 5. When six volunteers were given a daily dermal dose of the 0.5% formulation for five consecutive days, the plasma and urinary excretion kinetics of fluazifop could be accurately predicted by simple mathematical extrapolation of the kinetic data from the single exposure study at the equivalent daily dose. 6. It is concluded that fluazifop-butyl is only slowly and poorly absorbed through human skin and has a low potential to accumulate in man.

Administration, Cutaneous↗
PubMed1991

A physiologically based mathematical model for the human inhalation pharmacokinetics of 1,1,2-trichloro-1,2,2-trifluoroethane.

A physiologically based mathematical model is described for the human inhalation pharmacokinetics of 1,1,2-trichloro-1,2,2-trifluoroethane (FC113). Physiological parameters for the model are derived from the scientific literature. Partition coefficients are determined from in vitro measurements. Predictions of the resulting model for breath and blood concentrations compare well with results of a human volunteer study described in a companion paper (Woollen et al. 1990). Using this data some alternative models are also examined with different choices of physiological parameters and partition coefficients. The mathematical model is used to examine the consequences of metabolic elimination of FC113. A value for metabolic clearance is estimated using the during-exposure breath concentration data; however, the concentrations of FC113 in breath or blood during and after exposure are shown to be insensitive to metabolic clearance. Consequently, no firm conclusion can yet be drawn as to whether FC113 is metabolised by man.

Air Pollutants, Occupational↗
PubMed1990

Human inhalation pharmacokinetics of 1,1,2-trichloro-1,2,2-trifluoroethane (FC113).

Seven male volunteers were exposed to atmospheric concentrations of either 1980, 4100 or 7630 mg m-3 1,1,2-trichloro-1,2,2-trifluoroethane (FC113) for 4 h. Blood and expired air samples were collected during the exposure period and for several days subsequently and analysed for FC113. Blood and breath concentrations of FC113 were related to the administered dose with some variation between individuals. The low blood/breath ratios measured are consistent with the low solubility of FC113 in blood. The absorption and elimination of FC113 can be described by a three-compartment model and the average half-lives of elimination of FC113 in breath were 0.22, 2.3 and 29 h. A pulmonary retention during the exposure period of 14% was measured but only 2.6 to 4.3% of the dose was recovered unchanged in breath after the exposure period, suggesting that FC113 could be metabolised following inhalation exposure. It is concluded that a practical method for biological monitoring during occupational exposure would be to measure end-tidal breath concentrations of FC113 in samples taken the morning after exposure. The predictive value of such a measurement can be improved if the results are normalised to the body fat content of individual workers which can be estimated from height and weight measurements.

Administration, Inhalation↗
PubMedDate not supplied

Characterization of the interaction of 2-[2-nitro-4-(trifluoromethyl)benzoyl]-4,4,6,6,-tetramethyl- cyclohexane-1,3,5-trione with rat hepatic 4-hydroxyphenylpyruvate dioxygenase.

The synthetic beta-triketones are a novel family of chemicals, developed as herbicides that have activity on grass and broadleaf weeds and are selective in corn. Toxicological evaluation of a number of these chemicals has established that they interfere with rat hepatic tyrosine catabolism in vivo by inhibiting the enzyme 4-hydroxyphenylpyruvate dioxygenase (HPPD). This paper describes the kinetics of inhibition of rat hepatic HPPD in vitro by the representative beta-triketone 2-[2-nitro-4-(trifluoromethyl)benzoyl]-4,4,6,6- tetramethylcyclohexane-1,3,5-trione (1). A marked inhibition of rat hepatic HPPD was observed when 1 was incubated with the enzyme for 3 min at 37 degrees C prior to the initiation of the enzyme reaction by the addition of substrate. In this system, a concentration of 200 nM 1 resulted in a > 90% loss of HPPD activity, and an apparent IC50 was established at approximately 50 nM. The rate constant for the inactivation of HPPD by 1 was (1.5 +/- 0.2) x 10(-5) s-1 nM-1 as determined by progress curve data of oxygen consumed by HPPD with time. This inhibition is reversible in that the enzyme-inhibitor complex slowly dissociates, with approximately 5.5 +/- 0.6% of the enzyme activity being recovered by 6 h at 25 degrees C (t1/2, 25 degrees C, estimated at 101 +/- 14 h). In short, our studies establish 1 to be a tight-binding inhibitor of rat hepatic HPPD in vitro. This inhibition is characterized by the rapid inactivation of HPPD by the formation of an enzyme-inhibitor complex that dissociates extremely slowly with recovery of enzyme activity.

4-Hydroxyphenylpyruvate Dioxygenase↗