title: Development of a urinary biomarker for exposure to the organophosphate propetamphos: data from an oral and dermal human volunteer study.
abstract: Propetamphos is a member of the vinyl phosphate group of insecticides and is mainly used for sheep dipping. There have been no published metabolic studies on the effect of propetamphos in man to date, although the present authors have published the identification of a metabolite. The present paper presents data from a human volunteer study investigating the toxicokinetics of the organophosphorus pesticide propetamphos following oral and dermal exposure. Five volunteers ingested a propetamphos dose of 10 micrograms kg-1 (35 nmol kg-1) body weight. Following a washout of 4 weeks, a 100 mg (356 mumol) dermal dose of propetamphos was applied, occluded to 80 cm2 of the inner forearm, for 8 h to the same five volunteers. In a pilot study (several weeks before the main study), one volunteer also received an occluded dermal dose of 50 mg (178 mumol) propetamphos. Unabsorbed propetamphos on the skin was washed off after 8 h and collected. Blood and urine samples were collected over 30 and 54 h for the oral and dermal exposures respectively. Blood samples were analysed for plasma and erythrocyte cholinesterase. Urine samples were analysed for a urinary metabolite of propetamphos: methylethylphosphoramidothioate (MEPT). Following oral and dermal exposure, peak urinary MEPT levels occurred at 1 and 10-12 h respectively. The apparent urinary elimination half-lives of MEPT had means of 1.7 h (oral exposure) and 3.8 h (dermal exposure). Approximately 40% of the oral dose and 1% of the dermal dose were recovered as urinary MEPT or metabolites, which could be hydrolysed to MEPT. Approximately 90% of the dermal dose was recovered from the skin washings. Data from a volunteer showed that a doubling of the dermal dose resulted in approximately double the concentration of total MEPT. Alkaline hydrolysis of urine samples increased the level of MEPT detected after both oral and dermal doses. The increase was greater and statistically significant (p < 0.001, paired t-test) for the dermal dose. This increase in MEPT suggests the presence of other MEPT-containing metabolites or conjugates. The difference in the increase between oral and dermal doses raises the question of a difference in metabolism between the two routes. No individual showed a significant depression compared with their pre-exposure levels of erythrocyte acetyl cholinesterase or plasma cholinesterase activity for either dosing route. However, on a group basis, there was a statistically significant mean depression in plasma cholinesterase activity at 8 and 24 h for oral exposure, with a maximum mean depression of 7% from pre-exposure levels at 8 h. Hydrolysis of urine samples had the effect of reducing the interindividual coefficient of variation (CV) for total excretion of MEPT following both oral (CV reduced from 36 to 8%) and dermal (CV reduced from 40 to 17%) exposure. The ability to detect and follow the elimination of low doses of propetamphos by measurement of 'total' (after hydrolysis) urinary MEPT suggests it is a suitable biomarker of propetamphos exposure. The comparatively short elimination half-lives suggest a strategy for biological monitoring of occupational exposure based on samples collected at the end of the shift.
authors.affiliation: Health & Safety Laboratory, Broad Lane, Sheffield, S3 7HQ, UK. sarah.garfitt@hsl.gov.uk
authors.forename: S J
authors.initials: SJ
authors.lastname: Garfitt
authors.forename: K
authors.initials: K
authors.lastname: Jones
authors.forename: H J
authors.initials: HJ
authors.lastname: Mason
authors.forename: J
authors.initials: J
authors.lastname: Cocker
mesh_terms: D000279:Administration, Cutaneous; D000284:Administration, Oral; D000328:Adult; D015415:Biomarkers; D004784:Environmental Monitoring / Q000379:methods*; D005260:Female; D006801:Humans; D007306:Insecticides / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D009946:Organothiophosphorus Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D015415:Biomarkers; D007306:Insecticides; D009946:Organothiophosphorus Compounds; C035967:propetamphos