Influence of Aroclor 1254, phenobarbital, beta-naphthoflavone, and ethanol pretreatment on the biotransformation of cyclophosphamide in male and female rats.

The aim of the present study is to investigate the influence of the environmental factors, smoking and alcohol, on the biotransformation of cyclophosphamide (CP) in the rat in vivo and in vitro with S9 liver fractions. The biotransformation of CP was studied by the determination of the CP metabolites, nor-nitrogen mustard (NNM), 4-ketocyclophosphamide (KCP), and carboxyphosphamide (CAR). The effect of the environmental factors, smoking and alcohol consumption, on the biotransformation enzymes was mimicked by pretreatment of rats with beta-naphthoflavone and ethanol, respectively. Rats treated with olive oil and water served as controls and rats pretreated with Aroclor 1254 and phenobarbital were used as positive controls. The influence of sex and supplementation with NAD and GSH, mimicking a biological variation in NAD and GSH levels in rat and human liver, was also studied. Pretreatment of rats with Aroclor 1254 decreased the excretion of unmetabolized CP in urine, most likely due to an enhanced biotransformation. The in vitro hepatic biotransformation of CP in rats was strongly influenced by sex, by supplementation with NAD and GSH, and by pretreatment with the enzyme-inducers, phenobarbital and Aroclor 1254. No influence of pretreatment with the enzyme-inducers, beta-naphthoflavone and ethanol, was found. The results suggest that the influence of the environmental factors, alcohol consumption and smoking, on the biotransformation of CP in man will be negligible.

Absorption of polycyclic aromatic hydrocarbons through human skin: differences between anatomical sites and individuals.

In order to determine differences in absorption of polycyclic aromatic hydrocarbons (PAH) between anatomical sites and individuals, coal-tar ointment was applied to skin of volunteers at various sites. The surface disappearance of PAH and the excretion of urinary 1-OH-pyrene after skin application of coal-tar ointment were used as parameters for dermal PAH absorption. The surface disappearance was determined by the measurement of the fluorescence of PAH on skin. Surface disappearance measurements show low but significant differences in dermal PAH absorption between anatomical sites: shoulder > forehead, forearm, groin, > ankle, hand (palmar site). The average PAH absorption rate constant at different skin sites ranges from 0.036/h to 0.135/h (overall mean: 0.066/h). This indicates that after 6 h of exposure, 20-56% of a low dermal dose of PAH (e.g., about 1.0 ng pyrene/cm2) will be absorbed. The interindividual differences in PAH absorption are small (7%) in comparison with differences between anatomical sites (69%). Results based on the urinary excretion of 1-OH-pyrene are less clear. The site of application of the coal-tar ointment (dose: 2.5 mg/cm2 during 6 h) has no significant effect on the excreted amount of 1-OH-pyrene in urine. It is estimated that after coal-tar ointment application on skin, 0.3-1.4% of the pyrene dose (about 2 micrograms pyrene/cm2) becomes systemically available. For the accurate estimation of PAH uptake through skin of workers, it seems relevant to distinguish different body regions, not only because of the regional variation in percutaneous PAH absorption, but also because of the high dispersal of PAH contamination on skin of workers.

Occupational exposure of animal caretakers to cyclophosphamide.

Little is known about the exposure of animal caretakers to toxic agents during the administration of such chemicals to laboratory animals. In this study, we have investigated the environmental contamination with cyclophosphamide (CP) in an animal laboratory where mice were housed and injected with this compound. Also the contamination of gloves, sleeve protectors, and masks used for personal protection was studied. The uptake of CP by the animal caretakers was determined by the analysis of unmetabolized CP in urine. For the estimation of CP in the air, air samples were taken and filters of the air-circulation system were analyzed. On the filters, amounts of CP were detected corresponding with < 0.1-1.0 microgram/day. Environmental contamination was also measured by analysis of wipe samples taken from different spots (objects and surfaces). The presence of CP was not only observed in the room where the mice were housed and treated with CP but also in adjacent rooms (< 0.02-44 ng/cm2). The gloves used during the injection of CP were always contaminated (2-199 micrograms/pair). No penetration of the gloves was established. The sleeve protectors were incidentally contaminated (< 0.3-10 micrograms) and on the masks no CP was found (< 0.2 microgram). Eighty seven urine samples from four animal caretakers were analyzed for unmetabolized CP. In one sample, CP was detected (0.7 microgram). The results show that in this particular study animal caretakers are exposed to CP during their work.