Toxicokinetics of captan and folpet biomarkers in orally exposed volunteers.

The time courses of key biomarkers of exposure to captan and folpet was assessed in accessible biological matrices of orally exposed volunteers. Ten volunteers ingested 1 mg kg(-1) body weight of captan or folpet. Blood samples were withdrawn at fixed time periods over the 72 h following ingestion and complete urine voids were collected over 96 h post-dosing. The tetrahydrophthalimide (THPI) metabolite of captan along with the phthalimide (PI) and phthalic acid metabolites of folpet were then quantified in these samples. Plasma levels of THPI and PI increased progressively after ingestion, reaching peak values ~10 and 6 h post-dosing, respectively; subsequent elimination phase appeared monophasic with a mean elimination half-life (t(½) ) of 15.7 and 31.5 h, respectively. In urine, elimination rate time courses of PI and phthalic acid evolved in parallel, with respective t(½) of 27.3 and 27.6 h; relatively faster elimination was found for THPI, with mean t(½) of 11.7 h. However, phthalic acid was present in urine in 1000-fold higher amounts than PI. In the 96 h period post-treatment, on average 25% of folpet dose was excreted in urine as phthalic acid as compared with only 0.02% as PI. The corresponding value for THPI was 3.5%. Overall, THPI and PI appear as interesting biomarkers of recent exposure, with relatively short half-lives; their sensitivity to assess exposure in field studies should be further verified. Although not a metabolite specific to folpet, the concomitant use of phthalic acid as a major biomarker of exposure to folpet should also be considered.

Toxicokinetics of captan and folpet biomarkers in dermally exposed volunteers.

To better assess biomonitoring data in workers exposed to captan and folpet, the kinetics of ring metabolites [tetrahydrophthalimide (THPI), phthalimide (PI) and phthalic acid] were determined in urine and plasma of dermally exposed volunteers. A 10 mg kg(-1) dose of each fungicide was applied on 80 cm(2) of the forearm and left without occlusion or washing for 24 h. Blood samples were withdrawn at fixed time periods over the 72 h following application and complete urine voids were collected over 96 h post-dosing, for metabolite analysis. In the hours following treatment, a progressive increase in plasma levels of THPI and PI was observed, with peak levels being reached at 24 h for THPI and 10 h for PI. The ensuing elimination phase appeared monophasic with a mean elimination half-life (t(½) ) of 24.7 and 29.7 h for THPI and PI, respectively. In urine, time courses PI and phthalic acid excretion rate rapidly evolved in parallel, and a mean elimination t(½) of 28.8 and 29.6 h, respectively, was calculated from these curves. THPI was eliminated slightly faster, with a mean t(½) of 18.7 h. Over the 96 h period post-application, metabolites were almost completely excreted, and on average 0.02% of captan dose was recovered in urine as THPI while 1.8% of the folpet dose was excreted as phthalic acid and 0.002% as PI, suggesting a low dermal absorption fraction for both fungicides. This study showed the potential use of THPI, PI and phthalic acid as key biomarkers of exposure to captan and folpet.

Toxicokinetic modeling of captan fungicide and its tetrahydrophthalimide biomarker of exposure in humans.

Measurement of tetrahydrophthalimide (THPI) in urine has been used for the biomonitoring of exposure to the widely used captan fungicide in workers. To allow a better understanding of the toxicokinetics of captan and its key biomarker of exposure, a human multi-compartment model was built to simulate the transformation of captan into THPI and its subsequent excretion while accounting for other non-monitored metabolites. The mathematical parameters of the model were determined from best-fits to the time courses of THPI in blood and urine of five volunteers administered orally 1mg/kg and dermally 10mg/kg of captan. In the case of oral administration, the mean elimination half-life of THPI from the body (either through faeces, urine or metabolism) was found to be 13.43 h. In the case of dermal application, mean THPI elimination half-life was estimated to be 21.27 h and was governed by the dermal absorption rate. The average final fractions of administered dose recovered in urine as THPI were 3.6% and 0.02%, for oral and dermal administration, respectively. Furthermore, according to the model, after oral exposure, only 8.6% of the THPI formed in the GI reaches the bloodstream. As for the dermal absorption fraction of captan, it was estimated to be 0.09%. Finally, the average blood clearance rate of THPI calculated from the oral and dermal data was 0.18 ± 0.03 ml/h and 0.24 ± 0.6 ml/h while the predicted volume of distribution was 3.5 ± 0.6l and 7.5 ± 1.9l, respectively. Our mathematical model is in complete accordance with both independent measurements of THPI levels in blood (R(2)=0.996 for oral and R(2)=0.908 for dermal) and urine (R(2)=0.979 for oral and R(2)=0.982 for dermal) as well as previous experimental data published in the literature.

Evaluation of genotoxicity of captan, maneb and zineb in the wing spot test of Drosophila melanogaster: role of nitrosation.

The wing spot test in Drosophila melanogaster is a suitable system for the analysis of genotoxic activity of compounds that need metabolic transformation to render them active. We have analysed the genotoxicity of three fungicides for which it was reported that the metabolic processes taking place in vivo may determine their activity. The compounds analysed are captan, maneb, zineb and ethylenethiourea (ETU) (a metabolic derivative of ethylenebisdithiocarbamates like maneb and zineb). We have also evaluated the ability of ETU to form genotoxic derivatives in vivo analysing this compound in combined treatments with sodium nitrite. Both standard and high bioactivation NORR strains have been used. Captan, usually considered a mutagen in vitro but a non-mutagen in vivo, gave negative results in the wing spot test with both crosses. Positive results were obtained for maneb in the standard cross and for ETU in both the standard and the high bioactivation cross. The genotoxicities of maneb and ETU were higher when treatments were made on media in which nitrosation is favoured. A low absorption of the fungicide and an inefficient availability of the compound in the target may explain negative results obtained with zineb in both crosses. The results obtained in this study with the wing spot test demonstrate once again the suitability of this in vivo assay, in which absorption, distribution and metabolism processes take place, for the evaluation of genotoxicity of compounds to which humans are exposed.

Improved estimation of dermal pesticide dose to agricultural workers upon reentry.

Agricultural workers reentering fields after pesticide application to engage in hand labor activities are subject to potentially significant dermal exposures to residues on foliage and in soil. Environmental Protection Agency (EPA) guidelines for assessment of post-application exposures were originally described in the 1984 Pesticide Assessment Guidelines Subdivision K which is currently undergoing revision. A successor document will eventually appear as Series 875, Group B Postapplication Exposure Monitoring Test Guidelines. Regulatory protocols found in these documents utilize dislodgeable foliar residues, foliage-to-human-transfer coefficients, and duration of activity to estimate exposure. Dermal absorption factors are then used to estimate dose. However, the experiments from which absorption factors are derived typically involve constant or nearly constant exposures which are not consistent with assumed field exposure conditions. This can lead to inconsistent interpretation and questionable dose estimates. An AFL-CIO challenge to procedures used by EPA to estimate the dose of the fungicide captan [N-trichloromethylthio-4-cyclohexene-1,2-dicarboximide] to strawberry harvesters, which elicited a response from EPA, provides a useful opportunity for examination of the derivation and use of absorption factors. An improved, but still relatively simple, method for dermal dose estimation featuring explicit treatment of the time dependence of absorption has been developed. A benefit of the proposed method is capability for consideration of the effect of delay in post-shift washing on dose.

Captan fungicide exposures of strawberry harvesters using THPI as a urinary biomarker.

Clothing affords harvesters considerable protection against the elements and can retain substantial amounts of pesticide residue from treated crops. Normal work clothing of female harvesters was supplemented with rubber latex gloves and facial scarves to determine whether those measures reduced exposure. Captan fungicide exposures in female strawberry harvesters were assessed by determining urine clearance rates of tetrahydrophalimide (THPI). Clean rubber gloves were supplied to the 41 harvesters for the 3 days of the study period in October 1995. The workers were divided into two groups consisting of either bare-handed or gloved workers, and 24-h urine specimens were collected each day. Female harvesters who worked bare-handed cleared 5.3 microg captan equivalents as THPI with a range of 0.4 to 13.8 microg/person/day. Harvesters who worked wearing rubber latex gloves cleared only 2.0 microg captan equivalents with a range of 0.9 to 4.3 microg/person/day. In this case clean rubber latex gloves reduced absorbed dose by 38%, compared to the dose absorbed by bare-handed workers. These results additionally indicate that when a pesticide is avidly retained by rubber latex gloves and not readily absorbed dermally as captan, estimates of absorbed dose based on passive dosimetry data may be less reliable than exposure estimates derived from urine biomonitoring.

Captan metabolism in humans yields two biomarkers, tetrahydrophthalimide (THPI) and thiazolidine-2-thione-4-carboxylic acid (TTCA) in urine.

Captan fungicide (N-(trichloromethylthio)-4-cyclohexene-1,2-dicarboximide) metabolism in two human volunteers rapidly yields THPI (tetrahydrophthalimide) and TTCA (thiazolidine-2-thione-4-carboxylic acid). The work was done to evaluate usefulness of TTCA and THPI as biomarkers of occupational exposure and to compare human and rat dermal absorption and metabolism. THPI in 12h urine ranged from MDL (5 ppb) to 640 ppb and was stable for at least one year. TTCA was also a stable metabolite, but the MDL was 50 ppb. THPI was detectable in urine for 72 hours following oral dosages of 1 mg/kg, but most was eliminated 0-24 h. No THPI was detectable in urine following application of a chloroform solution to hands, forearms, or inguinal region. Dermal absorption and metabolism of captan are substantially different in humans and rats.

Dermal penetration of [14C]captan in young and adult rats.

Age dependence in dermal absorption has been a major concern in risk assessment. Captan, a chloroalkyl thio heterocyclic fungicide, was selected for study of age dependence as representative of this class of pesticides. Dermal penetration of [14C]captan applied at 0.286 mumol/cm2 was determined in young (33-d-old) and adult (82-d-old) female Fischer 344 rats in vivo and by two in vitro methods. Dermal penetration in vivo at 72 h was about 9% of the recovered dose in both young and adult rats. The percentage penetration was found to increase as dosage (0.1, 0.5, 2.7 mumol/cm2) decreased. Two in vitro methods gave variable dermal penetration values compared with in vivo results. A static system yielded twofold higher dermal penetration values compared with in vivo results for both young and adult rats. A flow system yielded higher dermal penetration values in young rats and lower penetration values in adults compared with in vivo results. Concentration in body, kidney, and liver was less in young than in adult rats given the same absorbed dosage. A physiological pharmacokinetic model was developed having a dual compartment for the treated skin and appeared to describe dermal absorption and disposition well. From this model, tissue/blood ratios of captan-derived radioactivity for organs were found to range from 0.35 to 3.4, indicating no large uptake or binding preferences by any organ. This preliminary pharmacokinetic model summarizes the experimental findings and could provide impetus for more complex and realistic models.