Acute toxicity of the fungicide captan to honey bees and mixed evidence for synergism with the insecticide thiamethoxam.

Honey bees are commonly co-exposed to pesticides during crop pollination, including the fungicide captan and neonicotinoid insecticide thiamethoxam. We assessed the impact of exposure to these two pesticides individually and in combination, at a range of field-realistic doses. In laboratory assays, mortality of larvae treated with captan was 80-90% greater than controls, dose-independent, and similar to mortality from the lowest dose of thiamethoxam. There was evidence of synergism (i.e., a non-additive response) from captan-thiamethoxam co-exposure at the highest dose of thiamethoxam, but not at lower doses. In the field, we exposed whole colonies to the lowest doses used in the laboratory. Exposure to captan and thiamethoxam individually and in combination resulted in minimal impacts on population growth or colony mortality, and there was no evidence of synergism or antagonism. These results suggest captan and thiamethoxam are each acutely toxic to immature honey bees, but whole colonies can potentially compensate for detrimental effects, at least at the low doses used in our field trial, or that methodological differences of the field experiment impacted results (e.g., dilution of treatments with natural pollen). If compensation occurred, further work is needed to assess how it occurred, potentially via increased queen egg laying, and whether short-term compensation leads to long-term costs. Further work is also needed for other crop pollinators that lack the social detoxification capabilities of honey bee colonies and may be less resilient to pesticides.

Difficulties in translating in vitro hazards of local acute irritants to relevant human risk: Learnings from Captan and Folpet.

In order to assess the regulatory value of New Approach Methodologies (NAMs), authors should provide their opinion on the physiological and exposure relevance of observed in vitro effects for correlation with predicted in vivo effects. Further, peer-reviewers should be encouraged to request such information during review. This is critical to scientifically transition to animal-free, reliable, robust and -- most importantly -- relevant regulatory toxicology and risk assessment approaches. Recently published studies using NAMs for the fungicides Captan and Folpet illustrate the difficulties and limitations of applying NAMs to adequately assess the toxicological relevance of these substances.

Nanopesticide risk assessment based on microbiome profiling - Community structure and functional potential as biomarkers in captan@ZnO35-45 nm and captan@SiO220-30 nm treated orchard soil.

Nanoformulation should minimise the usage of pesticides and limit their environmental footprint. The risk assessment of two nanopesticides with fungicide captan as an active organic substance and ZnO35-45 nm or SiO220-30 nm as nanocarriers was evaluated using the non-target soil microorganisms as biomarkers. The first time for that kind of nanopesticides next-generation sequencing (NGS) of bacterial 16 S rRNA and fungal ITS region and metagenomics functional predictions (PICRUST2) was made to study structural and functional biodiversity. During a 100-day microcosm study in soil with pesticide application history, the effect of nanopesticides was compared to pure captan and both nanocarriers. Nanoagrochemicals affected microbial composition, especially Acidobacteria-6 class, and alpha diversity, but the observed effect was generally more substantial for pure captan. As for beta diversity, the negative impact was detected only in response to captan and still observed on day 100. Fungal community in the orchard soil showed only a decrease in phylogenetic diversity in captan set-up since day 30. PICRUST2 analysis confirmed several times lower impact of nanopesticides considering the abundance of functional pathways and genes encoding enzymes. Furthermore, the overall data indicated that using SiO220-30 nm as a nanocarrier speeds up a recovery process compared to ZnO35-45 nm.

Excretion time courses of lambda-cyhalothrin metabolites in the urine of strawberry farmworkers and effect of coexposure with captan.

There are limited literature data on the impact of coexposure on the toxicokinetics of pesticides in agricultural workers. Using the largely employed pyrethroid lambda-cyhalothrin (LCT) and fungicide captan as sentinel pesticides, we compared individual temporal profiles of biomarkers of exposure to LCT in strawberry field workers following an application episode of LCT alone or in coexposure with captan. Participants provided all urine voided over a 3-day period after an application of a pesticide formulation containing LCT alone (E1) or LCT mixed with captan (E2), and in some cases following re-entry in treated field (E3). Pyrethroid metabolites were measured in all urine samples, in particular 3-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethyl-cyclopropanecarboxylic acid (CFMP), 3-phenoxybenzoic acid (3-PBA), and 4-hydroxy-3-phenoxybenzoic acid (4-OH3PBA). There were no obvious differences in individual concentration-time profiles and cumulative excretion of metabolites (CFMP, 3-PBA, 4-OH3BPA) after exposure to LCT alone or in combination with captan. For most workers and exposure scenarios, CFMP was the main metabolite excreted, but time courses of CFMP in urine did not always follow that of 3-PBA and 4-OH3BPA. Given that the latter metabolites are common to other pyrethroids, this suggests that some workers were coexposed to pyrethroids other than LCT. For several workers and exposure scenarios E1 and E2, values of CFMP increased in the hours following spraying. However, for many pesticide operators, other peaks of CFMP were observed at later times, indicating that tasks other than spraying of LCT-containing formulations contributed to this increased exposure. These tasks were mainly handling/cleaning of equipment used for spraying (tractor or sprayer) or work/inspection in LCT-treated field according to questionnaire responses. Overall, this study provided novel excretion time course data for LCT metabolites valuable for interpretation of biomonitoring data in workers, but also showed that coexposure was not a major determinant of variability in exposure biomarker levels. Our analysis also pointed out the importance of measuring specific metabolites.

Physiological (haematological, growth and endocrine) and biochemical biomarker responses in air-breathing catfish, Clarias batrachus under long-term Captan® pesticide exposures.

The sub-lethal toxicity of Captan® on selected haematological (Hemoglobin, Haematocrit, Mean Corpuscular Hemoglobin) growth (Condition factor, Hepatosomatic Index, Specific Growth Rate), biochemical (serum glucose, protein), and endocrine parameters (growth hormone, T3 and T4) in Clarias batrachus was examined under chronic exposures. Captan® was administered at predetermined exposure concentrations (0.53 and 1.06 mg/L) and monitored on days 15, 30, and 45 of the experimental periods. The experimental groups showed significantly lower values (p < 0.05) of haemoglobin content, hematocrit, MCH in Captan® exposed fish compared to control. Serum protein, k-factor and SGR were significantly lower in exposed fish. Endocrine responses (T3 and T4) emerged as the most sensitive biomarker category, depicting modulated responses between sub-chronic exposure at day-15 and chronic responses at day-45. In general, biomarker depictions indicate that Captan® exposures are capable of inducing stress-specific effects at the biochemical and physiological levels negatively impacting the overall health and longevity of such animals.

An adverse outcome pathway for small intestinal tumors in mice involving chronic cytotoxicity and regenerative hyperplasia: a case study with hexavalent chromium, captan, and folpet.

Small intestinal (SI) tumors are relatively uncommon outcomes in rodent cancer bioassays, and limited information regarding chemical-induced SI tumorigenesis has been reported in the published literature. Herein, we propose a cytotoxicity-mediated adverse outcome pathway (AOP) for SI tumors by leveraging extensive target species- and site-specific molecular, cellular, and histological mode of action (MOA) research for three reference chemicals, the fungicides captan and folpet and the transition metal hexavalent chromium (Cr(VI)). The gut barrier functions through highly efficient homeostatic regulation of SI epithelial cell sloughing, regenerative proliferation, and repair, which involves the replacement of up to 1011 cells per day. This dynamic turnover in the SI provides a unique local environment for a cytotoxicity mediated AOP/MOA. Upon entering the duodenum, cytotoxicity to the villous epithelium is the molecular initiating event, as indicated by crypt elongation, villous atrophy/blunting, and other morphologic changes. Over time, the regenerative capacity of the gut epithelium to compensate declines as epithelial loss accelerates, especially at higher exposures. The first key event (KE), sustained regenerative crypt proliferation/hyperplasia, requires sufficient durations, likely exceeding 6 or 12 months, due to extensive repair capacity, to create more opportunities for the second KE, spontaneous mutation/transformation, ultimately leading to proximal SI tumors. Per OECD guidance, biological plausibility, essentiality, and empirical support were assessed using modified Bradford Hill considerations. The weight-of-evidence also included a lack of induced mutations in the duodenum after up to 90 days of Cr(VI) or captan exposure. The extensive evidence for this AOP, along with the knowledge that human exposures are orders of magnitude below those associated with KEs in this AOP, supports its use for regulatory applications, including hazard identification and risk assessment.

Impact of pesticide coexposure: an experimental study with binary mixtures of lambda-cyhalothrin (LCT) and captan and its impact on the toxicokinetics of LCT biomarkers of exposure.

This study aimed at gaining more insights into the impact of pesticide coexposure on the toxicokinetics of biomarkers of exposure. This was done by conducting an in vivo experimental case-study with binary mixtures of lambda-cyhalothrin (LCT) and captan and by assessing its impact on the kinetic profiles of LCT biomarkers of exposure. Groups of male Sprague-Dawley rats were exposed orally by gavage to LCT alone (2.5 or 12.5 mg/kg bw) or to a binary mixture of LCT and captan (2.5/2.5 or 2.5/12.5 or 12.5/12.5 mg/kg bw). In order to establish the temporal profiles of the main metabolites of LCT, serial blood samples were taken, and excreta (urine and feces) were collected at predetermined intervals up to 48 h post-dosing. Major LCT metabolites were quantified in these matrices: 3-(2-chloro-3,3,3-trifluoroprop-1-enyl)-2,2-dimethyl-cyclopropane carboxylic (CFMP), 3-phenoxybenzoic acid (3-PBA), 4-hydroxy-3-phenoxybenzoic acid (4-OH3PBA). There was no clear effect of coexposure at the low LCT dose on the kinetics of CFMP and 3-PBA metabolites, based on the combined assessment of temporal profiles of these metabolites in plasma, urine and feces; however, plasma levels of 3-PBA were diminished in the coexposed high-dose groups. A significant effect of coexposure on the urinary excretion of 4-OH3PBA was also observed while fecal excretion was not affected. The temporal profiles of metabolites in plasma and in excreta were further influenced by the LCT dose. In addition, the study revealed kinetic differences between metabolites with a faster elimination of 3-PBA and 4-OH3BPA compared to CFMP. These results suggest that the pyrethroid metabolites CFMP and 3-PBA, mostly measured in biomonitoring studies, remain useful as biomarkers of exposure in mixtures, when pesticide exposure levels are below the reference values. However, the trend of coexposure effect observed in the benzyl metabolite pathway (in particular 4-OH3BPA) prompts further investigation.

Design, Synthesis, and Herbicidal Activity of Novel Diphenyl Ether Derivatives Containing Fast Degrading Tetrahydrophthalimide.

To seek new protoporphyrinogen oxidase (PPO) inhibitors with better biological activity, a series of novel diphenyl ether derivatives containing tetrahydrophthalimide were designed based on the principle of substructure splicing and bioisomerization. PPO inhibition experiments exhibited that 6c is the most potential compound, with the half-maximal inhibitory concentration (IC50) value of 0.00667 mg/L, showing 7 times higher activity than Oxyfluorfen (IC50 = 0.0426 mg/L) against maize PPO and similar herbicidal activities to Oxyfluorfen in weeding experiments in greenhouses and field weeding experiments. In view of the inspected bioactivities, the structure-activity relationship (SAR) of this series of compounds was also discussed. Crop selection experiments demonstrate that compound 6c is safe for soybeans, maize, rice, peanuts, and cotton at a dose of 300 g ai/ha. Accumulation analysis experiments showed that the accumulation of 6c in some crops (soybeans, peanuts, and cotton) was significantly lower than Oxyfluorfen. Current work suggests that compound 6c may be developed as a new herbicide candidate in fields.

Comparison of Gene Expression Responses in the Small Intestine of Mice Following Exposure to 3 Carcinogens Using the S1500+ Gene Set Informs a Potential Common Adverse Outcome Pathway.

Carcinogenesis of the small intestine is rare in humans and rodents. Oral exposure to hexavalent chromium (Cr(VI)) and the fungicides captan and folpet induce intestinal carcinogenesis in mice. Previously (Toxicol Pathol. 330:48-52), we showed that B6C3F1 mice exposed to carcinogenic concentrations of Cr(VI), captan, or folpet for 28 days exhibited similar histopathological responses including villus enterocyte cytotoxicity and regenerative crypt epithelial hyperplasia. Herein, we analyze transcriptomic responses from formalin-fixed, paraffin-embedded duodenal sections from the aforementioned study. TempO-Seq technology and the S1500+ gene set were used to analyze transcription responses. Transcriptional responses were similar between all 3 agents; gene-level comparison identified 126/546 (23%) differentially expressed genes altered in the same direction, with a total of 25 upregulated pathways. These changes were related to cellular metabolism, stress, inflammatory/immune cell response, and cell proliferation, including upregulation in hypoxia inducible factor 1 (HIF-1) and activator protein 1 (AP1) signaling pathways, which have also been shown to be related to intestinal injury and angiogenesis/carcinogenesis. The similar molecular-, cellular-, and tissue-level changes induced by these 3 carcinogens can be informative for the development of an adverse outcome pathway for intestinal cancer.

Toxicity effects of captan on different life stages of zebrafish (Danio rerio).

The objective of this study was to evaluate the toxicity and developmental effects of captan on different life stages (embryo and adult) of zebrafish (Danio rerio). The results showed that the 96-h lethal concentration 50 (LC50) values of embryo and adult zebrafish (exposed to captan) were 0.81(0.75-0.87) mg/L and 0.65(0.62-0.68) mg/L, respectively. The results of developmental effect experiment showed that captan can significantly decrease the heartbeats and inhibit the hatching rate and growth of zebrafish embryos. Moreover, captan exposure can induce a series of deformities, including pericardial edema, yolk sac edema, spine curvature, and tail bending, in zebrafish embryos during the developmental period. Among these, the most significant were tail bending and spine curvature.

Exposure to the Fungicide Captan Induces DNA Base Alterations and Replicative Stress in Mammalian Cells.

The classification of the fungicide captan (CAS Number: 133-06-2) as a carcinogen agent is presently under discussion. Despite the mutagenic effect detected by the Ames test and carcinogenic properties observed in mice, the genotoxicity of this pesticide in humans is still unclear. New information is needed about its mechanism of action in mammalian cells. Here, we show that Chinese Hamster Ovary (CHO) cells exposed to captan accumulate Fpg-sensitive DNA base alterations. In CHO and HeLa cells, such DNA lesions require the XRCC1-dependent pathway to be repaired. Captan also induces a replicative stress that activated the ATR signaling response and resulted in double-strand breaks and micronuclei. The replicative stress is characterized by a dramatic decrease in DNA synthesis due to a reduced replication fork progression. However, impairment of the XRCC1-related repair process did not amplify the replicative stress, suggesting that the fork progression defect is independent from the presence of base modifications. These results support the involvement of at least two independent pathways in the genotoxic effect of captan that might play a key role in carcinogenesis. Environ. Mol. Mutagen. 60:286-297, 2019. © 2018 Wiley Periodicals, Inc.

Captan-induced increase in the concentrations of intracellular Ca2+ and Zn2+ and its correlation with oxidative stress in rat thymic lymphocytes.

Captan, a phthalimide fungicide, is considered to be relatively nontoxic to mammals. There is a possibility that captan affects membrane and cellular parameters of mammalian cells, resulting in adverse effects, because of high residue levels. To test the possibility, we examined the effects of captan on rat thymic lymphocytes using flow-cytometry with appropriate fluorescent probes. Treatment with 10 and 30 µM captan induced apoptotic and necrotic cell death. Before cell death occurred, captan elevated the intracellular concentrations of Ca2+ and Zn2+ and decreased the concentration of cellular thiol compounds. These captan-induced phenomena are shown to cause cell death and are similar to those caused by oxidative stress. Captan also elevated the cytotoxicity of hydrogen peroxide. Results indicate that 10 and 30 µM captan cause cytotoxic effects on mammalian cells. Despite no report on the significant environmental toxicity hazard of captan in humans, it may exhibit adverse effects, described above, on wild organisms.

Effects of topical exposure to a mixture of chlorpyrifos, cypermethrin and captan on the hematological and immunological systems in male Wistar rats.

Most Thai orchid farmers heavily used pesticide mixtures, and were shown to have various hematologic/immunologic alterations. The present study investigated the effect of exposure of male Wistar rats to a mixture of three pesticides (chlorpyrifos, cypermethrin and captan) that are most often used by the farmers. Three groups of 10 rats were dermally exposed to three different doses (high, middle and low) for 28 consecutive days. The rats showed significant changes in body, liver, kidneys and adrenals weights. Significant changes were observed in various biological parameters including hematotoxicity (increased leukocyte and platelet counts, percent neutrophil, decreased RBC count, percent lymphocyte and eosinophil), hepatotoxicity (increased serum AST, decreased serum ALP, cholesterol, triglyceride, serum protein and albumin), and immunotoxicity (decrease in numbers of NK cells, decrease splenic proliferative response to LPS, and increase in serum IgG). These results confirm the potential health danger of exposure to these pesticide mixtures in orchid farmers.

Comparison of Toxicity and Recovery in the Duodenum of B6C3F1 Mice Following Treatment with Intestinal Carcinogens Captan, Folpet, and Hexavalent Chromium.

High concentrations of hexavalent chromium (Cr(VI)), captan, and folpet induce duodenal tumors in mice. Using standardized tissue collection procedures and diagnostic criteria, we compared the duodenal histopathology in B6C3F1 mice following exposure to these 3 carcinogens to determine whether they share similar histopathological characteristics. B6C3F1 mice ( n = 20 per group) were exposed to 180 ppm Cr(VI) in drinking water, 12,000 ppm captan in feed, or 16,000 ppm folpet in feed for 28 days. After 28 days of exposure, villous enterocyte hypertrophy and mild crypt epithelial hyperplasia were observed in all exposed mice. In a subset of mice allowed to recover for 28 days, duodenal samples were generally indistinguishable from those of unexposed mice. Changes in the villi and lack of observable damage to the crypt compartment suggest that toxicity was mediated in the villi, which is consistent with earlier studies on each chemical. These findings indicate that structurally diverse agents can induce similar (and reversible) phenotypic changes in the duodenum. These intestinal carcinogens likely converge on common pathways involving irritation and wounding of the villi leading to crypt regenerative hyperplasia that, under protracted high-dose exposure scenarios, increases the risk of spontaneous mutation and tumorigenesis.

Highly selective biomarkers for pesticides developed in Eisenia fetida using SELDI-TOF MS.

The repeated use of pesticides, and their subsequent residues, has contributed to severe adverse effects on the environment, including risks to human health. Therefore, it is important to assess the quality of the environment to ensure it remains free from pesticide residues. The six pesticides tested in this study showed high mortality on Eisenia fetida with LC50 values ranging from 7.7 to 37.9 g L(-1). The strongest lethal effect resulted from the organochlorine insecticide endosulfan (LC50=7.7 g L(-1)). Following exposure to the carbamate pesticides, acetylcholinesterase activity in E. fetida decreased dramatically in comparison to the control. Carboxylesterase activity was only lowered in E. fetida exposed to propoxur, when compared to the control. The remaining five pesticides had no significant effect on carboxylesterase activity in E. fetida. In order to discover pesticide-specific biomarkers with differentially expressed proteins after exposure to pesticides, protein patterns of pesticide-treated E. fetida were analyzed using SELDI-TOF MS with Q10 ProteinChips. Protein patterns were compared with their intensities at the same mass-to-charge ratios (m/z). All 42 peaks had intensities with associated p-values less than 0.089, and 40 of these peaks had associated p-values of 0.05. Using SELDI-TOF MS technology, selective biomarkers for the six pesticides tested were found in E. fetida; four proteins with 5425, 5697, 9523, and 9868 m/z were consistently observed in the earthworms following exposure to the carbamates.

A detailed urinary excretion time course study of captan and folpet biomarkers in workers for the estimation of dose, main route-of-entry and most appropriate sampling and analysis strategies.

Captan and folpet are two fungicides largely used in agriculture, but biomonitoring data are mostly limited to measurements of captan metabolite concentrations in spot urine samples of workers, which complicate interpretation of results in terms of internal dose estimation, daily variations according to tasks performed, and most plausible routes of exposure. This study aimed at performing repeated biological measurements of exposure to captan and folpet in field workers (i) to better assess internal dose along with main routes-of-entry according to tasks and (ii) to establish most appropriate sampling and analysis strategies. The detailed urinary excretion time courses of specific and non-specific biomarkers of exposure to captan and folpet were established in tree farmers (n = 2) and grape growers (n = 3) over a typical workweek (seven consecutive days), including spraying and harvest activities. The impact of the expression of urinary measurements [excretion rate values adjusted or not for creatinine or cumulative amounts over given time periods (8, 12, and 24 h)] was evaluated. Absorbed doses and main routes-of-entry were then estimated from the 24-h cumulative urinary amounts through the use of a kinetic model. The time courses showed that exposure levels were higher during spraying than harvest activities. Model simulations also suggest a limited absorption in the studied workers and an exposure mostly through the dermal route. It further pointed out the advantage of expressing biomarker values in terms of body weight-adjusted amounts in repeated 24-h urine collections as compared to concentrations or excretion rates in spot samples, without the necessity for creatinine corrections.

Effect of long-term zinc pollution on soil microbial community resistance to repeated contamination.

The aim of the study was to compare the effects of stress (contamination trials) on the microorganisms in zinc-polluted soil (5,018 mg Zn kg(-1) soil dry weight) and unpolluted soil (141 mg Zn kg(-1) soil dw), measured as soil respiration rate. In the laboratory, soils were subjected to copper contamination (0, 500, 1,500 and 4,500 mg kg(-1) soil dw), and then a bactericide (oxytetracycline) combined with a fungicide (captan) along with glucose (10 mg g(-1) soil dw each) were added. There was a highly significant effect of soil type, copper treatment and oxytetracycline/captan treatment. The initial respiration rate of chronically zinc-polluted soil was higher than that of unpolluted soil, but in the copper treatment it showed a greater decline. Microorganisms in copper-treated soil were more susceptible to oxytetracycline/captan contamination. After the successive soil contamination trials the decline of soil respiration was greater in zinc-polluted soil than in unpolluted soil.

Assessment of acute toxicity and histopathology of the fungicide captan in rainbow trout.

Acute toxicity of the fungicide, captan, to juvenile rainbow trout was evaluated under static-renewal test condition. Actual concentrations of captan ranged from 0.05 to 1.00 mg/L. The concentrations of captan that killed 50% of the rainbow trout (3.11±0.8 g) within 24 (24 h; LC(50)), 48, 72 and 96 h were 0.57±0.09, 0.49±0.10, 0.44±0.11 and 0.38±0.13 mg/L (95% confidence limits), respectively. None of the unexposed control fish died and the first fish died 6 h after exposure to captan (≥0.65 mg/L). Hypertrophy, separation of epithelium from lamellae, lamellar fusion, and epithelial cell necrosis were observed on captan exposed fish. Gills also had scattered areas of focal lamellar hyperplasia. Fish exposed to fungicide had inflammation and necrosis in liver, trunk kidney and spleen. In order, the most affected organs were gill, trunk kidney and liver.

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.

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.