[show abstract][hide abstract] ABSTRACT: To assess exposure to pyrethroids in the general population, one of most widely used method nowadays consists of measuring urinary metabolites. Unfortunately, interpretation of data is limited by the unspecified relation between dose and levels in biological tissues and excreta. The objective of this study was to develop a common multi-compartment toxicokinetic model to predict the time courses of two mainly used pyrethroid pesticides, permethrin and cypermethrin, and their metabolites (cis-DCCA, trans-DCCA and 3-PBA) in the human body and in accessible biological matrices following different exposure scenarios. Toxicokinetics was described mathematically by systems of differential equations to yield the time courses of these pyrethroids and their metabolites in the different compartments. Unknown transfer rate values between compartments were determined from best fits to available human data on the urinary excretion time courses of metabolites following an oral and dermal exposure to cypermethrin in volunteers. Since values for these coefficients have not yet been determined, a mathematical routine was programmed in MathCad to establish the possible range of values on the basis of physiological and mathematical considerations. The best combination of parameter values was then selected using a statistic measure (reliability factor) along with a statistically acceptable range of values for each parameter. With this approach, simulations provided a close approximation to published time course data. This model allows to predict urinary time courses of trans-DCCA, cis-DCCA and 3-PBA, whatever the exposure route. It can also serve to reconstruct absorbed doses of permethrin or cypermethrin in the population using measured biomarker data.
PLoS ONE 01/2014; 9(2):e88517. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Drinking water intake of arsenic (As) from private wells may represent a significant exposure pathway and induce oxidative DNA damage. We measured total As concentrations in hair and nails, and concentrations of the different species of As and its metabolites as well as 8-OHdG in urine of 110 non-smoking adults living in a rural region of the Province of Quebec, Canada. Significant differences in exposure biomarker levels were observed between individuals consuming drinking water with As levels of≤1.0,>1.0 -≤10 and>10 μg/l. Multivariate linear regression analysis also showed a significant relationship between estimated daily drinking water intakes of As and biomarker levels. Conversely, 8-OHdG levels were not significantly related to daily drinking water intakes of As or to hair, nail or urinary exposure biomarker levels, according to multivariate linear regression analysis. Even at the relatively low levels of As found in well water of our participants, water consumption significantly increases their body load of As, as confirmed by multiple matrix measurements, which reflected exposure over different time frames. However, this increased internal As dose was not associated with higher oxidative damage to DNA as reflected by urinary 8-OHdG levels.Journal of Exposure Science and Environmental Epidemiology advance online publication, 6 November 2013; doi:10.1038/jes.2013.80.
Journal of Exposure Science and Environmental Epidemiology 11/2013; · 3.19 Impact Factor
[show abstract][hide abstract] ABSTRACT: The impact polychlorinated biphenyl (PCB) exposure on thyroid status in pregnant women and newborns was investigated in various epidemiological studies, but findings show inconsistencies, and differences in biological indicators of exposure between studies limits comparison of results. The aim of this research was to use a procedure previously developed to standardize PCB biological concentration data between published studies to perform a systematic analysis of associations between PCB exposure and thyroid hormones (THs) (total and free T3 and T4) or thyroid stimulating hormone (TSH) in pregnant women and newborns. Biological concentrations from nineteen studies were expressed in total PCB equivalent per kg of lipids in maternal plasma (μgPCBMPEQkg(-1) lipids). Systematic analysis of the "standardized biological concentration-thyroid parameters" relationship was conducted through the application of methodological criteria in both pregnant women and newborns. Standardization of PCB levels and application of methodological criteria led to assign higher confidence to ten of the reviewed studies. Among the retained studies in pregnant women, only one reported a significant association between PCBs and total T3 levels, but no association were observed when circulating TSH and free T4 levels were used to assess thyroid function. Regarding the association between prenatal PCB exposure and thyroid status in newborns, a lack of significant association was consistently obtained in the retained studies assigned an overall high confidence. The weight of evidence of a significant impact of PCB exposure on TSH and TH levels at the described biological levels in pregnant women and newborns (mean<1000μgPCBMPEQkg(-1) lipids) appears low according to this systematical analysis.
[show abstract][hide abstract] ABSTRACT: 3-Hydroxybenzo(a)pyrene (3-OHBaP) in urine has been proposed as a biomarker of occupational exposure to polycyclic aromatic hydrocarbons. However, to reconstruct exposure doses in workers from biomarker measurements, a thorough knowledge of the kinetics of the benzo(a)pyrene (BaP) and 3-OHBaP given different routes of exposure is needed. A rat physiologically-based pharmacokinetic model of BaP and 3-OHBaP was built. Organs (tissues) represented as compartments were based on in vivo experimental data in rats. Tissue: blood partition coefficients, permeability coefficients, metabolism rates, excretion parameters, and absorption fractions and rates for different routes-of-entry were obtained directly from published in vivo time courses of BaP and 3-OHBaP in blood, various tissues and excreta of rats. The latter parameter values were best-fitted by least square procedures and Monte Carlo simulations. Sensitivity analyses were then carried out to ensure the stability of the model and the key parameters driving the overall modeled kinetics. This modeling pointed out critical determinants of the kinetics: (1) hepatic metabolism of BaP and 3-OHBaP elimination rate as the most sensitive parameters; (2) the strong partition of BaP in lungs compared to other tissues, followed by adipose tissues and liver; (3) the strong partition of 3-OHBaP in kidneys; (4) diffusion-limited tissue transfers of BaP in lungs and 3-OHBaP in lungs, adipose tissues and kidneys; (5) significant entero-hepatic recycling of 3-OHBaP. Very good fits to various sets of experimental data in rats from four different routes-of-entry (intravenous, oral, dermal and inhalation) were obtained with the model.
Journal of Pharmacokinetics and Biopharmaceutics 10/2013; · 2.06 Impact Factor
[show abstract][hide abstract] ABSTRACT: Physiological daily inhalation rates reported in our previous study for normal-weight subjects 2.6-96 years old were compared to inhalation data determined in free-living overweight/obese individuals (n = 661) aged 5-96 years. Inhalation rates were also calculated in normal-weight (n = 408), overweight (n = 225), and obese classes 1, 2, and 3 adults (n = 134) aged 20-96 years. These inhalation values were based on published indirect calorimetry measurements (n = 1,069) and disappearance rates of oral doses of water isotopes (i.e., (2) H2 O and H2 (18) O) monitored by gas isotope ratio mass spectrometry usually in urine samples for an aggregate period of over 16,000 days. Ventilatory equivalents for overweight/obese subjects at rest and during their aggregate daytime activities (28.99 ± 6.03 L to 34.82 ± 8.22 L of air inhaled/L of oxygen consumed; mean ± SD) were determined and used for calculations of inhalation rates. The interindividual variability factor calculated as the ratio of the highest 99th percentile to the lowest 1st percentile of daily inhalation rates is higher for absolute data expressed in m(3) /day (26.7) compared to those of data in m(3) /kg-day (12.2) and m(3) /m(2) -day (5.9). Higher absolute rates generally found in overweight/obese individuals compared to their normal-weight counterparts suggest higher intakes of air pollutants (in μg/day) for the former compared to the latter during identical exposure concentrations and conditions. Highest absolute mean (24.57 m(3) /day) and 99th percentile (55.55 m(3) /day) values were found in obese class 2 adults. They inhale on average 8.21 m(3) more air per day than normal-weight adults.
[show abstract][hide abstract] ABSTRACT: Acrylamide (AA) is a probable human carcinogen found in several foods. Little information is available regarding exposure of adolescents, a subgroup potentially consuming more AA-rich foods. We investigated the relationship between dietary AA intake and levels of biomarkers of exposure (urinary metabolites and hemoglobin adducts) in 195 non-smoking teenagers of Montreal Island aged 10-17 years. Dietary habits and personal characteristics were documented by questionnaire. AA and its metabolites were quantified in 12-h urine collections by LC-MS/MS. Hemoglobin adducts from 165 blood samples were also analyzed by LC-MS/MS. Most prevalent urinary metabolites were NACP and NACP-S, with respective geometric mean concentrations of 31.2 and 14.2 μmol/mol creatinine. Geometric mean concentrations of AAVal and GAVal (hemoglobin adducts of AA and glycidamide (GA) with N-terminal valine residues) were 45.4 and 45.6 pmol/g globin, respectively. AA intake during the 2 days before urine collection was a significant predictor of NACP+NACP-S urinary concentrations (P<0.0001). AA intakes during the month before blood collection (P<0.0001) and passive smoking (P<0.05) were associated with adduct levels. Levels of hemoglobin adducts were above biomonitoring equivalent values corresponding to a 1 × 10(-4) excess cancer risk, which may indicate the need to reduce AA exposure in the population.Journal of Exposure Science and Environmental Epidemiology advance online publication, 12 June 2013; doi:10.1038/jes.2013.34.
Journal of Exposure Science and Environmental Epidemiology 06/2013; · 3.19 Impact Factor
[show abstract][hide abstract] ABSTRACT: Impact of prenatal exposure to polychlorinated biphenyls (PCBs) on mental and motor development has been investigated in various children cohorts, but findings show temporal inconsistencies. Because a direct comparison of results obtained from different cohorts remains difficult, temporal relationship between biological PCB concentrations and long-term developmental effects is still not clearly established. The objective of this research was to use a procedure previously developed to standardize PCB biological concentration data across cohorts in order to perform a systematic analysis of temporal associations between prenatal PCB exposure and mental and motor development from neonatal period (or a young age) until school age. Prenatal exposure data from nine cohorts were standardized in terms of total PCBs per kg of lipids in maternal plasma. Systematic analysis of the "standardized biological concentration - development" relationship during follow-up of each cohort was then conducted through the application of Hill criteria. This led to retain six of the studied cohorts in the final analysis. A biological level of prenatal PCB exposure below which risk of mental or motor development should be negligible was established in the order of 1000 μg/kg of lipids in maternal plasma.
Regulatory Toxicology and Pharmacology 03/2013; · 2.13 Impact Factor
[show abstract][hide abstract] ABSTRACT: The distribution of acrylamide in food items frequently consumed by Canadian adolescents was determined along with estimates of their contribution to the overall dietary intake of acrylamide. A total of 196 non-smoking adolescents (10-17 years old) were recruited in Montreal Island population, Canada. Participants were invited to fill out a 2-day food diary and a food frequency questionnaire over the last month. 146 samples of foods most frequently consumed by participants were analyzed for acrylamide contents. The highest acrylamide contents were measured in deep-fried french fries and potato chips (mean ± SD: 1053 ± 657 and 524 ± 276 ng/g respectively). On the basis of the 2-day food diary, median total daily intake of acrylamide was estimated at 0.29 μg/kg b.w./d, as compared to 0.17 μg/kg b.w./d on the basis of the food frequency questionnaire. These values are similar to those reported in comparable populations. Deep-fried french fries consumption contributed the most to daily acrylamide intake (50%) followed by potato chips (10%), oven-baked french fries (8%) and breakfast cereals (8%). Margins of exposure based on genotoxic benchmark dose limits were estimated to be low (≈<100) in high-consumer adolescents, indicating the need to continue efforts to reduce dietary acrylamide exposure.
Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 03/2013; · 2.99 Impact Factor
[show abstract][hide abstract] ABSTRACT: Interactions between nanoparticles (NP), humans and the environment are not fully understood yet. Moreover, frameworks aiming at protecting human health have not been adapted to NP but are nonetheless applied to NP-related activities. Consequently, business organizations currently have to deal with NP-related risks despite the lack of a proven effective method of risk-management. To respond to these concerns and fulfill the needs of populations and industries, ÉquiNanos was created as a largely interdisciplinary provincial research team in Canada. ÉquiNanos consists of eight platforms with different areas of action, from adaptive decision-aid tool to public and legal governance, while including biological monitoring. ÉquiNanos resources aim at responding to the concerns of the Quebec nanotechnology industry and public health authorities. Our mandate is to understand the impact of NP on human health in order to protect the population against all potential risks emerging from these high-priority and rapidly expanding innovative technologies.
Nanomedicine: nanotechnology, biology, and medicine 09/2012; · 6.93 Impact Factor
[show abstract][hide abstract] ABSTRACT: Exposure to various pesticides has been characterized in workers and the general population, but interpretation and assessment of biomonitoring data from a health risk perspective remains an issue. For workers, a Biological Exposure Index (BEI®) has been proposed for some substances, but most BEIs are based on urinary biomarker concentrations at Threshold Limit Value - Time Weighted Average (TLV-TWA) airborne exposure while occupational exposure can potentially occurs through multiple routes, particularly by skin contact (i.e.captan, chlorpyrifos, malathion). Similarly, several biomonitoring studies have been conducted to assess environmental exposure to pesticides in different populations, but dose estimates or
health risks related to these environmental exposures (mainly through the diet), were rarely characterized. Recently, biological reference values (BRVs) in the form of urinary pesticide metabolites have been proposed for both occupationally exposed workers and children. These BRVs were established using toxicokinetic models developed for each substance, and correspond to safe levels of absorption in humans, regardless of the exposure scenario. The purpose of this chapter is to present a review of a toxicokinetic modeling approach used to determine biological reference values. These are then used to facilitate health risk assessments and decision-making on occupational and environmental pesticide exposures. Such
models have the ability to link absorbed dose of the parent compound to exposure biomarkers and critical biological effects. To obtain the safest BRVs for the studied population, simulations of exposure scenarios were performed using a conservative reference dose such as a no-observed-effect level (NOEL). The various examples discussed in this chapter show the importance of knowledge on urine collections
(i.e. spot samples and complete 8-h, 12-h or 24-h collections), sampling strategies, metabolism, relative proportions of the different metabolites in urine, absorption fraction, route of exposure and background contribution of prior exposures. They also show that relying on urinary measurements of specific metabolites appears more accurate when applying this approach to the case of occupational exposures.
Conversely, relying on semi-specific metabolites (metabolites common to a category of pesticides) appears more accurate for the health risk assessment of environmental exposures given that the precise pesticides to which subjects are exposed are often unknown. In conclusion, the modeling approach to define BRVs
for the relevant pesticides may be useful for public health authorities for managing issues related to health risks resulting from environmental and occupational exposures to pesticides.
[show abstract][hide abstract] ABSTRACT: Impact of prenatal PCB exposure on birth weight was investigated in various children cohorts and findings of published studies show inconsistencies. Because a direct comparison of results obtained from different studies remains difficult, the "biological concentration-birth weight" relationship is not clearly established. The objective of this research was to perform a systematic analysis of published epidemiological data to reassess relationship between prenatal PCB exposure and low birth weight, using toxicokinetic considerations and a novel standardization procedure of biological concentration data across studies. A systematic analysis of 20 epidemiological studies published up to 2011 on this topic was conducted. This was achieved through a standardization of reported exposure data in terms of total PCBs per kg of lipids in maternal plasma. Systematic analysis of the "standardized biological concentration-birth weight" relationship across studies was then conducted through the application of Hill criteria. Combining results of all 20 reviewed studies did not allow to establish an association between prenatal exposure to PCBs at the described levels and abnormal birth weight (<2500g). Our approach provides a framework for the use of published data to establish "PCB biological concentration-response" relationships.
Regulatory Toxicology and Pharmacology 06/2012; 64(1):161-76. · 2.13 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
Annals of Occupational Hygiene 03/2012; 56(7):815-28. · 2.16 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
[show abstract][hide abstract] ABSTRACT: Polybrominated diphenyl ethers (PBDEs) are flame retardants routinely detected in samples of cord blood and breast milk. Concerns have been raised with regard to the toxicity of both pre- and postnatal exposures towards the developing nervous system. Although there is an increasing body of literature on the disruption of brain cell functions by certain PBDE congeners in vitro, some challenges have yet to be tackled to enable the translation of in vitro findings into their in vivo counterparts. In this paper, we review findings on the PBDE neurotoxicity in human cells and discuss the research gaps to be addressed. Moreover, we propose a scheme for the incorporation of in vitro data in human risk assessment, namely through (i) the determination of in vitro cell benchmark levels; (ii) the consideration of uncertainties in establishing equivalency between the in vitro and the in vivo tissue benchmark levels (e.g., chronic vs. acute exposure, interactions with other chemicals); and (iii) relating tissue benchmark levels to surrogate levels of internal exposure. Alongside the assessment of brain dosimetry following exposure to PBDEs, in vitro neurotoxicity data provide a unique opportunity to evaluate the risks of prenatal and early life exposures on children neurodevelopment.
Toxicology in Vitro 06/2011; 25(8):1509-15. · 2.65 Impact Factor
[show abstract][hide abstract] ABSTRACT: Measurements of 3-hydroxybenzo(a)pyrene (3-OHBaP) in urine has been proposed for the biomonitoring of exposure to benzo(a)pyrene (BaP) in workers. To allow a better understanding of the toxicokinetics of BaP and its key biomarker, a multicompartment model was developed based on rat data previously obtained by this group. According to the model, iv injected BaP is rapidly distributed from blood to tissues (t₁/₂ = 3.65 h), with particular affinity for tissue lipid components and liver and lung proteins. BaP is then rapidly distributed to lungs, where significant tissue uptake occurs, followed by the skin, liver, and adipose tissues. Once in liver, BaP is readily metabolized, and 3-OHBaP is formed with a t₁/₂ of 3.32 h. Lung metabolism of BaP was also accounted for, but its contribution to the whole kinetics was found to be negligible. Once formed, 3-OHBaP is distributed from blood to the various organs almost as fast as the parent compound (t₁/₂ = 2.26 h). In kidneys, 3-OHBaP builds up as a result of the smaller rate of 3-OHBaP urinary excretion (t₁/₂ = 4.52 h) as compared with its transfer rate from blood to kidneys (t₁/₂ = 27.8 min). However, overall clearance of 3-OHBaP from the body is driven by its biliary transfer from liver to the gastrointestinal tract (t₁/₂ = 3.81 h). The model provides a great fit to independent sets of published data on 3-OHBaP urinary excretion time course (χ² = 0.019). This model proves useful in establishing the main biological determinants of the overall kinetics of these compounds.
[show abstract][hide abstract] ABSTRACT: 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.
Journal of Applied Toxicology 03/2011; 32(3):194-201. · 2.60 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
Journal of Applied Toxicology 03/2011; 32(3):202-9. · 2.60 Impact Factor
[show abstract][hide abstract] ABSTRACT: Captan and folpet are fungicides largely used in agriculture. They have similar chemical structures, except that folpet has an aromatic ring unlike captan. Their half-lives in blood are very short, given that they are readily broken down to tetrahydrophthalimide (THPI) and phthalimide (PI), respectively. Few authors measured these biomarkers in plasma or urine, and analysis was conducted either by gas chromatography coupled to mass spectrometry or liquid chromatography with UV detection. The objective of this study was thus to develop simple, sensitive and specific liquid chromatography-atmospheric pressure chemical ionization-tandem mass spectrometry (LC/APCI-MS/MS) methods to quantify both THPI and PI in human plasma and urine. Briefly, deuterated THPI was added as an internal standard and purification was performed by solid-phase extraction followed by LC/APCI-MS/MS analysis in negative ion mode for both compounds. Validation of the methods was conducted using spiked blank plasma and urine samples at concentrations ranging from 1 to 250 μg/L and 1 to 50 μg/L, respectively, along with samples of volunteers and workers exposed to captan or folpet. The methods showed a good linearity (R (2) > 0.99), recovery (on average 90% for THPI and 75% for PI), intra- and inter-day precision (RSD, <15%) and accuracy (<20%), and stability. The limit of detection was 0.58 μg/L in urine and 1.47 μg/L in plasma for THPI and 1.14 and 2.17 μg/L, respectively, for PI. The described methods proved to be accurate and suitable to determine the toxicokinetics of both metabolites in human plasma and urine.
Analytical and Bioanalytical Chemistry 02/2011; 399(6):2243-55. · 3.66 Impact Factor
[show abstract][hide abstract] ABSTRACT: Agricultural workers are exposed to folpet, but biomonitoring data are limited. Phthalimide (PI), phthalamic acid (PAA), and phthalic acid (PA) are the ring metabolites of this fungicide according to animal studies, but they have not yet been measured in human urine as metabolites of folpet, only PA as a metabolite of phthalates. The objective of this study was thus to develop a reliable gas chromatography-tandem mass spectrometry (GC-MS) method to quantify the sum of PI, PAA, and PA ring-metabolites of folpet in human urine. Briefly, the method consisted of adding p-methylhippuric acid as an internal standard, performing an acid hydrolysis at 100 °C to convert ring-metabolites into PA, purifying samples by ethyl acetate extraction, and derivatizing with N,O-bis(trimethylsilyl)trifluoro acetamide prior to GC-MS analysis. The method had a detection limit of 60.2 nmol/L (10 ng/mL); it was found to be accurate (mean recovery, 97%), precise (inter- and intra-day percentage relative standard deviations <13%), and with a good linearity (R (2) > 0.98). Validation was conducted using unexposed peoples urine spiked at concentrations ranging from 4.0 to 16.1 μmol/L, along with urine samples of volunteers dosed with folpet, and of exposed workers. The method proved to be (1) suitable and accurate to determine the kinetic profile of PA equivalents in the urine of volunteers orally and dermally administered folpet and (2) relevant for the biomonitoring of exposure in workers.
Analytical and Bioanalytical Chemistry 02/2011; 400(2):493-502. · 3.66 Impact Factor