RESUMO
To estimate half-lives for novel fluoroethers, the GenX Exposure Study obtained two serum measurements for per- and polyfluoroalkyl substances (PFAS) for 44 participants of age 12-86 years from North Carolina, collected 5 and 11 months after fluoroether discharges into the drinking water source were controlled. The estimated half-lives for these compounds were 127 days (95% confidence interval (95% CI) = 86, 243 days) for perfluorotetraoxadecanoic acid (PFO4DA), 296 days for Nafion byproduct 2 (95% CI = 176, 924 days), and 379 days (95% CI = 199, 3870 days) for perfluoro-3,5,7,9,11-pentaoxadodecanoic acid (PFO5DoA). Using these estimates and the literature values, a model was built that predicted PFAS half-lives using structural properties. Three chemical properties predicted 55% of the variance of PFAS half-lives based on 15 PFAS. A model with only molecular weight predicted 69% of the variance. Some properties can predict the half-lives of PFAS, but a deeper understanding is needed. These fluoroethers had biological half-lives longer than published half-lives for PFHxA and PFHpA (30-60 days) but shorter than those for PFOA and PFOS (800-1200 days). These are the first and possibly only estimates of human elimination half-lives of these fluoroethers.
Assuntos
Ácidos Alcanossulfônicos , Fluorocarbonos , Poluentes Químicos da Água , Humanos , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Éteres , Poluentes Químicos da Água/análise , Caprilatos , Fluorocarbonos/análiseRESUMO
Non-dioxin-like polychlorinated biphenyls (ndl-PCBs) are a subclass of persistent bioaccumulative pollutants able to enter the food chain. We investigated the transfer of ndl-PCBs from contaminated feed into meat and liver of fattening chickens. A total of 48 chicks were divided into five treatment and one control groups. Treated animals were fed with contaminated diets (11.7 ± 0.4 µg/kg sum of indicator ndl-PCBs; 88% dry matter (DM)) before slaughter for different subperiods of time: 16, 23, 28, 32, and 36 days for groups 1-5, respectively. One day after the end of each subperiod, three animals per group were slaughtered to determine the congener-specific ndl-PCB content. All remaining animals were fed the control feed until slaughter on day 37 to probe depuration. We used these data to generate congener-specific physiologically based toxicokinetic (PBTK) models for indicator ndl-PCBs. The models show that PCBs 28, 138, 153, and 180 form a more slowly eliminated cluster (with an observed transfer rate into meat over 74% and observed half-lives over 8.7 days) than PCBs 52 and 101 (with a transfer rate under 13% and half-lives under 2.6 days). Our simulations show that ndl-PCB levels in feed lower than 3.9 (long 56-day) or 4.4 µg/kg (short 37-day fattening period) would be necessary to ensure the current maximum level in muscle meat (fat basis), according to EU Regulations 1881/2006 and 1259/2011. The PBTK models are made available in the Python and Food Safety Knowledge Exchange formats.
Assuntos
Dioxinas , Bifenilos Policlorados , Dibenzodioxinas Policloradas , Animais , Galinhas , Carne/análise , Bifenilos Policlorados/análiseRESUMO
New synthetic opioids (NSOs) pose a public health concern since their emergence on the illicit drug market and are gaining increasing importance in forensic toxicology. Like many other new psychoactive substances, NSOs are consumed without any preclinical safety data or any knowledge on toxicokinetic (TK) data. Due to ethical reasons, controlled human TK studies cannot be performed for the assessment of these relevant data. As an alternative animal experimental approach, six pigs per drug received a single intravenous dose of 100 µg/kg body weight (BW) of U-47700 or 1000 µg/kg BW of tramadol to evaluate whether this species is suitable to assess the TK of NSOs. The drugs were determined in serum and whole blood using a fully validated method based on solid-phase extraction and LC-MS/MS. The concentration-time profiles and a population (pop) TK analysis revealed that a three-compartment model best described the TK data of both opioids. Central volumes of distribution were 0.94 L/kg for U-47700 and 1.25 L/kg for tramadol and central (metabolic) clearances were estimated at 1.57 L/h/kg and 1.85 L/h/kg for U-47700 and tramadol, respectively. The final popTK model parameters for pigs were upscaled via allometric scaling techniques. In comparison to published human data, concentration-time profiles for tramadol could successfully be predicted with single species allometric scaling. Furthermore, possible profiles for U-47700 in humans were simulated. The findings of this study indicate that unlike a multiple species scaling approach, pigs in conjunction with TK modeling are a suitable tool for the assessment of TK data of NSOs and the prediction of human TK data.
Assuntos
Benzamidas/farmacocinética , Cromatografia Líquida/métodos , Espectrometria de Massas em Tandem/métodos , Tramadol/farmacocinética , Administração Intravenosa , Analgésicos Opioides/farmacocinética , Analgésicos Opioides/toxicidade , Animais , Benzamidas/toxicidade , Humanos , Drogas Ilícitas/farmacocinética , Drogas Ilícitas/toxicidade , Masculino , Modelos Biológicos , Especificidade da Espécie , Suínos , Distribuição Tecidual , Toxicocinética , Tramadol/toxicidadeRESUMO
BACKGROUND: Children are exposed to p,p'-dichlorodiphenyltrichloroethane (p,p'-DDT) and p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) through placental and lactational transfer. Some studies have suggested that early-life exposure to these compounds could lead to increased body mass index (BMI) during childhood. Our aim was to assess whether children's exposure during the first 2 years of life is associated with BMI z-score in Japanese children at 42 months of age. METHODS: We used data from a birth cohort (n = 290) of the Tohoku Study of Child Development. p,p'-DDT and p,p'-DDE levels were measured in breast milk samples collected 1 month after birth, and levels in children were estimated using a toxicokinetic model for three exposure periods (0-6 months, 6-12 months, 12-24 months). Associations between exposure estimates and BMI z-score at 42 months of age were assessed using multivariate linear regression models. RESULTS: We found no significant association between levels of p,p'-DDT measured in breast milk or estimated in children and BMI z-score. However, we observed associations between estimated p,p'-DDE levels in girls during all postnatal exposure periods and BMI z-score; for each log increase in the estimated p,p'-DDE levels, BMI z-score increased by 0.23 (C.I. 95%: 0.01, 0.45) for the 0-6 months exposure period, 0.26 (C.I. 95%: 0.06, 0.47) for the 6-12 months exposure period, and 0.24 (C.I. 95%: 0.05, 0.43) for the 12-24 months exposure period. CONCLUSION: In this study of Japanese children, estimated postnatal p,p'-DDE levels were associated with increased BMI z-score at 42 months of age, mostly in girls. These results are in line with previous studies supporting that early-life exposure to p,p'-DDE may be associated with higher BMI during childhood.
Assuntos
Índice de Massa Corporal , DDT/metabolismo , Diclorodifenil Dicloroetileno/metabolismo , Exposição Ambiental , Poluentes Ambientais/metabolismo , Leite Humano/química , Desenvolvimento Infantil , Pré-Escolar , Feminino , Humanos , Inseticidas/metabolismo , Japão , Estudos Longitudinais , MasculinoRESUMO
Toxicokinetic modeling is a useful tool to describe or predict the behavior of a chemical agent in the human or animal organism. A general model based on four compartments was developed in a previous study to quantify the effect of human variability on a wide range of biological exposure indicators. The aim of this study was to adapt this existing general toxicokinetic model to three organic solvents--methyl ethyl ketone, 1-methoxy-2-propanol, and 1,1,1,-trichloroethane--and to take into account sex differences. In a previous human volunteer study we assessed the impact of sex on different biomarkers of exposure corresponding to the three organic solvents mentioned above. Results from that study suggested that not only physiological differences between men and women but also differences due to sex hormones levels could influence the toxicokinetics of the solvents. In fact the use of hormonal contraceptive had an effect on the urinary levels of several biomarkers, suggesting that exogenous sex hormones could influence CYP2E1 enzyme activity. These experimental data were used to calibrate the toxicokinetic models developed in this study. Our results showed that it was possible to use an existing general toxicokinetic model for other compounds. In fact, most of the simulation results showed good agreement with the experimental data obtained for the studied solvents, with a percentage of model predictions that lies within the 95% confidence interval varying from 44.4 to 90%. Results pointed out that for same exposure conditions, men and women can show important differences in urinary levels of biological indicators of exposure. Moreover, when running the models by simulating industrial working conditions, these differences could be even more pronounced. A general and simple toxicokinetic model, adapted for three well-known organic solvents, allowed us to show that metabolic parameters can have an important impact on the urinary levels of the corresponding biomarkers. These observations give evidence of an interindividual variability, an aspect that should have its place in the approaches for setting limits of occupational exposure.
Assuntos
Biomarcadores/urina , Butanonas/farmacocinética , Anticoncepcionais Orais Hormonais/metabolismo , Exposição Ambiental , Modelos Biológicos , Propilenoglicóis/farmacocinética , Fatores Sexuais , Toxicocinética , Tricloroetanos/farmacocinética , Adulto , Butanonas/urina , Citocromo P-450 CYP2E1/metabolismo , Feminino , Humanos , Masculino , Compostos Orgânicos , Propilenoglicóis/urina , Solventes , Tricloroetanos/metabolismo , Tricloroetanos/urina , Adulto JovemRESUMO
Diethyl phthalate (DEP) has been most frequently detected in personal care products (PCPs) as a solvent followed by indoor air as one of the semi-volatile organic compounds (SVOCs). Human exposure to DEP predominantly occurs via dermal uptake. However, the available physiologically based toxicokinetics (PBTK) models are developed in rats for risk assessment of DEP exposure resulting from the oral than dermal pathway. To address this issue, DEP in simulated PCPs was dermally administrated to five adult volunteers at real population levels. Following the construction of a dermal absorption model for DEP, the dermal PBTK modeling of DEP involving PCPs and air-to-skin exposure routes in humans was developed for the first time. The data of monoethyl phthalate (MEP) in serum or urine obtained from published human studies and this study were applied to calibrate and validate the developed dermal PBTK model. Monte Carlo simulation was used to evaluate model uncertainty. The dermal absorption fraction of DEP was obtained to be 56.2% for PCPs exposure and 100% for air-to-skin exposure, respectively. Approximate 24.9% of DEP in exposed skin became absorbed into systemic circulation. Model predictions were generally within 2-fold of the observed MEP levels in human serum or urine. Uncertainty analysis showed 90% of the predicted variability (P95/P5) fell within less than one order of magnitude. Assuming human intake of 5 mg/kg bw per day, the predicted serum area under the curve at steady state of DEP from the dermal route was 1.7 (PCPs) and 2.4 (air) times of those from the peroral route, respectively. It suggested that dermal exposure to DEP would pose greater risk to human health compared with oral exposure. The application of the developed dermal PBTK model provides a valuable insight into health risk assessment of DEP in humans.
Assuntos
Cosméticos , Ácidos Ftálicos , Compostos Orgânicos Voláteis , Adulto , Animais , Humanos , Ácidos Ftálicos/análise , Ratos , Medição de Risco , Solventes , ToxicocinéticaRESUMO
Hydraulic fracturing creates large volumes of flowback and produced water (FPW). The waste is a complex mixture of organic and inorganic constituents. Although the acute toxicity of FPW to freshwater organisms has been studied, few have attempted to discern the interaction between organic and inorganic constituents within this matrix and its role in toxicity. In the present study, bioaccumulation assays (7-d uptake and 7-d elimination period) with FPW (1% dilution) were conducted with the freshwater oligochaete, Lumbriculus variegatus, to evaluate the toxicokinetics of inorganic elements. To evaluate the interacting role of organics, bioaccumulation of elements in unmodified FPW was compared to activated carbon treated FPW (AC-modified). Differences in uptake and elimination rates as well as elimination steady state concentrations between unmodified and AC-modified treatments indicated that the organics play an important role in the uptake and depuration of inorganic elements in FPW. These differences in toxicokinetics between treatments aligned with observed growth rates in the worms which were higher in the AC-modified treatment. Whether growth differences resulted from increased accumulation and changes in toxicokinetic rates of inorganics or caused by direct toxicity from the organic fraction of FPW itself is still unknown and requires further research.
Assuntos
Fraturamento Hidráulico , Oligoquetos , Poluentes Químicos da Água , Animais , Bioacumulação , Sedimentos Geológicos , Águas Residuárias , Água , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/toxicidadeRESUMO
The impacts of dietary nitrates and nitrites on human health have been a controversial topic for many years. However, the risk and benefit assessment of nitrates and nitrites is complicated by the large variation in nitrate and nitrite intake among people and the endogenous nitrite formation in the body. This study conducted a probabilistic risk-benefit assessment of dietary nitrates and nitrites based on internal dose by integrating exogenous and endogenous exposures with human trial data on cardiovascular benefits. A total diet study was carried out to quantify the age-specific dietary intakes of nitrates and nitrites. A previously well-validated human toxicokinetic model was used to predict internal doses for different age groups. In addition, the integrated approach was applied to different populations from different countries/regions based on reported exposure estimates to conduct a comprehensive risk-benefit assessment of dietary nitrates and nitrites. The results demonstrated that vegetable consumption was the main contributor to the internal nitrate and nitrite levels in all age groups. Exposure to nitrates and nitrites exceeding acceptable daily intakes in a variety of foods showed cardiovascular benefits. The probabilistic risk assessment showed that the exposure to nitrates and nitrites did not pose an appreciable health and safety risk. Therefore, the present results suggest that dietary nitrates and nitrites have clear cardiovascular benefits that may outweigh potential risks. Our analysis contributes significantly to addressing the controversy regarding risks and benefits from dietary nitrates and nitrites, and our approach could be applied to other dietary constituents with the potential for both risks and benefits.
Assuntos
Nitratos , Nitritos , Dieta , Exposição Dietética , Humanos , Nitratos/análise , Nitratos/toxicidade , Nitritos/análise , ToxicocinéticaRESUMO
Polychlorinated biphenyls (PCBs) are persistent organic pollutants triggering numerous adverse effects. Because they are present in various food, dietary exposure of the population to these contaminants must be estimated to assess the related health risk. However, the classical risk assessment approach allows only short-term estimates of exposure and does not account for dietary changes, evolution of food contaminations and bioaccumulation of PCBs through life. The approach presented here assesses lifetime PCB exposure trajectories according to birth year and individual sociodemographic profiles. Moreover, a physiologically based toxicokinetic model was developed to simulate lifetime PCB plasma concentrations, while considering physiological changes with age. A focus on the long-term impact of breastfeeding is also presented in order to consider the risk related to PCBs and due to the mother-to-child transfer. For example, the exposure of an individual born in 1972 exceeds the critical value of 20 ng PCB/kg bw/day half as often as an individual born in 1932 throughout their lifetime but 13 times more often than an individual born in 2012, according to our simulations. In addition, even if breastfeeding clearly leads to much higher dietary exposures than formula feeding, the long-term impact on PCB body burden remains negligible. Risk assessment related to PCB lifetime trajectories is described and discussed.
Assuntos
Bifenilos Policlorados , Bioacumulação , Dieta , Feminino , Contaminação de Alimentos , Humanos , Transmissão Vertical de Doenças Infecciosas , Pessoa de Meia-Idade , Bifenilos Policlorados/análiseRESUMO
Ephedrine (EPH) is an alkaloid commonly used to relieve nasal congestion caused by colds, allergic rhinitis, rhinitis, and sinusitis, and to control bronchial asthma. It is also be used as a raw material in the manufacture of methamphetamine. Although the distribution of EPH in surface waters has been widely studied, its uptake, internal distribution, and toxicokinetic processing in exposed organisms have not been well investigated. In this study, we investigated the uptake, disposition, and toxicokinetics of EPH in zebrafish (Danio rerio) in a semi-static exposure system. EPH was consistently detected in zebrafish biological samples, with the highest concentrations of 84.97 ng·g-1 detected in the brain tissue of fish in the high treatment group. Over the 14-d exposure period, the relative abundance of mean concentrations of EPH in biological samples generally followed the order of brain > ovary > liver > intestine > muscle. The uptake rate constants (Ku), elimination rate constants (Ke), and half-lives of EPH in the biological tissues were in the ranges 0.23-570.31 L·(kg·d)-1, 1.22-6.11 d-1, and 0.12-0.57 d, respectively. The observed bioconcentration factor (BCFo) and kinetically-derived bioconcentration factor (BCFk) were similar, ranging 0.24-337.33 L·kg-1 and 0.13-316.43 L·kg-1, respectively. These results are helpful for understanding the behavior of psychoactive substances in aquatic organisms and have directive significance for studying their toxicity and ecological risks to aquatic organisms.
Assuntos
Poluentes Químicos da Água , Peixe-Zebra , Animais , Organismos Aquáticos , Efedrina/toxicidade , Feminino , Toxicocinética , Poluentes Químicos da Água/toxicidadeRESUMO
The aim of this study was to assess the impact of exposure to tap water lead concentration ([Pb]TW) occurring in schools or daycares on blood lead level (BLL) of attending children. Given the potentially wide variations in space and time of ([Pb]TW) documented in the literature, a simple probabilistic toxicokinetic (STK) model that allows the simulation of the time-varying evolution of BLL in response to these variations was developed. Thus, basic toxicokinetic equations were assembled to simulate BLL in a typical infant, toddler and pupil. The STK model's steady-state BLL predictions showed good correspondence when validated against Integrated Exposure and Uptake BioKinetic model predictions for comparable [Pb]TW values. Exposures to three distributions of [Pb]TW in specific sets of Canadian schools and daycares documented in the scientific literature were simulated probabilistically with Monte Carlo simulations. For the highest distribution of [Pb]TW simulated (median, 90th percentile = 24, 412 µg/L), average annual BLL (median, 97.5th percentile) varies between 1.5 and 6.4 µg/dL in infant and 1.1 and 3 µg/dL in pupils. Toddler's results were midway between those from the infants and pupils. Under this exposure scenario, the infant may present BLL > 5 µg/dL for a significant number of days over the course of the academic year (median; 97.5th: 17; 227 days). However, peak exposure may remain unnoticed if rare and drowned out by the background BLL. In conclusion, even if they may be sparse, peak exposure episodes to [Pb]TW in schools and daycares may suffice to increased BLL in attending individuals. This finding emphasizes the need for further characterization of [Pb]TW in schools and daycares in order to identify potentially problematic institutions and therefore avoid undesirable exposures for the children attending them.
RESUMO
This study aimed to estimate the dietary risk of nitrates and nitrites in vegetables based on internal dose in a probabilistic manner by integrating exogenous exposure based on measured concentrations in vegetables with endogenous exposure using a toxicokinetic (TK) model. We optimized and validated a previous TK model and incorporated Monte Carlo simulations to account for variability across different age populations for predicting internal dose. High levels of nitrates were detected in leafy vegetables (from 545 ± 274 to 1641 ± 873 mg/kg). Nitrite contents of vegetables were generally low (from 1.26 ± 1.40 to 8.20 ± 14.1 mg/kg). The dietary risk was found to be different based on internal versus external dose, suggesting that it is critical to include endogenous nitrite formation into risk assessment. Nitrate and nitrite exposure from vegetables is unlikely to result in appreciable risks for most populations but may be a potential risk for preschoolers.
Assuntos
Nitratos/metabolismo , Nitritos/metabolismo , Verduras/química , Verduras/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Dieta , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Nitratos/toxicidade , Nitritos/toxicidade , Medição de Risco , Toxicocinética , Adulto JovemRESUMO
Enantioselective degradation and biotransformation are critical processes affecting the bioaccumulation and toxicity of chiral pesticides in the environment. In the present study, enantioselective uptake, biotransformation and elimination of a current use pesticide, fipronil in a benthic invertebrate, Lumbriculus variegatus were assessed using a sediment bioaccumulation test. Toxicokinetic models were constructed to quantitatively describe kinetic processes of fipronil enantiomers. The degradation of fipronil in sediment significantly affected chemical uptake, thus degradation kinetic model was incorporated into toxicokinetic modeling. It was shown that S-(+)-fipronil degraded faster than R-(-)-fipronil in sediment, with dissipation rate constants being 0.090⯱â¯0.008 and 0.023⯱â¯0.006 1/d, respectively. As a result, R-(-)-enantiomer preferentially accumulated in sediment over time. Similarly, higher concentrations of R-(-)-fipronil were detected in L. variegatus compared with S-(+)-fipronil. Toxicokinetic modeling showed R-(-)-fipronil had larger uptake and elimination rate coefficients and apparent maximum reaction rate, but a smaller apparent half-saturation constant than S-(+)-fipronil. Preferential uptake of R-(-)-fipronil from sediment to L. variegatus was the main reason for greater R-(-)-fipronil concentrations in organism. Biotransformation of fipronil in L. variegatus was also enantioselective, yet it played fewer roles on enantioselective bioaccumulation than uptake. Overall, our findings highlight the importance of selective degradation, uptake and biotransformation of sediment-associated fipronil on its enantioselective bioaccumulation in benthic invertebrates, which helps to improve the accuracy for assessing aquatic toxicity of the chiral pesticide. CAPSULE: Enantioselective bioaccumulation of sediment-associated fipronil in Lumbriculus variegatus was quantitatively explained by selective degradation, uptake, biotransformation and elimination parameters using a combination of degradation and toxicokinetic modeling.
Assuntos
Oligoquetos/fisiologia , Pirazóis/metabolismo , Poluentes Químicos da Água/metabolismo , Animais , Biodegradação Ambiental , Oligoquetos/metabolismo , Pirazóis/toxicidade , Estereoisomerismo , Poluentes Químicos da Água/toxicidadeRESUMO
Physiologically based toxicokinetic (PBTK) modeling enables researchers to predict internal tissue concentrations for various species exposed to exogenous compounds through different routes at varying concentrations without having to run in vivo experiments for each scenario. Parameters for the models may be gathered from in vivo or in vitro measurements, cross-species or cross-chemical extrapolations, literature reviews, or other models. The PBTK models, described using ordinary differential equations (ODEs), are then simulated using these parameters for a given compound/exposure/species scenario. Although they are potentially useful for regulatory toxicology, the complexity of ODE programming and simulation remains a barrier for many would-be researchers. Petri nets, a graphical modeling framework, offers a more intuitive approach to PBTK modeling. To demonstrate their utility and ease of use, we present a model of waterborne fluoranthene exposure to rainbow trout (Oncorhynchus mykiss) written and simulated in Snoopy, a graphical Petri net development and simulation software package. We converted an existing ODE PBTK model and evaluated the Petri net model against the ODE model results. The simulated tissue concentrations of the Petri net model closely mirrored the simulated concentrations of the ODE model. To convert the ODE model to a Petri net model, we introduced a new parameter, blood volume (V BLOOD ). Sensitivity analysis found V BLOOD to be very robust when varied over an order of magnitude. The resulting Petri net PBTK model has a number of advantages over ODE models, while maintaining equivalent predictive functionality. Environ Toxicol Chem 2019;00:1-10. © 2019 SETAC.
Assuntos
Modelos Biológicos , Fenômenos Fisiológicos , Toxicocinética , Animais , Simulação por Computador , Fluorenos/toxicidade , Oncorhynchus mykiss/fisiologia , Fatores de TempoRESUMO
Bioaccumulation and biotransformation are critical processes modifying toxicity of easily metabolizable chemicals to aquatic organisms. In this study, tissue-specific accumulation, biotransformation and elimination of a current-use pesticide fipronil in tilapia (Oreochromis niloticus) were quantified by combining in vivo measurements and a newly developed multi-compartmental toxicokinetic model. Waterborne fipronil was taken up via gills and metabolized rapidly and solely to fipronil sulfone. Significant decrease of fipronil residues in liver and intestine during exposure period strongly suggested the induction of metabolism in these two organs. Significant transport of fipronil and fipronil sulfone in the liver-bile-intestine system implied that hepatobiliary excretion and enterohepatic re-absorption played important roles in fipronil metabolism and system circulation of the parent compound and the metabolite. The multi-compartmental model quantitatively described the highly dynamic inter-compartmental transport and rapid branchial clearance of fipronil in fish. Modeling results also suggested that uptake and biotransformation were the stronger driving forces for the inter-compartmental transport of fipronil in fish than the inherent partitioning capacity. Overall, our findings highlight the importance of biotransformation on internal disposition of fipronil in fish, which helps to improve aquatic toxicity assessment of this pesticide.
Assuntos
Modelos Biológicos , Praguicidas/farmacocinética , Praguicidas/toxicidade , Pirazóis/farmacocinética , Pirazóis/toxicidade , Tilápia/metabolismo , Poluentes Químicos da Água/farmacocinética , Poluentes Químicos da Água/toxicidade , Animais , Biotransformação , Brânquias/metabolismo , Mucosa Intestinal/metabolismo , Fígado/metabolismo , ToxicocinéticaRESUMO
Being advertised and distributed as attractive substitutes of cannabis, synthetic cannabinoids (SC) are gaining increasing relevance in forensic and clinical toxicology. As no data from controlled human studies are available, SC are sold and consumed without the knowledge of their toxicokinetic (TK) and toxicodynamic properties. Hence, animal models coupled with mathematical approaches should be used to ascertain those properties. Therefore, a controlled pig TK study allowing for extrapolation to human data was performed. For this purpose, eleven pigs received a single pulmonary dose of 200⯵g/kg body weight each of Δ9-tetrahydrocannabinol (THC), 4-ethylnaphthalene-1-yl-(1-pentylindole-3-yl)methanone (JWH-210) as well as 2-(4-methoxyphenyl)-1-(1-pentyl-indole-3-yl)methanone (RCS-4) via an ultrasonic nebulizer. Blood and urine samples were repeatedly drawn over 8â¯h. Serum-concentration-time profiles of the parent compounds were determined using LC-MS/MS. Urine specimens were analyzed by LC-HR-MS/MS in order to elucidate the main metabolites. Maximum serum concentrations were reached 10-15â¯min after beginning of nebulization and amounted to 66⯱â¯36â¯ng/mL for THC, 41⯱â¯11â¯ng/mL for JWH-210, and 34⯱â¯8.9â¯ng/mL for RCS-4. The serum-concentration-time profiles of THC, JWH-210, and RCS-4 were best described by three-compartment models with first order absorption and elimination processes. Absorption from the lungs to serum was modeled by first-order processes. The determination of the bioavailability yielded 23.0%, 24.2%, and 45.7% for THC, JWH-210, and RCS-4, respectively. Furthermore, the developed THC model was upscaled to humans using allometric scaling techniques. A successful prediction of human concentration-time profiles could be done. Also the metabolic patterns were in good agreement with human data. In conclusion, these findings are the first reported regarding the TK properties of SC after pulmonary administration to pigs. The presented method of TK serves as an appropriate predictor of human TK of cannabinoids.
Assuntos
Canabinoides/administração & dosagem , Canabinoides/toxicidade , Pulmão/efeitos dos fármacos , Nebulizadores e Vaporizadores , Administração por Inalação , Animais , Canabinoides/metabolismo , Relação Dose-Resposta a Droga , Humanos , Pulmão/metabolismo , Masculino , Suínos , ToxicocinéticaRESUMO
Nanopesticides are novel plant protection products offering numerous benefits. Because nanoparticles behave differently from dissolved chemicals, the environmental risks of these materials could differ from conventional pesticides. We used soil-earthworm systems to compare the fate and uptake of analytical-grade bifenthrin to that of bifenthrin in traditional and nanoencapsulated formulations. Apparent sorption coefficients for bifenthrin were up to 3.8 times lower in the nano treatments than in the non-nano treatments, whereas dissipation half-lives of the nano treatments were up to 2 times longer. Earthworms in the nano treatments accumulated approximately 50% more bifenthrin than those in the non-nano treatments. In the non-nano treatments, most of the accumulated material was found in the earthworm tissue, whereas in the nano treatments, the majority resided in the gut. Evaluation of toxicokinetic modeling approaches showed that models incorporating the release rate of bifenthrin from the nanocapsule and distribution within the earthworm provided the best estimations of uptake from the nano-formulations. Overall, our findings indicate that the risks of nanopesticides may be different from those of conventional formulations. The modeling presented provides a starting point for assessing risks of these materials but needs to be further developed to better consider the behavior of the nanoencapsulated pesticide within the gut system. Environ Toxicol Chem 2018;37:1420-1429. © 2018 SETAC.
Assuntos
Meio Ambiente , Nanopartículas/química , Oligoquetos/metabolismo , Praguicidas/metabolismo , Medição de Risco , Solo/química , Animais , Meia-Vida , Modelos Biológicos , Piretrinas/metabolismo , Fatores de RiscoRESUMO
In the scientific field of physiologically based toxicokinetic modeling the complexity of the model used depends on the complexity of the problem to be handled, leading to a broad range of existing models from simple 1-box models to complex multicompartment models. Most of these models work with lumped parameters, for example, an uptake efficiency parameter that can only be obtained with a fit of experimental data. The authors' goal was a model that is completely based on well-defined physiological and physicochemical parameters. Lumped parameters fitted on training data sets would limit the model's applicability. This would enable a new view on process understanding for uptake, distribution, and elimination procedures. Eventual goals are a better localization of chemicals within the organism itself, and to set the stage for future extensions toward ionic compounds and active transport across membranes. The model evaluation reported in the present study has shown that uptake, clearance, and bioaccumulation data for nonpolar chemicals are well predicted. Environ Toxicol Chem 2017;36:1538-1546. © 2016 SETAC.
Assuntos
Peixes , Modelos Biológicos , Toxicocinética , Poluentes Químicos da Água/farmacocinética , Poluentes Químicos da Água/toxicidade , AnimaisRESUMO
In recent years, because of the potential human toxicity, concern on perfluoroalkyl substances (PFASs) has increased notably with special attention to perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS). Unfortunately, there is currently an important knowledge gap on the burdens of these chemicals in most human tissues, as the reported studies have been mainly focused on plasma. In order to overcome these limitations, the use of physiologically-based pharmacokinetic (PBPK) models has been extended. The present study was aimed at testing an existing PBPK model for their predictability of PFOS and PFOA in a new case-study, and also to adapt it to estimate the PFAS content in human tissue compartments. Model validation was conducted by means of PFOA and PFOS concentrations in food and human drinking water from Tarragona County (Catalonia, Spain), and being the predicted results compared with those experimentally found in human tissues (blood, liver, kidney, liver and brain) of subjects from the same area of study. The use of human-derived partition coefficient (Pk) data was proven as more suitable for application to this PBPK model than rat-based Pk values. However, the uncertainty and variability of the data are still too high to get conclusive results. Consequently, further efforts should be carried out to reduce parametric uncertainty of PBPK models. More specifically, a deeper knowledge on the distribution of PFOA and PFOS within the human body should be obtained by enlarging the number of biological monitoring studies on PFASs.