Dermal Dose Research Articles

Toxicokinetic model of the pyrethroid pesticide lambda-cyhalothrin, main exposure route and dose reconstruction predictions in agricultural workers.

A toxicokinetic model of the pyrethroid insecticide lambda-cyhalothrin (LCT) was developed to relate absorbed doses to urinary cis-3-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropanecarboxylic acid (CFMP) metabolite levels used as a biomarker of exposure. The model then served to reconstruct absorbed doses in agricultural workers and their probability of exceeding the EFSA Acceptable occupational Exposure Level (AOEL). The toxicokinetic model was able to reproduce the temporal profiles of CFMP in the urine of operators spraying pesticides using the optimized model parameters (adjusted to human volunteer data). Modeling also showed that simulation of an inadvertent oral exposure mainly was the exposure scenario giving the best fit to CFMP urinary time-course data in applicators. With the dermal model parameters optimized from data in volunteers, simulation of a dermal exposure in applicators did not allow to reproduce the observed peak excretions and urinary metabolite levels; extremely high applied dermal doses would be required but still simulated dermal penetration rate would remain too slow. Simulation of an inhalation exposure allowed to reproduce the observed time-courses, but with unrealistic air concentrations. For applicators with the highest urinary concentrations, there was a probability of exceeding the AOEL at some points during the biomonitoring period [>50% probability of exceeding for 27% of 24-h samples]; for non-applicator workers the probability of exceeding the AOEL value was very low [corresponding value of 5%]. Furthermore, the median [95% CI] estimates of 10 000 Monte Carlo simulations led to a biological reference value corresponding to the AOEL of 116 [113-119] ng/kg bw/d and 7.5 [7.3-7.7] μg/L. Overall, 7% of applicators and 1% of workers performing weeding and strawberry picking had a probability of exceeding this biological reference value. As a next step, it would be interesting to apply these methods to multiple exposure to various contaminants.

THE PROBLEM OF REGULATING FUNGICIDES ON THE SKIN SURFACE FOR OCCUPATIONAL SKIN DISEASE IN AGRICULTURAL WORKERS’ RISK PREDICTION

The aim. To establish the norms of fungicides on the skin surface and predicting the risk of occupational skin pathology in agricultural workers to develop measures to prevent diseases caused by dermal exposure to pesticides. Materials and methods. The natural experiment was performed in accordance with modern requirements (European Food Safety Authority (2022), and the risk assessment was carried out according to the Recommendations (Approved by the Ministry of Health of Ukraine No. 324 issued on 13.05.2009) with different methods of spraying techniques: rod, air blast fan spraying, pre-sowing, aviation, knapsack treatment. 17 series of natural experiments were performed, and the air of the working zone area (n =56) and dermal exposure (n =56) were analyzed for each worker with different pesticide application methods. Quantitative determination of pesticide content was carried out by gas-liquid and high-performance liquid chromatography methods. The results were statistically processed using a package of licensed statistical programs MedStat v.5.2 (Copyright © 2003-2019) and Microsoft® Excel® for Microsoft 365 MSO. Results. It was established that there is pesticide contamination, mainly of the gloves of tank filling operators when preparing working solutions. No contamination of the skin surface was detected; only pesticide residues were present on the surface of the workers’ overalls. A comparison of the exposure dose in case of percutaneous exposure during the performance of technological operations with different methods of processing, dermal equivalents of Acceptable Operator Exposure Level of pesticide to workers’ skin (DE AOEL) and the allowable dermal dose for professional contingents (ADderm) and the hazard coefficients by dermal exposure (HCderm) showed that that dermal exposure during individual technological operations with different processing methods had a reliable difference between processing methods, but there is no difference within one application method. Conclusions. During the comparison of the hazard coefficients for dermal exposure, calculated according to different models, no significant difference was found between the risks calculated according to DE AOEL and ADderm for individual technological operations in various treatment methods, except for the operator who performed knapsack treatment and the risk calculated according to ADderm is significantly lower compared to the DE AOEL risk.

Potential health risks to disinfection workers from exposure to active substances in COVID-19 biocidal products

The importance of disinfection has recently been emphasized due to the increasing risk of the spread of infections such as coronavirus disease-2019 (COVID-19). In addition, disinfection for preventing the spread of COVID-19 is highly recommended. The increased use of biocidal products raises concerns regarding the potential health risks from exposure among disinfection workers. This study aimed to assess these exposure and health risks using questionnaires targeting disinfection workers who were exposed to the active substances in biocidal products used for disinfection during the COVID-19 pandemic. A follow-up survey was conducted among 271 disinfection workers for 10 working days within two weeks, and exposure factors with reference to disinfection were evaluated through interview-administered questionnaires. An exposure algorithm was used to evaluate the exposure of disinfection workers during disinfection. The hazard index (HI) was calculated by dividing the inhalation concentration obtained using the exposure algorithm and the dermal dose according to occupational exposure limits (OEL). A sensitivity analysis was conducted to identify the exposure factors with the greatest impact on the inhalation and dermal exposure algorithms. A logistic regression analysis was performed to verify the relationship with health effects and sociodemographic and exposure characteristics. The average number of disinfections performed during 10 working days was 17.5 ± 12.3 times. The type of disinfection work was divided into 2806 cases of COVID-19 prevention and disinfection and 1956 cases of regular pesticide application to prevent and remove any pests. The HI was ≥1, indicating a potential health risk, with the use of ethanol (6.50E+00), quaternary ammonium compounds (QACs; 1.49E+01), and benzalkonium chloride (BKC; 1.73E+00). Dermal exposure was more hazardous than inhalation exposure for 6 of the 11 active substances in biocidal products. The weight fraction and exposure time were the factors that most significantly influenced the inhalation and dermal exposure algorithms in the sensitivity analysis. Higher exposure concentrations were more likely to affect health (AOR: 3.239, 95% CI: 1.155–9.082). This study provides valuable information regarding the exposure and risk of disinfection workers to 11 biocidal active substances included in common disinfectants. Our results suggest that the use of ethanol, BKC, and QACs has potential health risks to disinfection workers, with a higher possibility of negative health impacts with increasing exposure concentration.

Удосконалення методології досліджень та оцінки інгаляційного та дермального впливу хімічних засобів захисту рослин. Частина ІІ.

Introduction. In the first part of the article, a comparative analysis of the domestic and international research methodology and assessment of the impact of plant protection products (PPP) on agricultural workers and the population is carried out. The analysis showed that the existing methodological approaches in Ukraine need to be improved. In particular, methodological approaches and procedures for their implementation should comply with international requirements for measuring external inhalation and dermal doses, calculating absorbed doses of the active substance (AS) PPP that affect persons subject to protection. Purpose of the Study. To develop procedures for studying and calculating the impact of the PPP on the operator, worker, outsider and resident during and after the application of the PPP that meet international requirements. Materials and Methods. A scientific analysis of domestic and foreign normative, methodological documents and scientific sources regulating the organization of research, measurement and calculation of the impact of PPP on agricultural workers and the population during and after the use of these products is carried out. Results. Based on the results of the analysis, procedures for sampling, delivery, storage of samples, description of data, calculation of exposure and absorbed doses of AS affecting the body of the operator, worker, outsider and resident by inhalation and dermal routes are proposed. Conclusions. The use of the proposed procedures will ensure that the studies comply with international requirements, and the results of their implementation will ensure the subsequent assessment and management of the PPP exposure risk to protected people. Keywords: plant protection products (PPP), inhalation and dermal exposure, operator, worker, outsider, resident, exposure and absorbed doses.

Human metabolism and excretion kinetics of the surfactant 2,4,7,9-tetramethyl-5-decyne-4,7-diol (TMDD) after oral and dermal administration.

2,4,7,9-Tetramethyl-5-decyne-4,7-diol (TMDD) is a non-ionic surfactant with a wide range of applications. TMDD is considered a high-production chemical and, due to its low biodegradation rate, possesses a potentially high prevalence in the environment. However, despite its widespread use, toxicokinetic data and data on internal exposure to TMDD in the general population are completely lacking. Hence, we developed a human biomonitoring (HBM) method for TMDD. Our approach included a metabolism study with four subjects, who were administered an oral dose of 75µg TMDD/kg body weight and a dermal dose of 750µg/kg body weight. Terminal methyl-hydroxylated TMDD (1-OH-TMDD) was previously identified as the main urinary metabolite in our lab. The results of the oral and dermal applications were used to determine the toxicokinetic parameters of 1-OH-TMDD as a biomarker of exposure. Finally, the method was applied to 50 urine samples from non-occupationally exposed volunteers. Results show that TMDD was rapidly metabolized, with an average tmax of 1.7h and a rapid and almost complete (96%) excretion of 1-OH-TMDD until 12h after oral dosage. Elimination was bi-phasic, with half-lives of 0.75-1.6h and 3.4-3.6h for phases 1 and 2, respectively. The dermal application resulted in a delayed urinary excretion of this metabolite with a tmax of 12h and complete excretion after about 48h. The excreted amounts of 1-OH-TMDD represented 18% of the orally administered TMDD dose. The data of the metabolism study demonstrated a fast oral as well as substantial dermal resorption of TMDD. Moreover, the results indicated an effective metabolism of 1-OH-TMDD, which is excreted rapidly and completely via urine. Application of the method to 50 urine samples revealed a quantification rate of 90%, with an average concentration of 0.19ng/mL (0.97nmol/g creatinine). With the urinary excretion factor (Fue) derived from the metabolism study, we estimated an average daily intake of 1.65µg TMDD from environmental and dietary sources. In conclusion, 1-OH-TMDD in urine is a suitable biomarker of exposure to TMDD and can be applied for biomonitoring of the general population.

Incorporating oral, inhalation and dermal bioaccessibility into human health risk characterization following exposure to Chromated Copper Arsenate (CCA)-contaminated soils

Exposure to potentially toxic metal(loid)s (PTMs) in soil may happen via ingestion, inhalation, and dermal pathway. A more accurate risk characterization should consider PTM bioavailability. Using ten soil samples collected in the Montreal area (Canada) near CCA-treated utility poles, this study aims to characterize non-carcinogenic and carcinogenic human health risks associated with As, Cr, Cu, Pb, and Zn through a multi-pathway exposure approach. This innovative study incorporates, for the first time, the bioaccessible fraction of the metal(loid)s for three exposure routes and two different scenarios. For the residential and industrial scenarios, the oral and dermal pathways yielded a hazard index (HI) much higher than 1 with and without bioaccessibility considerations (range 1.7 – 349 without bioaccessibility and 0.8–134 with bioaccessibility), whereas the inhalation pathway caused a lower hazard (HI < 1). For the dermal pathway, the hazard quotient was higher when bioaccessibility of field-collected samples was considered due to inherent assumptions from the US EPA soil approach to calculate the dermal dose. For carcinogenic risk, As and Pb were the most significant contributors to risk for the oral pathway, followed by the same elements for the dermal pathway. The overall carcinogenic risk was higher than the acceptable risk ( > 10−4) with and without bioaccessibility considerations (range 1.9E-4 – 9.6E-3 without bioaccessibility and 6.8E-5 – 3.8E-3 with bioaccessibility). Bioaccessibility tests provide a more accurate assessment of exposure to PTMs compared to total concentrations in soils.

The fabrication and assessment of mosquito repellent cream for outdoor protection

Mosquito-borne infections like dengue, malaria, chikungunya, etc. are a nuisance and can cause profound discomfort to people. Due to the objectional side effects and toxicity associated with synthetic pyrethroids, N,N-diethyl-3-methylbenzamide (DEET), N,N-diethyl phenylacetamide (DEPA), and N,N-di ethyl benzamide (DEBA) based mosquito repellent products, we developed an essential oil (EO) based mosquito repellent cream (EO-MRC) using clove, citronella and lemongrass oil. Subsequently, a formulation characterization, bio-efficacy, and safety study of EO-MRC were carried out. Expression of Anti-OBP2A and TRPV1 proteins on mosquito head parts were studied by western blotting. In-silico screening was also conducted for the specific proteins. An FT-IR study confirmed the chemical compatibility of the EOs and excipients used in EO-MRC. The thermal behaviour of the best EOs and their mixture was characterized by thermogravimetric analysis (TGA). GC–MS examination revealed various chemical components present in EOs. Efficacy of EO-MRC was correlated with 12% N,N-diethyl benzamide (DEBA) based marketed cream (DBMC). Complete protection time (CPT) of EO-MRC was determined as 228 min. Cytotoxicity study on L-132 cell line confirmed the non-toxic nature of EO-MRC upon inhalation. Acute dermal irritation study, acute dermal dose toxicity study, and acute eye irritation study revealed the non-toxic nature of EO-MRC. Non-target toxicity study on Danio rerio confirmed EO-MRC as safer for aquatic non-target animals. A decrease in the concentration of acetylcholinesterase (AChE) was observed in transfluthrin (TNSF) exposed Wistar rats. While EO-MRC did not alter the AChE concentrations in the exposed animals. Results from western blotting confirmed that Anti-OBP2A and TRPV1 proteins were inhibited in TNSF exposed mosquitoes. Mosquitoes exposed to EO-MRC showed a similar expression pattern for Anti-OBP2A and TRPV1 as the control group. In silico study revealed eight identified compounds of the EOs play significant roles in the overall repellency property of the developed product. The study emphasizes the mosquito repellent activity of EO-MRC, which could be an effective, eco-friendly, and safer alternative to the existing synthetic repellents for personal protection against mosquitoes during field conditions.

A Review of the Main Considerations for Formulation Development in Preclinical Toxicology Studies.

The main considerations for the development of a formulation for preclinical safety assessment testing are explored. Intravenous, inhalation, oral and dermal dosing are given focus and although different dose routes do present their own individual challenges there are common themes that emerge. In each case it is necessary to maximise exposure to achieve high doses to satisfy regulatory requirements for safety assessment testing. This often involves producing formulations that are at the limits of solubility and maximum volumes possible for administration to different test species by the chosen route. It is concluded that for all routes it is important to thoroughly explore the stability of the test item in the proposed formulation matrix well ahead of dosing any animals, giving careful consideration to which excipients are used and what their underlying toxicity profile may be for the relevant preclinical species. In addition, determining the maximum achievable concentrations and weighing that against the maximum volumes that can be given by the chosen route in all the test species at an early stage will also give a read on whether it would be theoretically possible to achieve suitably high enough doses to support clinical work. Not doing so can cause delays in the development programme and may have ethical repercussions.

Effects of architecture structure on volatile organic compound and polycyclic aromatic hydrocarbon diffusion in Singapore's Integrated Transport Hubs

Millions of passengers wait for buses at Integrated Transport Hubs (ITH) daily in metropolitan cities. Environmental exposure and associated risk for passengers is of great public concern. In this study, eight volatile organic compounds (VOCs) and the 16 EPA priority polycyclic aromatic hydrocarbons (PAHs) were analyzed in airborne samples collected from indoor waiting areas (Indoor) and bus parks of nine Singapore ITH, which comprises of two types of architectural structure (i.e., fully sheltered and open/partially enclosed). The median concentrations of total VOCs (TVOCs), total gaseous PAHs (TgPAHs) and total airborne particles-adsorbed PAH (TpPAHs) concentrations in Indoor were 30.42 μg/m3, 18.99 ng/m3 and 1.38 ng/m3; respectively. A strong correlation (r ≥ 0.75, p < 0.001) was observed between Indoor and bus parks air compounds. The “Indoor” to bus park pollutant concentration ratio (I/B ratio) showed lower values in the bus interchanges with fully sheltered bus parks (TVOCs: 0.98; TgPAHs: 0.76; TpPAHs: 0.71) than those with open/partially enclosed ones (TVOCs: 1.28; TgPAHs: 1.31; TpPAHs: 0.90). This result suggests that fully sheltered structure may cause the accumulation of air pollutants. The daily VOC and PAH exposure for commuters were further estimated by considering inhalation and dermal doses using Monte Carlo simulation (n = 100,000). Overall, the result showed that the risk is still within international guideline values. In sum, the effect of architecture structure on the migration of air pollutants should be taken into consideration in future transport hub design to reduce pollutant exposure to commuters.

A Physiological-Based Pharmacokinetic Model For The Broad Spectrum Antimicrobial Zinc Pyrithione: II. Dermal Absorption And Dosimetry In The Rat

ABSTRACT The broad spectrum antimicrobial/antifungal zinc pyrithione (ZnPT) is used in products ranging from antifouling paint to antidandruff shampoo. The hazard profile of ZnPT was established based upon comprehensive toxicological testing, and products containing this biocide have been safely used for years. The purpose of this study was to create a dermal physiologically based pharmacokinetic (PBPK) model for ZnPT in the rat for improving dose–response analysis of ZnPT-induced toxicity where reversible hindlimb weakness was the endpoint used as the basis for ZnPT risk assessments. Previously, we developed a PBPK model which simulated the kinetics of pyrithione (PT) and its major metabolites 2-(methylsulfonyl)pyridine and S-glucuronide conjugates in blood and tissues of rats following oral ZnPT administration. The dermal model was optimized utilizing in vitro dermal penetration investigations conducted with rat skin and with historical data from a dermal repeat dose study using rats. The model replicated the observed temporal patterns and elimination kinetics of [14C]PT equivalents in blood and urine during and following repeated dermal dosing and replicated the observed dose-dependencies of absorption, blood [14C]PT equivalents and plasma PT concentrations. The model provided internal dosimetry predictions for a benchmark dose analysis of hindlimb weakness in rats that combined dermal, gavage and dietary studies into a single internal dose–response model with area-under-the-curve (AUC) for plasma PT, the toxic moiety in the rat, as the internal dose metric. This PBPK model has predictive validity for calculating internal doses of PT and/or [14C]PT equivalents from different routes of exposure in the rat.

Pharmacokinetics of Bisphenol A in Humans Following Dermal Administration

Background Human exposures to bisphenol A (BPA) are widespread. Sources include food packaging and cash register receipts. Assessments of human health risk from BPA exposure rely on pharmacokinetic data for estimation of internal dose following human exposure. We addressed uncertainties regarding human pharmacokinetics of BPA following dermal exposure through an examination of absorption, distribution, metabolism and excretion in humans following dermal administration. Methods We dermally administered deuterated BPA (d6-BPA) to 10 subjects (6 men, 4 women) at a dose of 100 µg/kg over a 12-hour period and collected blood and urine samples over a follow-up period of three or six days. Using total and unconjugated (“free”) d6-BPA concentrations in serum, we calculated the elimination half-life and area under the curve. Results Detectable serum levels of total d6-BPA and unconjugated BPA were observed at 1.4 hours and 2.8 hours, respectively, after start of dermal administration, with maximum serum concentrations (Cmax) of 3.26 nM and 0.272 nM, respectively. Beginning at approximately seven hours and continuing to 12 hours, the rate of increase in free and total serum d6-BPA slowed. The elimination half-lives of total d6-BPA and free d6-BPA were 17.9 ± 4.88 h and 14.8 ± 4.06 h, respectively. Unconjugated d6-BPA was a greater percentage of the area under the curve of total serum BPA (8.95%) compared to 0.56% in our previously published oral study. Recovery of total administered d6-BPA in urine was ~1% of the applied dose after three days. Analysis of the area under the curve for dermal and oral administration revealed 2.3% of the dermal dose became systemically available. Conclusions These data confirm predictions that pharmacokinetics of BPA differ following oral and dermal exposure. Dermal exposure resulted in a longer apparent serum elimination half-life and higher free:total d6-BPA ratio compared to oral. This abstract does not represent EPA policy.

Pharmacokinetics of bisphenol A in humans following dermal administration

BackgroundHuman exposures to bisphenol A (BPA) are widespread. The current study addresses uncertainties regarding human pharmacokinetics of BPA following dermal exposure. ObjectiveTo examine the absorption, distribution, metabolism and excretion of BPA in humans following dermal administration. MethodsWe dermally administered deuterated BPA (d6-BPA) to 10 subjects (6 men and 4 women) at a dose of 100 µg/kg over a 12-hour period and conducted blood and urine analysis from the beginning of dosing through a three- or six-day period. We present time-course serum and urine concentrations of total and unconjugated (“free”) d6-BPA and used this information to calculate terminal half-life and area under the curve. Results and ConclusionsDetectable serum levels of total d6-BPA were observed at 1.4 h after the start of dosing, and a maximum serum concentration (Cmax) of 3.26 nM was observed. Free d6-BPA was detectable in serum 2.8 h after start of dermal administration, with Cmax of 0.272 nM. Beginning at approximately seven hours and continuing to 12 h (which corresponds to cessation of exposure), the concentration of free and total serum d6-BPA plateaued. The terminal half-lives of total d6-BPA and free d6-BPA in the body were 21.4 ± 9.81 h and 17.6 ± 7.69 h, respectively. Elimination from the body was rate-limited by kinetics in the dermal compartment. Free d6-BPA was a greater percentage of the area under the curve of total serum BPA (8.81%) compared to the 0.56% observed in our previously published oral study. Recovery of total d6-BPA in urine was <2% of the applied dose after six days. Analysis of the area under the curve for dermal and oral administration revealed that 2.2% of the dermal dose became systemically available. These data are in line with prior studies indicating how pharmacokinetics of BPA differ following oral and dermal exposures. Dermal exposure resulted in a longer apparent half-life and higher free:total d6-BPA ratio compared to oral.

Human metabolism and urinary excretion kinetics of the UV filter Uvinul A plus® after a single oral or dermal dosage.

Hexyl 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoate, better known under its trading name Uvinul A plus® is a UV filter mainly used in sunscreens, but also present in other cosmetic products with a maximum concentration of 10% (w/w) according to the EU directive. In this study we investigated the human metabolism after a single oral and a single dermal dose of Uvinul A plus®, respectively. Samples collected within 72h of administration were analyzed with a newly developed UHPLC-MS/MS method. Results of the study revealed three major urinary metabolites, namely 2-(4-amino-2-hydroxybenzoyl)benzoic acid (AHB), 2-(4-(ethylamino)-2-hydroxybenzoyl)benzoic acid (EHB) and 2-(4-(diethylamino)-2-hydroxybenzoyl)benzoic acid (DHB), representing 52% of the administered oral dose. The three major metabolites are further converted into four minor metabolites with an additional hydroxyl group in the aniline moiety. Toxicokinetic parameters (amount excreted, tmax, elimination constant and half-life t1/2) and conversion factors were determined for the three major metabolites. The conversion factors were used to estimate the mean daily exposure to Uvinul A plus® in spot urine samples from 58 volunteers not intentionally exposed to Uvinul A plus® derived from a pilot study. The three major metabolites were quantifiable in 26% of the samples. In 35% of the samples, at least one major metabolite could be quantified. The daily systemic exposure to Uvinul A plus® was estimated to approximately 8.1-9.3μg/d by applying the combined conversion factor for all three major metabolites. In conclusion, a very low systemic exposure to DHHB was observed with regard to the no observed adverse effect level (NOAEL) as an established threshold for chronic uptake.

Toxicokinetics of a urinary metabolite of tebuconazole following controlled oral and dermal administration in human volunteers

Tebuconazole (TEB) is a widely used triazole fungicide, but the toxicokinetics of its human metabolites are not fully described. For proper interpretation of biological monitoring data, knowledge on the metabolism and elimination of the compound is required. A human volunteer study was performed with the aim to describe the time courses of urinary excretion after controlled oral and dermal administration of TEB. Six healthy volunteers (three males and three females) received on separate occasions a single oral dose of 1.5 mg of TEB and a single dermal dose of 2.5 mg during 1 h. In addition to a pre-exposure urine sample, complete urine voids were collected over 48 h post-administration. The main metabolite hydroxy-tebuconazole (TEB-OH) was quantified in each urine sample. Peak excretion rates after oral and dermal administration were reached after 1.4 and 21 h, mean elimination half-lives were 7.8 and 16 h, and recoveries within 48 h were 38% and 1%, respectively. The time courses of excretion were compared to simulations with an established physiologically based toxicokinetic model for TEB that was extended with a parallel model for TEB-OH. Overall, TEB-OH was rapidly excreted into urine after oral exposure, and renal elimination was considerably slower after dermal exposure. Urinary time courses between individuals were similar. The model predictions were in good agreement with the observed time courses of excretion.

A Variance Decomposition Approach for Risk Assessment of Groundwater Quality

This research focuses on the assessment of fluoride doses in groundwater adopting the mathematical model employed by the USEPA. A total of 456 groundwater samples were tested to assess the spatial distribution of fluoride contamination in the study areas. Three age groups (children, teens and adults) were selected for two-way pathway exposure (potential dose and dermal dose) assessment. For uncertainty and sensitivity of inputs variables, a new emerging Sobol sensitivity analysis (SSA) technique was used to determine the relative importance of inputs using Monte Carlo simulation. Three types of effects, first-order effect (FOE), second-order effect (SOE) and total effect (TE) were calculated. The results showed that 96% of the samples analysed were within the standard acceptable level (1.5 mg l−1) of WHO guidelines. The spatial distribution depicts that the eastern and south-eastern parts of the study area have the higher concentrations with the few spots of elevated concentration in the middle of the north and the south-west areas. The mean value of Hazard Index for children in the study region is less than 1, whereas the 95th percentile exceeded the value of 1 for both children and teens. The FOE shows the concentration of fluoride (Cw) is highly sensitive followed by exposure frequency (EF), intake rate (IRw) and body weight (BW). The SOE scores revealed that IRw–BW are the most important input parameters for the assessment of oral health risk. For the dermal model, the highest value of Sobol score was recorded for interactions Cw–SA for adults followed by teens and children. Further, the results show that the older-age groups have more dermal risk than the younger-age groups. The research explores the feasibility of SSA technique to investigate the effects of individual input parameters for health risk model and whether it can be applied to another contaminant.

Biomarkers of Exposure to Pyrimethanil After Controlled Human Experiments.

Pyrimethanil (PYM) is a fungicide used pre- and post-harvest on many crops. It has a low acute toxicity but is of toxicological concern because of its antiandrogenic properties. The aim of the current work was to investigate some metabolism and estimate elimination kinetics of PYM in humans after experimental oral and dermal exposure. A liquid chromatography triple quadrupole mass spectrometry (LC–MS-MS) method was developed and validated for the analysis of PYM and its metabolite 4-hydroxypyrimethanil (OH–PYM) in human urine. The method was applied to analyze urine obtained from two volunteers experimentally exposed to PYM. The elimination of OH–PYM seemed to follow first-order kinetics and a two-phase excretion. After the oral exposure, the elimination half-life of OH–PYM in the rapid phase was 5 and 3 h for the female and male volunteer, respectively. In the slower phase, it was 15 h in both volunteers. After the dermal exposure, the half-life in the rapid phase was 8 h in both volunteers. In the slower phase, it was 30 and 20 h, respectively. About 80% of the oral dose was recovered as urinary OH–PYM in both volunteers. The dermal dose recovered as urinary OH–PYM was 9.4% and 19%, in the female and male volunteer, respectively. OH–PYM was mainly found as a conjugate of sulfonate and glucuronic acid. No free PYM was found. The analytical method showed good within-run, between-run and between-batch precision with a coefficient of variation between 6% and 12%. A limit of detection of 0.1 ng/mL and a limit of quantification of 0.4 ng/mL were achieved for both the analytes. The method was applied to biomonitor PYM exposure in populations in Sweden. OH–PYM was detected in nearly 50% and 96% of samples from the environmentally and occupationally exposed populations, respectively.

Exposure to Total Volatile Organic Compounds (TVOCs) from Household Spray Products

Emission of volatile organic compounds from the use of household spray products has a negative impact on health and environment. Total Volatile Organic Compounds (TVOCs) concentration levels emitted from forty –five registered consumer spray products in Nigeria were measured using MultiRAE TVOCs gas monitor. Human exposure to emitted TVOCs through inhalation, ingestion or through dermal route was evaluated using the ConsExpo spray model. The average TVOCs emission from all the investigated samples was in the range of 1664 and 560994.7 µg m-3 with an average of 63632.2 µg m-3. Generally for all the samples considered, the average released concentrations, inhaled dose, dermal doses, and average deposition rates were in the ranges of 1.83E+04 – 1.00E+06 µg m-3; 1.47E+03 – 8.01E+04 µg ; 3.41E+04 – 4.84E+05 µg; and 1.79E+01 – 1.01E+03 µg s-1, respectively. The results provide information that could be used to significantly improve human exposure and risk assessment to emitted aerosols from spray products.DOI: http://dx.doi.org/10.5755/j01.erem.73.4.19316

An interspecies correlation model to predict acute dermal toxicity of plant protection products to terrestrial life stages of amphibians using fish acute toxicity and bioconcentration data

This paper presents a model to predict acute dermal toxicity of plant protection products (PPPs) to terrestrial amphibian life stages from (regulatory) fish data. By combining existing concepts, including interspecies correlation estimation (ICE), allometric relations, lethal body burden (LBB) and bioconcentration modelling, an equation was derived that predicts the amphibian median lethal dermal dose (LD50) from standard acute toxicity values (96-h LC50) for fish and bioconcentration factors (BCF) in fish. Where possible, fish BCF values were corrected to 5% lipid, and to parent compound. Then, BCF values were adjusted to an exposure duration of 96 h, in case steady state took longer to be achieved. The derived correlation equation is based on 32 LD50 values from acute dermal toxicity experiments with 15 different species of anuran amphibians, comprising 15 different PPPs. The developed ICE model can be used in a screening approach to estimate the acute risk to amphibian terrestrial life stages from dermal exposures to PPPs with organic active substances. This has the potential to reduce unnecessary testing of vertebrates.

ACUTE DERMAL TOXICITY STUDY OF ARECA CATECHU LINN. EXTRACT IN SPRAGUE-DAWLEY RATS

ABSTRACTObjective: Areca catechu Linn. or biji pinang is one of the most widely used psychoactive substance with several hundred million users worldwide,predominantly in Southern Asia. However, details of the dermal toxicity of A. catechu L. are still undiscovered. The objective of this study is toinvestigate the in vivo acute dermal toxicity of aqueous extract of A. catechu L. at dose 15,000 mg/kg body weight in Sprague-Dawley rats.Methods: The acute dermal toxicity of A. catechu L. nut extract was investigated in rats, as per OECD Guidelines 402 for acute toxicity protocols. Thebody weight, possibility of death, general signs, and behavior activity parameters were measured for 14 days to ascertain the median lethal dose(LD50) of the extract. At the end of the study, all the animals in all the treated group were sacrificed.Results: The LD50 was found to be &gt;15,000 mg/kg body weight. There was significant weight increase (p&lt;0.05) in treated group when comparedto control group. No mortality was observed during whole 14 days study period. A single dose of 15,000 mg/kg of body weight did not producetreatment-related signs of toxicity in any of animal tested.Conclusion: A single dermal dose to A. catechu L. aqueous extract had no toxic effects on mortality, clinical signs, body weight changes, and grossfindings in female rats at a dose of 15,000 mg/kg of body weight. Subsequently, the concentrate can be employed for pharmaceuticals nutrient plants.Keywords: A. catechu L., Acute dermal toxicity, LD50.

Estimation of human percutaneous bioavailability for two novel brominated flame retardants, 2-ethylhexyl 2,3,4,5-tetrabromobenzoate (EH-TBB) and bis(2-ethylhexyl) tetrabromophthalate (BEH-TEBP)

2-Ethylhexyl-2,3,4,5-tetrabromobenzoate (EH-TBB) and bis(2-ethylhexyl)tetrabromophthalate (BEH-TEBP) are novel brominated flame retardants used in consumer products. A parallelogram approach was used to predict human dermal absorption and flux for EH-TBB and BEH-TEBP. [14C]-EH-TBB or [14C]-BEH-TEBP was applied to human or rat skin at 100nmol/cm2 using a flow-through system. Intact rats received analogous dermal doses. Treated skin was washed and tape-stripped to remove “unabsorbed” [14C]-radioactivity after continuous exposure (24h). “Absorbed” was quantified using dermally retained [14C]-radioactivity; “penetrated” was calculated based on [14C]-radioactivity in media (in vitro) or excreta+tissues (in vivo). Human skin absorbed EH-TBB (24±1%) while 0.2±0.1% penetrated skin. Rat skin absorbed more (51±10%) and was more permeable (2±0.5%) to EH-TBB in vitro; maximal EH-TBB flux was 11±7 and 102±24pmol-eq/cm2/h for human and rat skin, respectively. In vivo, 27±5% was absorbed and 13% reached systemic circulation after 24h (maximum flux was 464±65pmol-eq/cm2/h). BEH-TEBP in vitro penetrance was minimal (<0.01%) for rat or human skin. BEH-TEBP absorption was 12±11% for human skin and 41±3% for rat skin. In vivo, total absorption was 27±9%; 1.2% reached systemic circulation. In vitro maximal BEH-TEBP flux was 0.3±0.2 and 1±0.3pmol-eq/cm2/h for human and rat skin; in vivo maximum flux for rat skin was 16±7pmol-eq/cm2/h. EH-TBB was metabolized in rat and human skin to tetrabromobenzoic acid. BEH-TEBP-derived [14C]-radioactivity in the perfusion media could not be characterized. <1% of the dose of EH-TBB and BEH-TEHP is estimated to reach the systemic circulation following human dermal exposure under the conditions tested. Chemical compounds studied in this article2-Ethylhexyl 2,3,4,5-tetrabromobenzoate (PubChem CID: 71316600; CAS No. 183658-27-7 FW: 549.92g/mol logPest: 7.73–8.75 (12)) Abdallah et al., 2015a. Other published abbreviations for 2-ethylhexyl-2,3,4,5-tetrabromobenzoate are TBB EHTeBB or EHTBB Abdallah and Harrad, 2011.bis(2-ethylhexyl) tetrabromophthalate (PubChem CID: 117291; CAS No. 26040-51-7 FW: 706.14g/mol logPest: 9.48-11.95 (12)). Other published abbreviations for bis(2-ethylhexyl)tetrabromophthalate are TeBrDEPH TBPH or BEHTBP.