Daily Exposure Values Research Articles

Thiuram vulcanization accelerators in human urine and their human exposure.

Thiuram vulcanization accelerators (TVAs) have been identified in multiple dust samples, suggesting a broad extent of their human exposure. However, until recently, the presence of these compounds in human urine, which is an ideal medium for evaluating exposure levels, has not been examined. In this study, we conducted a comprehensive analysis of ten types of TVAs in urine samples collected from 201 individuals residing in Quzhou City, China. Our findings revealed the presence of eight TVAs in the human urine samples, with detection frequencies varying between 14% and 91%. Among these TVAs, tetramethylthiuram disulfide (TMTD; mean 5.3ng/mL, range<LOD-19ng/mL) was identified as the most predominant analyte in collected human urine, followed by tetramethylthiuram monosulfide (TMTM; 2.5ng/mL, < LOD-16ng/mL) and tetraethylthiuram disulfide (TETD; 1.6ng/mL, < LOD-15ng/mL). Males exhibited significantly higher average levels of TETD (2.2±0.61ng/mL versus 1.3±0.31ng/mL; p<0.01) and tetrabutylthiuram disulfide (TBTD; 0.53±0.23ng/mL versus 0.23±0.11ng/mL; p<0.01) in their urine samples than females. Moreover, we found a significantly (p<0.05) negative correlation between urinary TETD and TBTD levels and human age. The highest average human daily exposure value was observed for TMTD (168ng/kg bw/day), followed by TMTM (79ng/kg bw/day) and TETD (51ng/kg bw/day). To our awareness, this study marks the first comprehensive assessment of TVAs in human urine. The obtained results provide valuable insights into understanding the extent of human exposure to these compounds.

Establishment of a measuring unit based on Arduino board for recording vibrations on an agricultural tractor during tillage process

When it comes to agricultural tractor ergonomics, vibration is one of the most important factors to consider. However, little research has been done to evaluate this parameter and its impact on workers’ health. Therefore, the aim of this study was to fabricate a portable vibration measurement unit (PVMU) based on an Arduino microcontroller and a vibration sensor (accelerometer ADXL335). The PVMU performance was tested in combination with a commercially available three-axis USB vibration measurement device (VB10). Furthermore, the vibration measurements were used to calculate the tractor driver’s whole-body vibration load according to ISO 2631-1 along three perpendicular axes (X, Y, and Z) during soil tillage using a disk harrow under different tillage speeds of 4.0, 5.5, and 7.0 km/h at a tillage depth of 15 cm in a sandy loam soil. Performance tests of the PVMU and the commercially available three-axis USB vibration meter (VB10) revealed a highly significant level of agreement based on a correlation coefficient of 0.9822. It was found that the vibration level increases with increasing tillage speed. The highest vibration level, 0.80 m/sec2, was observed in the vertical direction (Z-axis) at a tillage speed of 7.0 km/h. The lowest vibration level, 0.12 m/sec2, was observed in the lateral direction (Y-axis) at a tillage speed of 4.0 km/h. The dominant frequency range of vibration transmitted to the tractor seat was found to be between 2.04 Hz and 20.14 Hz. The daily exposure values that is, A (8) determined during this study to assess the health hazards due to vibration for tractor drivers ranged from 0.01 m/sec2 to 0.06 m/sec2 lower than the recommended exposure action value (EAV) limit that is, 0.5 m/sec2. This means that there is no health risk for the driver during the soil tillage using a disk harrow plow. The PVMU proposed in this study is very reliable and can be used as a vibration assessment tool for other agricultural tractor-implement combinations.

A spectrometric analysis of variedly purified cinnabar in a siddha drug- linga chendhooram.

A siddha drug, linga chendhooram was prepared from cinnabar (lingam) and Citrullus colocynthis L. The transition of heavy metals concentration throughout theprocess were analysed to comprehend the significance ofdrug preparatory methods. In addition to that the main constituent cinnabar was purified from two different methods to comparatively analyse the significance of purification methods. Atomic absorption spectrometric studies were employed to obtain the concentration of class I heavy metals (lead, arsenic, cadmium and mercury) in all five samples- raw cinnabar (R), cinnabar purified (P1 and P2) from purification method 1 and 2, linga chendhooram (D1 and D2) prepared from P1 and P2. Based on the permissible limits given by The Ayurvedic Pharmacopoeia of India, except cadmium the concentrations of all other three heavy metals were found to be above the limit in P1, P2, D1 and D2. According to the oral Permitted Daily Exposure values for elemental impurities given in ICH Q3D(R1) Guidelines, D1 was within the permissible limits for both single and double oral doses whereas D2 showed a slight increase in the concentration of lead in a single oral dose itself. The drug preparatory method showed a reduction of the heavy metals concentration and comparative analysis of the purification methods revealed a substantial reduction of heavy metals concentration in the end drug D1 when compared with D2 showing that the methods of purification and drug preparation in siddha system plays a vital role in reducing the concentrations of heavy metals accordingly.

Comparison of Excipients in Approved Parenteral Products and Their Maximum Daily Exposure Values.

The following article analyses the excipients used in the parenteral formulations registered by the U.S. Food and Drug Administration (FDA) in the years 2011 and 2021. It adds real-word data for parenteral excipients in approved products from the New Zealand Medicines and Medical Devices Safety Authority (Medsafe) and the Irish Health Products Regulatory Authority (HPRA) in 2021. Maximum daily exposures (MDEs) for all parenteral excipients that had their amount listed either in the Medsafe or HPRA database are presented. Altogether, there were 355 excipients found in the parenteral dosage forms across all markets (US, New Zealand, and Ireland). Only 90 excipients (25.3%) were found in all three markets. In contrast, there were 187 (52.7%) excipients found in only one market. The MDE values of parenteral excipients from New Zealand and Ireland are frequently higher than the values found in the FDA inactive ingredients database (IID), adding important new information when the toxicity of these excipients is considered. There is a heterogenicity between the markets in use of parenteral excipients, with the US market leading in the number of total excipients as well as excipients present only in the US market. Nevertheless, there are several excipients not found in the US market that are registered in other markets. The comprehensive listing of parenteral excipients used worldwide presented in this article enables formulation scientists to quickly reference all potential parenteral excipients that are already proven safe and acceptable when designing a new parenteral formulation. Further, a list of new values for the MDE, often higher than those listed in the IID, provides important information for formulation scientists and toxicologists about the potential toxicity of these excipients.

Risiko Paparan Formaldehida dari Beberapa Jenis Ikan pada Masyarakat di Kecamatan Dramaga, Bogor, Jawa Barat

Residual formaldehyde compounds may be found in fish either naturally or intentionally added. Exposure of formaldehyde from food can cause damage to the gastrointestinal tract, liver, kidney, and is carcinogenic in humans. This study aims to estimate the risk value of formaldehyde exposure level due to fish consumption in the community population in Dramaga Subdistrict with deterministic approach. Fish consumption data was obtained from a consumption survey using a semi food frequency questionnaire (FFQ). The fish consumption survey was conducted on 505 respondents with an age range of 5-60 years and over. Formaldehyde analysis was conducted on four types of fish that are popular and often consumed by the community, namely salted peda fish, salted anchovy rice fish, salted japuh fish, and fresh anchovy fish. The results showed that formaldehyde levels in four types of fish range from 8.30 – 105.09 mg/kg. The average daily consumption of salted peda, salted anchovy rice, salted japuh, and fresh anchovy was 11.58±8.32; 8.85±4.93; 7.72±4.51; and 9.85±6.45 (g/day). The average daily exposure values of formaldehyde in salted peda, salted anchovy rice, salted japuh, and fresh anchovy were 0.0025; 0.0088; 0.0146; and 0.0014 (mg/kg bw/day). The overall of daily exposure value is still below the maximum oral exposure limit of 0.2 (mg/kg bb/day). The value of exposure risk with hazard quotient (HQ) in four types of fish is 0.007–0.073. The HQ was found to be below 1, indicating risk level of exposure to formaldehyde in the community in Dramaga Subdistrict is still within safe limits.

Pasta cooking influence on in vitro bioaccessibility of type B trichothecenes, acrylamide and hydroxymethylfurfural

The study evaluated the effect of cooking time on the levels of type B trichothecenes (TCTB), acrylamide (AA) and hydroxymethylfurfural (HMF) in semolina pasta and their bioaccessibilities in order to propose strategies to reduce the daily exposure of these natural and processing contaminants. Three brands of commercial pasta were submitted to different cooking times (7, 10 and 13 min). Subsequently, the in vitro bioaccessibility trials, permeation across the intestinal membrane and estimation of daily exposure were carried out. The lowest cooking time (7 min) resulted in high reductions of TCTB (88%) and AA + HMF (76.7%) contents found on the raw pasta. The concentrations of deoxynivalenol (DON) and AA were higher after the digestion (bioaccessibilities >100%) than after the pasta cooking. About 25.6% of DON and 100% of AA found in the small intestine digestible fraction were able to permeate the intestinal membrane. The risk of exposure was below the recommended safe limits since the estimated daily exposure values were 0.22 µg/kg per body weight/day for DON and 0.26 µg/kg per body weight/day for AA. Therefore, cooking pasta for 7 min at a pasta:water ratio of 1:10 (w/v) mitigates the contaminants and promotes the greater formation of resistant starch.

Vibration Assessment of a 12-kW Self-Propelled Riding-Type Automatic Onion Transplanter for Transplanting Performance and Operator Comfort

Vibration assessment of upland crop machinery under development is essential because high vibrational exposures affect machine efficiency, service life of components, degradation of the working environment, and cause health risks to the operator. It is intensively assessed for automobiles as well as large off-road agricultural vehicles (i.e., tractors). However, it is mostly overlooked in the case of the small or medium riding-type upland utility vehicles. Therefore, the vibration exposures of a 12-kilowatt self-propelled riding-type automatic onion transplanter were measured and evaluated to assess the performance of onion transplantation and the operator’s comfort in this study. Different types of driving surfaces, operating statuses (static and driving), and load conditions were considered to analyze the vibration exposure. The precision of transplantations was evaluated while operating the transplanter on the soil surface with different driving speeds and load conditions. Tri-axial accelerometers and a LabVIEW-coded program were used for data acquisition. The vibrational exposures were evaluated based on ISO standards, and power spectral density (PSD) was estimated to assess the major frequencies. According to the statistical analysis, the daily exposure value (A(8)) and the vibration dose value (VDV) varied from 10 to 15 ms−2 and 20 to 31 ms−1.75, respectively, which exceeded the ISO 2631-1 standards (i.e., A(8): 1.15 ms−2 and VDV: 21 ms−1.75). The calculated health risk factor (RA) was moderate. Moreover, a high weighted acceleration (around 8 ms−2) was observed on the seedling conveyor belt, which might result in missing seedlings during transplanting. The vibration exposures of the developed onion transplanter need to be minimized following the ISO standards, and vibration reduction would also improve the market competitiveness.

Derivation of the permitted daily exposure value for p-tert-butylphenol as an impurity in pharmaceutical products

Derivation of the permitted daily exposure value for p-tert-butylphenol as an impurity in pharmaceutical products

Evaluation of sound levels in elective orthopaedic theatres during primary hip and knee arthroplasty

BackgroundOrthopaedic surgery involves tools which could cause noise-induced hearing loss in theatre staff. Threshold levels for occupational noise exposure have been developed in the U.K., above which action is required to reduce exposure. The aims of our study were to determine whether equivalent continuous sound pressure levels during elective arthroplasty can be measured using readily available materials, and to assess whether noise exposure levels stand within acceptable occupational noise exposure levels. Materials and methodsSound pressure levels of orthopaedic saws were recorded using the MicW i436 connected to an iPhone 4S and the iOS SoundMeter application, and using a professional sound meter.Equivalent sound pressure levels were recorded for total hip replacement (THR) and total knee replacement (TKR) using the MicW i436 SoundMeter application. Data obtained was then used to calculate a “worst case” daily exposure value to assess if sound levels were compliant with U.K. guidelines. ResultsSound pressure levels recorded using the MicW i436 and Soundmeter application were accurate compared to professional soundmeter readings. THR showed equivalent sound pressure levels (LAeq) of 77 dBA and TKR showed a LAeq of 80 db. Calculated “worst case” scenarios for daily noise exposure using these values did not meet the lower exposure action values set out by U.K. guidelines. ConclusionsIt is possible to accurately measure continuous sound pressure levels during elective orthopaedic surgery using readily available materials. Noise exposure values during TKR meet lower exposure action values, and when “worst case” daily exposure levels are calculated this level is still lower than the threshold.

Polycyclic Aromatic Hydrocarbons and Birth Defects in California

Background: Ambient air pollution has been associated with several birth defects, though few studies have examined polycyclic aromatic hydrocarbons (PAHs), specifically. Our aim was to assess the relationship between maternal exposure to ambient PAHs in the first two months of pregnancy and risk of several structural birth defects as part of the Berkeley-Stanford Children’s Environmental Health Center (Children’s Health and Air Pollution Study).Methods: PAHs were assessed through a combination of intermittent monitoring and estimated PAH concentrations based on daily, collected NO and CO measurements in the San Joaquin Valley of California. Daily exposure values were spatially interpolated from the air quality monitoring stations’ locations to women’s residence locations in early pregnancy using inverse distance-squared weighting with a maximum interpolation radius of 25 km. We used data from 1028 cases and 975 controls from the California center of the National Birth Defects Prevention Study (1997-2011) to examine quartiles of exposure to risk of neural tube defects (N=281), gastroschisis (N=223), and cleft lip with or without cleft palate (N=364) or cleft palate only (N=162). Models were adjusted for maternal race/ethnicity, education and vitamin use in early pregnancy. Results: We found suggestive associations between PAHs and neural tube defects including spina bifida and anencephaly with evidence of an exposure-response across quartiles of PAHs. High ambient PAHs during the first two months of pregnancy were associated with a small increased risk of neural tube defects [odds ratio (OR)=1.23; 95% confidence interval (CI):0.83, 1.82]. We found inverse associations between PAHs and risk of gastroschisis (OR=0.58; 95% CI:0.37, 0.90) and cleft lip with or without cleft palate (OR=0.66; 95% CI:0.46, 0.95).Conclusions: Some results were in the unexpected direction, but results are consistent with our previous observed associations between other traffic-related air pollutants and neural tube defects in the San Joaquin Valley of California.

Permitted Daily Exposure Values: Application Considerations in Toxicological Risk Assessments.

Permitted daily exposure (PDE) values are used by some toxicologists to support the safety qualification of various types of impurities found in a drug substance (DS) or drug product (DP). Permitted daily exposure values are important tools for the toxicologist, but one must be aware of their limitations to ensure that they are used appropriately and effectively in the risk assessment process. First, a toxicologist must always perform a comprehensive analysis of all available animal and human safety data for an impurity, including identifying any data gaps that may exist. Second, if adequate data are available and there are no genotoxicity concerns, an appropriate well-designed repeat-dose toxicity study in animals should be chosen to calculate the PDE. It is important to note that PDE values qualify general systemic toxicity and not necessarily local toleration end points such as irritation and sensitization that are more concentration than dose dependent. In addition, a PDE value calculated from a general toxicity study in animals may not necessarily qualify for reproductive toxicology end points. Lastly, PDE values should never be thought of as analytical limits for or acceptable levels of an impurity in a DS or DP, as this ignores quality considerations. Using safety information from several chemicals as proxy impurities, this article serves as an educational primer to facilitate a better understanding of the development and use of PDE values in the risk assessment process.

Indoor and outdoor PM2.5 exposure, and anxiety among schoolchildren in Korea: a panel study.

This panel study aimed to evaluate the associations between short-term exposure to indoor and outdoor PM2.5 and anxiety in schoolchildren. During 3 waves in March, July, and November 2018 with 7days per wave, 52 children aged 10years were recruited from two schools in a city in Korea. To assess outdoor exposure, we used PM2.5 concentration measures for every hour at the national measurement station (NMS) closest to the two participating schools. To assess indoor exposure, we measured PM2.5 concentration at the children's homes and in classrooms, based on 30-min average. Based on time-activity logs, personal average daily exposure values were calculated for each participant, according to exposure values assessed at 30-min intervals by location. Children's anxiety was assessed via the Korean version of the State Anxiety Inventory for children every day during each wave. Linear mixed effects model was conducted to analyze the association between PM2.5 exposure and anxiety using repeated measurements. Personal exposure to PM2.5 by time-activity log was the highest in March and at home. A low correlation coefficient was observed between PM2.5 concentrations at home and at the NMS (ρ= 0.36, p< 0.0001) whereas a high correlation coefficient was observed between PM2.5 concentrations in classrooms and at the NMS (ρ= 0.64, p< 0.0001). There was no association between PM2.5 exposure and anxiety in children based on the analysis of repeated measurements during the study period. Since previous studies reported controversial results, long-term follow-up studies are needed in various regions to further investigate the associations between PM2.5 exposure and children's mental health.

The Hazardous Level of Heavy Metals in Different Medicinal Plants and Their Decoctions in Water: A Public Health Problem in Brazil.

The determination of Cd, Co, Cr, Cu, Fe, Na, Zn, and Pb by inductively coupled plasma-optical emission spectrometry (ICP OES) was performed on dry matter and decoctions of the medicinal plants Cordia salicifolia, Chiococca alba (L.) Hitchc., and Echites peltata used as an appetite suppressant and diuretic in Brazil. The accuracy of the measurements was analyzed by the spike recovery test. Results showed that the concentration of these seven metals (Cd, Co, Cr, Cu, Fe, Na, and Zn) in dry plant samples is below the oral concentration of elemental impurities established by the United States Pharmacopoeia Convention (USP). However, there are no concentration limits for Fe, Na, and Zn established by the USP in drug substances and excipients. Levels higher than the recommended value by the USP were observed for Pb and the lowest for Cd, Co, Cr, and Cu, both in dried plant samples and their decoctions. In the decoctions prepared from these plants were found elements such as Cd, Co, Cr, Cu, Fe, Na, Zn, and Pb. In the decoction prepared from 40 g C. salicifolia leaves and 40 g C. alba wood, the content of Cd is above the oral daily exposure value set by the USP. Hazard index (HI) for decoctions prepared from these plants exceeded the threshold (1). Given the uncertainties associated with the estimates of toxicity values and exposure factors, futures researches should address the possible toxicity in humans. Uncontrolled selling and long-term ingestion of medicinal plants can cause toxicity and interfere with the effect of drugs. Limited knowledge on the interaction potential of medicinal plants poses a challenge and public health problem in Brazil and other countries.

Vibration Levels of Used Chainsaws

Although professional chainsaws have come a long way regarding technical and ergonomic development since first introduced into forestry, they still remain a high-risk tool that can cause serious health problems. In this research, three types of used professional chainsaws were observed regarding harmful vibrations they emit and possible connection to years in use, chainsaw type, characteristics and level of vibrations. Measurements were performed in accordance with the recommendations of ISO 5349:2001. For the measurements, a measuring chain consisting of a triaxial accelerometer manufactured by Bruel &amp; Kjaer and a vibrometer of the same manufacturer Type 4447. To evaluate the emitted vibrations, a daily exposure value A(8) was used. Exposure durations to predefined working operations were identical for every used chainsaw to enable the possibility of equal comparability. Obtained results indicate that the daily vibration exposure A(8) is not affected by the years in use of the chainsaw. Results also show that the power and chainsaw type have an influence on daily vibration exposure. The recommendation for the praxis is to use even lighter and smaller chainsaw wherever is possible.

PM Origin or Exposure Duration? Health Hazards from PM-Bound Mercury and PM-Bound PAHs among Students and Lecturers.

This study assessed inhalation exposure to particulate matter (PM1)-bound mercury (Hgp) and PM1-bound polycyclic aromatic hydrocarbons (PAHs) among university students. For this purpose, simultaneous indoor (I) and outdoor (O) measurements were taken from two Polish technical universities (in Gliwice and Warsaw) located in distinct areas with respect to ambient concentrations and major sources of PM. The indoor geometric mean concentrations of Hgp were found to be 1.46 pg·m−3 and 6.38 pg·m−3 in Warsaw and Gliwice, while the corresponding outdoor concentrations were slightly lower at 1.38 pg·m−3 and 3.03 pg·m−3, respectively. A distinct pattern was found with respect to PAH concentrations with estimated I/O values of 22.2 ng·m−3/22.5 ng·m−3 in Gliwice and 10.9 ng·m−3/11.12 ng·m−3 in Warsaw. Hazard quotients (HQs) as a result of exposure to Hgp for students aged 21 ranged from 3.47 × 10−5 (Warsaw) to 1.3 × 10−4 (Gliwice) in terms of reasonable maximum exposure (RME). The non-cancer human health risk value related to Hgp exposure was thus found to be below the acceptable risk level value of 1.0 given by the US EPA. Daily exposure values for lecture hall occupants, adjusted to the benzo(a)pyrene (BaP) toxicity equivalent (BaPeq), were 2.9 and 1.02 ng·m−3 for the Gliwice and Warsaw students, respectively. The incremental lifetime cancer risk (ILCR) values with respect to exposure to PM1-bound PAHs during the students’ time of study were 5.49 × 10−8 (Warsaw) and 1.43 × 10−7 (Gliwice). Thus, students’ exposure to indoor PAHs does not lead to increased risk of lung cancer.

Determination of As, Cd, Hg and Pb in continuous use drugs and excipients by plasma-based techniques in compliance with the United States Pharmacopeia requirements

Some inorganic impurities are toxic to human health even when present at low concentrations and therefore must be carefully monitored in products as continuous use drugs. This work aimed the development of a simple microwave-assisted digestion procedure for different types of drugs and excipients and the analytical determination of elemental impurities according to the new regulations of the United States Pharmacopeia (USP) 232 and 233 using inductively coupled plasma optical emission spectrometry (ICP-OES) or inductively coupled plasma mass spectrometry (ICP-MS). Eight drugs samples and two excipients of different brands were microwave-assisted digested with inverse aqua regia. Addition and recovery experiments were performed according to J values, once permissible daily exposure value is specific for each element and estimated according to the maximum daily dose of drug indicated by the label. Samples were spiked with values of 1.5J in order to check accuracies for As, Cd, Hg, and Pb. Recoveries obtained by ICP-OES ranged from 75 to 148% and for ICP-MS ranged from 74 to 120%. The limits of detection for ICP-OES ranged from 0.4 to 17mgkg−1 and for ICP-MS from 7.4 to 41.6μgkg−1. Both analytical methods were adequate in terms of accuracies and sensitivities. Considering the maximum daily dose, all drugs samples and excipients contained As, Cd, Hg and Pb below the maximum limits stipulated by USP since all of them presented contents below respective limits of detection.

Calculation of a permitted daily exposure value for the solvent 2-methyltetrahydrofuran

In response to increasing concerns around the potential environmental impact of industrial chemicals, the pharmaceutical industry is seeking alternatives for traditional solvents used during the manufacturing process. Taking into consideration the principles of green chemistry, 2-methyltetrahydrofuran (2-MeTHF) is proposed as a suitable replacement for the structurally similar solvent tetrahydrofuran (THF). 2-MeTHF is derived from renewable sources and is more easily recovered thereby facilitating its reuse. However, 2-MeTHF is currently not included in the International Conference on Harmonisation (ICH) Q3C residual solvent guidelines and there is no Permitted Daily Exposure (PDE) limit proposed below which there would be negligible safety concerns for patients exposed to it as a residual impurity in a drug product.To enable the calculation of a PDE, a GLP compliant 3-month repeat-dose oral toxicity study in rats with a 1-month recovery period was conducted with doses of 2-MeTHF of 0, 80, 250, 500 and 1000 mg/kg/day. Administration of doses of up to 1000 mg/kg/day was tolerated. Based upon minimal observed effects on the liver at ≥500 mg/kg/day, the NOAEL in this study was considered to be 250 mg/kg/day.Inclusion of this NOAEL, and a safety factor of 250 a PDE of 50 mg/day was derived to support the safe use of 2-MeTHF in the pharmaceutical industry.

Environmental Phthalate Diesters as hMT1 and hMT2 Melatonin Receptor Ligands

Phthalates esters are commonly used plasticizers that have been linked to endocrine disruption and developmental alterations. Humans are exposed to these ubiquitous synthetic compounds via inhalation of ambient air, dermal contact with consumer products, and ingestion through food and drinking water. It is estimated from urinary metabolite levels that in the US, median adult daily exposure values for phthalate levels are about 8.5–16.8 μg/kg bw/day (Wittassek et al., Mol Nutr Food Res. 55:7–31, 2011). Using integrated pharmacoinformatics‐molecular docking approaches we discovered that several phthalate diesters show structural similarities to melatonin receptor ligands and bind with relatively high docking scores to melatonin binding pockets on in silico hMT1 and hMT2 melatonin receptor models. An assortment of phthalates including three monoesters and ten diesters with alkyl and/or aromatic substituents were tested for competition with 2‐[125I]‐iodomelatonin (100 nM) binding to hMT1 and hMT2 receptors stably expressed in CHO cells to assess binding affinity (Ki) as well as apparent intrinsic efficacy in the presence of GTP (100 μM). In GPCR binding assays, GTP decouples G proteins from receptors causing decreased affinity (rightward shift) for agonists but not for antagonists. Phthalate diesters with aromatic substituents (BBzP: Benzyl Butyl Phthalate; DPP: Diphenyl Phthalate) exhibited the highest affinities toward both hMT1 (BBzP Ki: 2.6 ± 0.3 μM, n=8; DPP Ki: 2.9 ± 0.7 μM, n=8) and hMT2 (BBzP Ki: 1.3 ± 0.2 μM, n=9; DPP Ki: 0.66 ± 0.10 μM, n=9) receptors. Among phthalates with alkyl substituents, four carbon (C4; DBP: Dibutyl Phthalate) and six carbon (C6; DHP: Dihexyl Phthalate) chain length diesters best competed for binding to hMT1 receptors with affinities ranging from 5 to 8 μM. hMT2 receptors did not show any preference to chain lengths of C6 or shorter (DEP: Diethyl Phthalate; DMP: Dimethyl Phthalate; DPrP: Dipropyl Phthalate; DBP; DHP), as all Ki values were between 2 and 7 μM. DBP and BBzP bound to melatonin receptors with affinities in the low micromolar range, however their respective monoester metabolites, MBP (Monobutyl Phthalate) and MBzP (Monobenzyl Phthalate), did not compete for binding to either receptor. The presence of GTP caused a leftward shift of the binding competition curves for both BBzP and DPP at hMT1 melatonin receptors (BBzP KiGTP/KiControl: 3.8; DPP KiGTP/KiControl: 2.6) suggesting inverse agonist efficacy. Little or no shift (BBzP KiGTP/KiControl: 1.3; DPP KiGTP/KiControl: 1.5) on competition curves for hMT2 melatonin receptors suggests antagonist efficacy. Together these data suggest that phthalate diesters could interact with hMT1 and hMT2 receptors to disrupt melatonin receptor‐mediated signaling processes in target tissues.Support or Funding InformationSupported by ES 023684 to MLD and RVR.

Testing a cumulative and aggregate exposure model using biomonitoring studies and dietary records for Italian vineyard spray operators

The need for improved tools to estimate the cumulative and aggregate exposure to compounds such as plant protection products (PPPs) is recognised in the EU Regulation 1107/2009. A new model has been developed to estimate the exposure within a population to single compounds or compounds within a Cumulative Action Group, considering dietary and non-dietary sources and multiple exposure routes. To test the model a field study was carried out in Italy with operators applying tebuconazole fungicides, with measurements of dermal exposure collected. Whole urine samples were collected and analysed to provide values for the absorbed dose of tebuconazole, with duplicate diet samples collected and analysed as a measure of dietary exposures. The model provided predicted values of exposure for combined dietary and non-dietary routes of exposures which were compared to the measured absorbed dose values based on urinary analysis. The model outputs provided mean daily exposure values of 1.77 (±1.96) µg a.s./kg BW which are comparable to measured mean values from the biomonitoring field study of 1.73 (±1.31) µg a.s./kg BW. To supplement the limited measurement data available, comparisons against other models were also made and found to be comparable.

Risk of preeclampsia from exposure to particulate matter (PM₂.₅) speciation chemicals during pregnancy.

To determine whether maternal exposure to particulate matter (PM₂.₅) speciation chemicals during pregnancy is associated with the risk of preeclampsia. We allocated average daily exposure values for 36 ambient particulate matter speciation chemicals to mothers during their first trimester and their entire pregnancy. The main outcome of interest was preeclampsia occurrence. Adjusted odd ratios and 95% confidence intervals were computed. The odds for preeclampsia were increased per interquartile range increase in pollutants for exposure to elemental carbon during the first trimester of pregnancy (odds ratio = 1.08; confidence interval = 1.01 to 1.16) and during the entire pregnancy period (odds ratio = 1.05; confidence interval = 1.01 to 1.11). The most substantial risk for preeclampsia was observed for PM2.5 aluminum exposure during the entire pregnancy, resulting in 10% increased risk (odds ratio = 1.10; confidence interval = 1.03 to 1.18) per interquartile range increase in aluminum. Maternal exposure to PM2.5, aluminum, and elemental carbon during pregnancy increases the risk of preeclampsia.