Relative Potency Factors Research Articles

Predicting the Activation of the Androgen Receptor by Mixtures of Ligands Using Generalized Concentration Addition.

Concentration/dose addition is widely used for compounds that act by similar mechanisms. But it cannot make predictions for mixtures of full and partial agonists for effect levels above that of the least efficacious component. As partial agonists are common, we developed generalized concentration addition, which has been successfully applied to systems in which ligands compete for a single binding site. Here, we applied a pharmacodynamic model for a homodimer receptor system with 2 binding sites, the androgen receptor, that acts according to the classic homodimer activation model: Each cytoplasmic monomer protein binds ligand, undergoes a conformational change that relieves inhibition of dimerization, and binds to DNA response elements as a dimer. We generated individual dose-response data for full (dihydroxytestosterone, BMS564929) and partial (TFM-4AS-1) agonists and a competitive antagonist (MDV3100) using reporter data generated in the MDA-kb2 cell line. We used the Schild method to estimate the binding affinity of MDV3100. Data for individual compounds fit the homodimer pharmacodynamic model well. In the presence of a full agonist, the partial agonist had agonistic effects at low effect levels and antagonistic effects at high levels, as predicted by pharmacological theory. The generalized concentration addition model fits the empirical mixtures data-full/full agonist, full/partial agonist, and full agonist/antagonist-as well or better than relative potency factors or effect summation. The ability of generalized concentration addition to predict the activity of mixtures of different types of androgen receptor ligands is important as a number of environmental compounds act as partial androgen receptor agonists or antagonists.

Levels and inhalation health risk of neonicotinoid insecticides in fine particulate matter (PM2.5) in urban and rural areas of China

Neonicotinoid insecticide (NEO) concentrations in ambient fine particulate matter (PM2.5) and daily exposure via inhalation were investigated during spring and fall in an urban area in Beijing and in urban and rural areas of Zhengzhou, Henan Province, China. Four NEOs, including imidacloprid, acetamiprid, thiamethoxam and clothianidin, were assessed using a QuEChERS (quick, easy, cheap, effective, rugged, safe) extraction procedure coupled to liquid chromatography–tandem mass spectrometry. Of 64 PM2.5 samples, 100% contained at least two NEOs (imidacloprid and acetamiprid). Imidacloprid was detected at the highest levels, ranging from 4.33 to 1.13 × 102 pg m−3. A relative potency factor method that considered different toxicities was used to integrate the four NEO concentrations. The total NEO concentrations in air in the Zhengzhou rural area (mean: 80.86 pg m−3) were higher than those in urban areas. Differences between seasons were not significant (p > 0.05). The highest value for the total average daily dose via inhalation of four NEOs (ADDinh,total), 91.0 pg kg−1 day−1, was found in rural children <6 years old. The ADDinh,total of rural residents was significantly higher than that of urban residents when there was no intensive pesticide application. Although the ADDinh,total values were below the current chronic reference dose, when possible joint toxicity and the increasing use of NEOs are considered, a potential health risk via inhalation is evident. We believe this study is the first to characterize NEO levels in fine particulate matter and to evaluate inhalation exposure in urban and rural residents under nonoccupational scenarios in China. It will enhance our understanding of exposure to NEOs and provide a basis for risk management decisions.

Cumulative dietary risk assessment overarching different regulatory silos using a margin of exposure approach: A case study with three chemical silos

Risk assessment of chemicals occurring in our diet is commonly performed for single chemicals without considering exposure to other chemicals. We performed a case study on risk assessment of combined dietary exposure to chemicals from different regulatory silos, i.e. pesticides (PPRs), persistent organic pollutants (POPs) and food additives (FAs). Chemicals were grouped into the cumulative assessment group (CAG) liver steatosis using a component-based approach. Based on literature, the CAG included 144 PPRs, 49 POPS and 7 FAs for which concentration data were available.For each silo, chronic combined dietary exposure was assessed for adults and children of nine European countries following the most commonly used exposure methodologies in Europe and by using a relative potency factor approach. For risk characterization, a Margin of Exposure (MOE) was calculated. To overarch the risk across silos, a normalised combined margin of exposure (nMOET) approach was proposed.This case study demonstrated that risk assessment of combined exposure to chemicals can be performed within regulatory silos. It also highlighted important differences in the conservatism of exposure scenarios, the derivation of point of departures and the subsequent acceptable MOEs between the silos. To overarch the risk despite these differences, a nMOET approach can be used.

Perfluoroalkyl substances and anthropomorphic measures in children (ages 3–11 years), NHANES 2013–2014.

BackgroundPerfluoroalkyl acids (PFAAs) are man-made compounds that are persistent in the environment and highly bioaccumulative in the body. Humans are exposed to a mixture of these substances, and the effects of these mixtures may be different than the effects noted for individual compounds. Prenatal exposure to PFAAs has been associated with decreased birth weight. The objective of the present study is to evaluate concurrent serum PFAA levels, as single compounds and as mixtures, in relation to anthropomorphic measures in children. MethodsUsing multivariate linear regression, we evaluated the association between single or PFAA mixtures and with height-for-age (HAZ), weight-for-age (WAZ), and BMI (BMIZ) z-scores in children (ages 3–11 years) participants of the National Health and Nutrition Examination Survey (NHANES) 2013–2014. Analyses were also stratified by sex. The PFAA mixture was based on relative potency factors express in terms of PFOA equivalency (CmixRPFi) or as molar sum of the PFAA congeners (∑molPFAA). ResultsThere was a statistically significant association of PFHxS and PFOS with decreased HAZ in boys. The significantly decreased HAZ in boys was also found when the PFAAs were analyzed as mixtures: CmixRPFi (β = −0.33; 95%CI: 0.63, −0.04) or ΣmolPFAAs (β = −0.30; 95%CI: 0.56, −0.04). In boys, PFHxS was also associated with decreased WAZ and BMIZ. The only statistically significant association found in girls was between decreased HAZ and PFHxS. ConclusionsWe found sex differences in the association between concurrent serum PFAA levels and anthropomorphic measures in children 3–11 years old. PFAA levels, as single congeners or as mixture concentrations were associated with decreased height-for-age z-score in boys.

Application of a combined aggregate exposure pathway and adverse outcome pathway (AEP-AOP) approach to inform a cumulative risk assessment: A case study with phthalates

Advancements in measurement and modeling capabilities are providing unprecedented access to estimates of chemical exposure and bioactivity. With this influx of new data, there is a need for frameworks that help organize and disseminate information on chemical hazard and exposure in a manner that is accessible and transparent. A case study approach was used to demonstrate integration of the Adverse Outcome Pathway (AOP) and Aggregate Exposure Pathway (AEP) frameworks to support cumulative risk assessment of co-exposure to two phthalate esters that are ubiquitous in the environment and that are associated with disruption of male sexual development in the rat: di(2-ethylhexyl) phthalate (DEHP) and di-n-butyl phthalate (DnBP). A putative AOP was developed to guide selection of an in vitro assay for derivation of bioactivity values for DEHP and DnBP and their metabolites. AEPs for DEHP and DnBP were used to extract key exposure data as inputs for a physiologically based pharmacokinetic (PBPK) model to predict internal metabolite concentrations. These metabolite concentrations were then combined using in vitro-based relative potency factors for comparison with an internal dose metric, resulting in an estimated margin of safety of ~13,000. This case study provides an adaptable workflow for integrating exposure and toxicity data by coupling AEP and AOP frameworks and using in vitro and in silico methodologies for cumulative risk assessment.

An adverse outcome pathway-based approach to assess steatotic mixture effects of hepatotoxic pesticides in vitro

Exposure to complex chemical mixtures requires a tiered strategy for efficient mixture risk assessment. As a part of the EuroMix project we developed an adverse outcome pathway (AOP)-based assay toolbox to investigate the combined effects of the liver steatosis-inducing compounds imazalil, thiacloprid, and clothianidin in human HepaRG hepatocarcinoma cells. Compound-specific relative potency factors were determined using a benchmark dose approach. Equipotent mixtures were tested for nuclear receptor activation, gene and protein expression, and triglyceride accumulation, according to the molecular initiating events and key events proposed in the steatosis AOP. All three compounds affected the activity of nuclear receptors, but not key genes/proteins as proposed. Triglyceride accumulation was observed with three different methods. Mixture effects were in agreement with the assumption of dose additivity for all the combinations and endpoints tested. Compound-specific RPFs remained similar over the different endpoints studied downstream the AOP. Therefore, it might be possible to reduce testing to a smaller battery of key tests. The results demonstrate the suitability of our in vitro assay toolbox, integrated within an AOP framework and combined with the RPF approach, for the analysis of steatotic effects of chemical mixtures. However, mRNA results suggest that the steatosis AOP still needs improvement.

The MCRA toolbox of models and data to support chemical mixture risk assessment

A model and data toolbox is presented to assess risks from combined exposure to multiple chemicals using probabilistic methods. The Monte Carlo Risk Assessment (MCRA) toolbox, also known as the EuroMix toolbox, has more than 40 modules addressing all areas of risk assessment, and includes a data repository with data collected in the EuroMix project. This paper gives an introduction to the toolbox and illustrates its use with examples from the EuroMix project. The toolbox can be used for hazard identification, hazard characterisation, exposure assessment and risk characterisation. Examples for hazard identification are selection of substances relevant for a specific adverse outcome based on adverse outcome pathways and QSAR models. Examples for hazard characterisation are calculation of benchmark doses and relative potency factors with uncertainty from dose response data, and use of kinetic models to perform in vitro to in vivo extrapolation. Examples for exposure assessment are assessing cumulative exposure at external or internal level, where the latter option is needed when dietary and non-dietary routes have to be aggregated. Finally, risk characterisation is illustrated by calculation and display of the margin of exposure for single substances and for the cumulation, including uncertainties derived from exposure and hazard characterisation estimates.

Relative potency factor approach enables the use of in vitro information for estimation of human effect factors for nanoparticle toxicity in life-cycle impact assessment

The major theme of the NRC report “Toxicity Testing in the Twenty-first Century” is to replace animal testing by using alternative in vitro methods. Therefore, it can be expected that in the future in vivo data will be replaced with in vitro data. Hence, there is a need for new strategies to make use of the increasing amount of in vitro data when developing human toxicological effect factors (HEF) to characterize the impact category of human toxicity in life cycle assessment (LCA). Here, we present a new approach for deriving HEF for manufactured nanomaterials (MNMs) based on the combined use of in vitro toxicity data and a relative potency factor (RPF) approach. In vitro toxicity tests with nano-CuO, nano-Ag and nano-ZnO and their corresponding ions were performed on THP-1, CaCo-2 and Hep-G2 cell lines. The ratio of the here calculated EC50 of the ionic form and the nanoform corresponds to the Relative Potency Factor (RPF). Using this approach, HEFs (case/kgintake) for the aforementioned nanoparticles were obtained. Non-carcinogenic HEFs (case/kgintake) for exposure via ingestion of 5.9E-01, 7.5E-03 and 2.5 E-02 were calculated for nano-Ag, nano-CuO and nano-ZnO, respectively. The HEF values here proposed were compared with HEF values extrapolated from in vivo toxicity data reported in the literature. The here presented procedure is the most appropriate approximation currently available for using in vitro toxicity data on MNM for application in the field of LCIA.

Dietary exposure to neonicotinoid insecticides and health risks in the Chinese general population through two consecutive total diet studies

Neonicotinoid insecticides are ubiquitous in food and the environment due to their wide use. Growing evidence suggests the adverse effects of neonicotinoids in many species, including mammals. Some studies have reported the urinary concentrations of neonicotinoids in human biological monitoring, but the potential risks of neonicotinoids on human health based on long-term chronic exposure studies in any general population have been rarely tackled. In this study, the dietary exposure to neonicotinoids of the Chinese adult population was studied on the basis of composite dietary samples collected from the 5th (2009–2012) and 6th (2015–2018) Chinese total diet studies (TDS). Residue levels of ten neonicotinoids were determined in 528 composite dietary samples from 24 provinces in China. Most of the samples (53.3% and 70.5% in the 5th and 6th TDS, respectively) that we analyzed contained the multi-residue of neonicotinoids. Imidacloprid and acetamiprid were the most frequently detected neonicotinoids, and thiamethoxam and clothianidin were increasingly used and found in the 6th TDS. The estimated daily intake (EDI) for total neonicotinoids was calculated to evaluate health risk of the Chinese adult population based on a relative potency factor assessment method. The mean EDIs of total neonicotinoids in the 5th and 6th TDS respectively reached 598.95 and 710.38 ng/kg bw per day. Although the mean EDIs of total neonics in 6th TDS was relatively higher than that in 5th TDS, no statistical difference was observed (p > 0.05). Vegetables were the main source of dietary exposure, but exposure via cereals and beverages and water must also be addressed in China. Although the average exposure for total neonicotinoids was much lower than the current chronic reference dose (57 μg/kg bw per day), the dietary exposure risks of a general population for total neonicotinoids should not be overlooked due to the ubiquity of neonicotinoids in food and the environment.

Neonicotinoid insecticides in the drinking water system – Fate, transportation, and their contributions to the overall dietary risks

Neonicotinoids (Neonics) have become the most widely used insecticides around the world in recent years. Due to the hydrophilic character, neonics are emerging contaminants in drinking water. In this study, we aimed to characterize and quantify the fate and transport of neonics in the drinking water treatment system and their contributions to the overall dietary risks. Seven neonics in 97 surface and drinking water samples in the city of Hangzhou, China were analyzed. The relative potency factor method was adopted in order to calculate the total neonics concentrations. We then used the Monte Carlo simulation to calculate the chronic daily intake (CDI) of total neonics from water consumption. All 16 surface water samples collected from two rivers contained at least two neonics, and more than 93% of those contained 3 or more neonics. Imidacloprid was detected in all 16 surface water samples, followed by clothianidin and acetamiprid with average concentrations of 11.9, 7.6, 17.6 ng L-1, respectively. The drinking water treatment plants removed approximately 50% of neonics from surface water. However, 68 out of 71 tap water samples that we collected from the household faucets contained at least one neonic, with the highest average concentrations of 5.8 ng L-1 for acetamiprid. The maximum of CDIs of total neonics from water consumption for adult and children were 10.2 and 12.4 ng kg-1 d-1, respectively, which are significantly lower than the acceptable daily intake (ADI). The results presented here shown drinking water consumption only represented an insignificant portion of dietary risks of total neonics, mainly due to the modern drinking water treatment technologies that are capable of removing significant amount of neonics from drinking water. However, the ubiquity of neonics in the drinking water sources to kitchen faucets, should be a concern for public health.

Update of the risk assessment of di-butylphthalate (DBP), butyl-benzyl-phthalate (BBP), bis(2-ethylhexyl)phthalate (DEHP), di-isononylphthalate (DINP) and di-isodecylphthalate (DIDP) for use in food contact materials.

The EFSA Panel on Food Contact Materials, Enzymes and Processing Aids (CEP Panel) was asked by the European Commission to update its 2005 risk assessments of di‐butylphthalate (DBP), butyl‐benzyl‐phthalate (BBP), bis(2‐ethylhexyl)phthalate (DEHP), di‐isononylphthalate (DINP) and di‐isodecylphthalate (DIDP), which are authorised for use in plastic food contact material (FCM). Dietary exposure estimates (mean and high (P95)) were obtained by combining literature occurrence data with consumption data from the EFSA Comprehensive Database. The highest exposure was found for DINP, ranging from 0.2 to 4.3 and from 0.4 to 7.0 μg/kg body weight (bw) per day for mean and high consumers, respectively. There was not enough information to draw conclusions on how much migration from plastic FCM contributes to dietary exposure to phthalates. The review of the toxicological data focused mainly on reproductive effects. The CEP Panel derived the same critical effects and individual tolerable daily intakes (TDIs) (mg/kg bw per day) as in 2005 for all the phthalates, i.e. reproductive effects for DBP (0.01), BBP (0.5), DEHP (0.05), and liver effects for DINP and DIDP (0.15 each). Based on a plausible common mechanism (i.e. reduction in fetal testosterone) underlying the reproductive effects of DEHP, DBP and BBP, the Panel considered it appropriate to establish a group‐TDI for these phthalates, taking DEHP as index compound as a basis for introducing relative potency factors. The Panel noted that DINP also affected fetal testosterone levels at doses around threefold higher than liver effects and therefore considered it conservative to include it within the group‐TDI which was established to be 50 μg/kg bw per day, expressed as DEHP equivalents. The aggregated dietary exposure for DBP, BBP, DEHP and DINP was estimated to be 0.9–7.2 and 1.6–11.7 μg/kg bw per day for mean and high consumers, respectively, thus contributing up to 23% of the group‐TDI in the worst‐case scenario. For DIDP, not included in the group‐TDI, dietary exposure was estimated to be always below 0.1 μg/kg bw per day and therefore far below the TDI of 150 μg/kg bw per day. This assessment covers European consumers of any age, including the most sensitive groups. Based on the limited scope of the mandate and the uncertainties identified, the Panel considered that the current assessment of the five phthalates, individually and collectively, should be on a temporary basis.

Validity of using a relative potency factor approach for the risk management of dioxin-like polychlorinated naphthalenes.

Here, we characterized the dioxin-like activities of 42 polychlorinated naphthalenes (PCNs) and 6 technical Halowax formulations by using the DR-CALUX (dioxin-responsive chemically activated luciferase expression) assay with rat hepatoma luciferase-expressing H4IIE cells. Of the 42 PCNs examined, 31 showed dioxin-like activities, for which the mass-based REP-EC5TCDD (potency relative to that of 2,3,7,8-tetrachlorodibenzo-p-dioxin based on the 5% effective concentration determined from the dose-response curve for 2,3,7,8-TCDD) ranged from 0.00000012 to 0.0051, indicating that some of the PCNs (e.g., 1,2,3,6,7,8-HxCN and 1,2,3,4,6,7-HxCN) had dioxin-like activities that were equal to or higher than the WHO-TEFs and the mass-based REP-EC5TCDD reported for dioxins such as octachlorodibenzo-p-dioxin, octachlorodibenzofuran, 3,3',4,4'-tetrachlorobiphenyl (PCB-77), 3,4,4',5-tetrachlorobiphenyl (PCB-81), and 3,3',4,4',5,5'-hexachlorobiphenyl (PCB-169). For PeCNs to OCN with high dioxin-like activities, REPs determined in previous studies were comparable to the REP values obtained in the present study. The TCDD-EQs (2,3,7,8-TCDD equivalents) obtained experimentally for the Halowax formulations decreased in the order HW1051 (37mg/kg)>HW1014 (30mg/kg)>HW1013 (5.6mg/kg)>HW1099 (2.9mg/kg)>HW1001 (0.60mg/kg)>HW1031 (<0.10mg/kg) and were comparable to the theoretical TCDD-EQs calculated by multiplying the concentration and REP of each PCN. In addition, the theoretical TCDD-EQs for PCNs in emission gases produced by thermal processes were below the Japanese emission standard of 0.1-10ng WHO-toxicity equivalent (TEQ)/m3N, and 3 to 4 orders of magnitude lower than the corresponding WHO-TEQ. Based on a comparison of theoretical and experimental TCDD-EQs, we found that our REP-based approach was suitable for the risk management of industrially produced and unintentionally generated dioxin-like PCNs. This approach will be particularly useful for the risk management of unintentionally generated PCNs in emission gases because the contribution of dioxin-like PCNs to the whole dioxin-like toxicity of emission gases can be elucidated.

Structure-dependent hepato-cytotoxic potencies of selected pyrrolizidine alkaloids in primary rat hepatocyte culture

Contamination of food, feed and herbal medicines with plants containing pyrrolizidine alkaloids (PA) leads to measurable amounts of PA in many products. Since a number of PA are hepatotoxic in humans and animals and hepato-carcinogenic in animal experiments, the assessment of the relative toxic potencies of widely occurring PA contaminants warrants detailed investigation. Here, we studied the hepato-cytotoxic potencies of a number of relevant PA congeners in rat hepatocytes in primary culture. It was found that cyclic and open di-esters were much more toxic than mono-esters. Furthermore, the hepatocellular levels of cytochrome P450-catalyzed 7-benzoxyresorufin O-dealkylase (BROD) activity decreasing over time in culture, played an important role for activation of PA into cytotoxic metabolites. With a highly toxic PA (lasiocarpine), inhibition of BROD activity with ketoconazole markedly reduced toxicity while this was not obvious with the less toxic congener lycopsamine. Depletion of cellular glutathione with buthionine sulfoximine had no significant influence on the effects of highly toxic PA whereas it slightly increased toxicity of less potent congeners. Overall, our data partially confirm previously published structure-dependent interim Relative Potency (iREP) factors although for echimidine and monocrotaline in particular, substantial deviations were found, possibly due to specific toxicokinetic properties of these congeners.

Characterization of a multianalyte GC-MS/MS procedure for detecting and quantifying polycyclic aromatic hydrocarbons (PAHs) and PAH derivatives from air particulate matter for an improved risk assessment

A correct description of the concentration and distribution of particle bound polycyclic aromatic hydrocarbons is important for risk assessment of atmospheric particulate matter. A new targeted GC-MS/MS method was developed for analyzing 64 PAHs including compounds with a molecular weight >300, as well as nitro-, methyl-, oxy- and hydroxyl derivatives in a single analysis. The instrumental LOD ranged between 0.03 and 0.7 pg/μL for PAHs, 0.2–7.9 pg/μL for hydroxyl and oxy PAHs, 0.1–7.4 pg/μL for nitro PAHs and 0.06–0.3 pg/μL for methyl-PAHs. As an example for the relevance of this method samples of PM10 were collected at six sampling sites in Medellin, Colombia, extracted and the concentration of 64 compounds was determined. The 16 PAHs from the EPA priority list contributed only from 54% to 69% to the sum of all analyzed compounds, PAH with high molecular weight accounted for 8.8%–18.9%. Benzo(a)pyrene equivalents (BaPeq) were calculated for the estimation of the life time cancer (LCR). The LCR according to the samples ranged from 2.75 × 10−5 to 1.4 × 10−4 by a calculation with toxic equivalent factors (TEF) and 5.7 × 10−5 to 3.8 × 10−4 with potency equivalent factor (PEF). By using the new relative potency factors (RPF) recommended by US Environmental Protection Agency (U.S.EPA) the LCR ranged from 1.3 × 10−4 to 7.2 × 10−4. Hence, it was around six times higher than the well-known TEF. The novel method enables the reliable quantification of a more comprehensive set of PAHs bound on PM and thus will facilitate and improve the risk assessment of them.

Neonicotinoids and carbendazim in indoor dust from three cities in China: Spatial and temporal variations

Neonicotinoid insecticides (NNIs) are a relatively new class of insecticides, and carbendazim (CBDZ) is a representative antifungal biocide. The occurrence of them in indoor dust was not documented in China. In this study, 336 indoor dust samples were collected from 3 cities, including Taiyuan (October 2016), Wuhan (October 2016 and 2018), and Shenzhen (February 2019), located in North, Central, and South China, for determination of the residues of six NNIs, two of their metabolites, and CBDZ. Acetamiprid (ACE), imidacloprid (IMI), and CBDZ were found to be the major target analytes in dust samples from all selected cities with detection frequencies of 98.8%, 99.7%, and 95.2%, respectively. At least one target NNI was detected for all of the dust samples, with the median concentration of 25.8 ng/g for the imidacloprid-equivalent total neonicotinoids (IMIeq: generated by the relative potency factor method), and the median for CBDZ was 35.8 ng/g. Higher levels of several NNIs and CBDZ were found in urban areas of Taiyuan and Wuhan than those in rural areas. A significant increase of the NNI residues was observed in dust of Wuhan from 2016 to 2018 (while not significant for CBDZ). Finally, the estimated daily intake (EDI) of IMIeq and CBDZ for infants and toddlers were higher than that found in other age groups through dust ingestion, which indicated that infants and toddlers may be susceptible to current residue of NNIs and CBDZ in indoor dust, and dust ingestion of NNIs might be <1% of that reported for dietary intakes in China. This is the first study to report the residue levels of NNIs and CBDZ in dust samples from indoor environment in China.

Receptor-mediated potencies of polycyclic aromatic hydrocarbons in urban sediments: comparisons of toxic equivalency risk assessment

The Klip River, flowing through South Africa’s most populated urban area—Soweto and Lenasia—is subject to various pollution and anthropogenic influences, including great concentrations of polycyclic aromatic hydrocarbons. The aims were to determine the aryl-hydrocarbon receptor-mediated potencies of the 16 priority polycyclic aromatic hydrocarbons in sediments of the Klip River, using chemical- and bio-analytical assessments of hazard, and to compare these results with international sediment quality guidelines. Sediment samples were collected from nine sites during the dry seasons of 2013 and 2014. Two sets of toxic equivalents were calculated from analytically obtained polycyclic aromatic hydrocarbon concentrations using: (1) 2,3,7,8-tetrachlorodibenzo-p-dioxin equivalency factors and (2) relative potency factors for fish. The fraction of the sediment extracts containing polycyclic aromatic hydrocarbons was assayed with the H4IIE-luc reporter gene bio-assay, and the aryl-hydrocarbon receptor potency expressed as bio-assay equivalents. The bio-assay equivalents and tetrachlorodibenzo-p-dioxin equivalency factors were compared to Canadian sediment quality guidelines and of the three approaches, the bio-assay equivalents and the relative potency factors for fish proved the most protective. Results of this study are proof of the utility of combining biological analysis with instrumental analysis when predicting hazard. Even though there were instances where the bio-assay equivalents were orders of magnitude greater than the tetrachlorodibenzo-p-dioxin equivalency factors, the results still showed similar trends. It was concluded that hazard from aryl-hydrocarbon receptor-mediated potency to adversely affect aquatic organisms in the Klip River was relatively great, which indicated the need for further investigation into possible mitigations.

Burden of disease at the same limit of exposure to airborne polycyclic aromatic hydrocarbons varies significantly across countries depending on the gap in longevity

Atmospheric polycyclic aromatic hydrocarbons (PAHs) disproportionately affect human health across the globe, and differential exposure is believed to drive the unequal health burden. Therefore, this study assessed and compared the burden of disease, in disability-adjusted life years (DALYs), at the same level (or limit) of exposure to atmospheric PAHs in nine countries. We calculated the DALYs per person-year per ng/m3 of benzo[a]pyrene from ten cancers and thirty-four non-cancer adverse outcomes using published toxicity information and country-specific disease severity. Exposure duration was averaged over 30 years and we adjusted for early-life vulnerability to cancer. The DALYs per person-year per ng/m3 of fifteen other individual PAHs was calculated using relative potency factors, and toxicity factors derived from quantitative structure-activity relationships. We found that even at the same level of exposure to PAHs, the incremental burdens of disease varied substantially across countries. For instance, they varied by about 2–3 folds between Nigeria and the USA. Countries having the lowest longevity had the highest DALYs per person-year per ng/m3 of each PAH. Kruskal-Wallis test (α = 0.05) showed that the variation across countries was significant. The post hoc tests detected a significant difference between two countries when the gap in longevity was >10 years. This suggests that countries having very low average life expectancy require more stringent PAH limit. Linear or exponential function of average longevity gave valid approximation of the DALYs per person-year per ng/m3 of benzo[a]pyrene or phenanthrene, respectively. Furthermore, we used global gridded surface benzo[a]pyrene concentrations and global population dataset for 2007, with spatial resolution of 0.1° × 0.1°, to calculate the contribution of differential exposures to the estimated DALYs per person-year. We found that in six out of nine countries, differential exposures to PAH contribute less to the estimated health loss than differential severities of the diseases. This indicates that the risk to health from PAHs may be underreported if the severities of the diseases in the countries are not considered.

Neonicotinoid insecticides in surface water from the central Yangtze River, China

Neonicotinoid insecticides (NNIs) are extensively used insecticides worldwide, yet the data on NNIs residues in the Yangtze River, China is scarce. Occurrence and distribution of six NNIs and a metabolite (desmethyl-acetamiprid) in surface water were investigated in the central Yangtze River, China at 20 sites from March to July and September 2015. Acetamiprid (ACE), imidacloprid (IMI) and thiamethoxam (THM) were the most frequently detected NNIs and IMI had a highest median concentration of 4.37 ng/L, followed by ACE (2.50 ng/L), THM (1.10 ng/L), nitenpyram (NTP; 0.34 ng/L), clothianidin (CLO; 0.10 ng/L), and thiacloprid (THCP; 0.02 ng/L). Significantly higher concentrations and detection frequencies of NNIs were observed in the summer than in the spring, which may be explained by the heavier precipitation in summer. Spatial variation with higher levels among the lower sites than the upper sites may be related with the agriculture land use. NNI contamination presented a low risk to aquatic life according to the risk quotient method, while IMI had potential risk to aquatic life according to the threshold of IMI (8.3 ng/L) in freshwater recommended in Netherland. Using the relative potency factors method for chronic cumulative risk assessment for NNIs, potential exposure to NNIs through water ingestion are three orders of magnitude lower than the recommended relative chronic reference dose. Ongoing environmental monitoring of NNIs is needed due to the increase use of NNIs in China.

A national-scale cumulative exposure assessment of organophosphorus pesticides through dietary vegetable consumption in China

Using the data from the “Agro-product Quality and Safety Risk Monitoring Plan” of the Ministry of Agriculture of China between 2012 and 2016, acute and chronic risk assessments of cumulative exposure to organophosphorus pesticides (OPPs) through vegetable consumption were conducted. The concentrations of 19 OPPs were measured in a total of 75,655 vegetable samples from urban and rural sites located in 31 provinces and covering 95 vegetable raw agricultural commodities (RACs). The results showed that 4989 samples (6.59%) contained at least one OPP and that 615 samples (0.81%) contained various combinations of OPPs. From the multiexposure data, the cumulative exposure was estimated for 19 OPPs using an equivalence approach, where the contribution of each OPP was calculated according to its measured concentration and its relative potency factor (RPF) with respect to acetylcholinesterase (AChE) inhibition of the index compound methamidophos. The cumulative exposure levels of OPPs were compared across ten age and sex subpopulation groups of Chinese under lower boundary (LB) and upper boundary (UB) scenarios to handle left-censored residue data. The highest cumulative exposure level of OPPs was observed in the subpopulation of children aged 2–7 years under the UB scenario. The P99.9 and P97.5 exposure levels in different subpopulation groups under both LB and UB scenarios did not exceed the acute reference dose (ARfD) or chronic acceptable daily intake (ADI) of methamidophos, respectively. This study is the first to investigate the cumulative exposure of OPPs in relation to neurotoxic health risks in China on the national level.

An integrated assessment and spatial-temporal variation analysis of neonicotinoids in pollen and honey from noncrop plants in Zhejiang, China

Recent studies have shown that neonicotinoids in pollen and honey (collected by honeybees) are likely to pose risks to honeybees. However, data on the integrated residue and spatial-temporal variation of neonicotinoids from noncrop plants, the principle sources of pollen for honey bees, are very limited, especially in China. In this study, we employed a novel assessment method based on the relative potency factor to calculate the integrated residue of seven neonicotinoids in pollen and honey samples collected from noncrop plants in 12 stations of Zhejiang province in three consecutive months. The integrated concentration of neonicotinoids (IMIRPF) ranged from no detected (ND) to 34.93 ng/g in pollen and ND to 8.51 ng/g in honey. Acetamiprid showed the highest detection frequency of 41.7%, followed by clothianidin (33.3%) and dinotefuran (22.2%). The highest IMIRPF occurred in April for stations in the fringe areas of Zhejiang province, whereas for stations in the central areas of Zhejiang province, the IMIRPF in May was relatively higher than the other two months. In terms of spatial change, the pollution variation of pollen samples in Lin'an—Tonglu—Pujiang was relative highly polluted—lightly polluted—highly polluted. For honey samples, spatial variation showed a single trend, and peak values were found in Wenzhou, which may be attributed to the local climate and farming practices. This fundamental information will be helpful to understand the effects of neonicotinoids on honeybees foraging habits.