Benchmark Dose Research Articles

Benchmark dose in the presence of co-exposure to melamine and di-(2-ethylhexyl) phthalate and urinary renal injury markers in pregnant women

Benchmark dose in the presence of co-exposure to melamine and di-(2-ethylhexyl) phthalate and urinary renal injury markers in pregnant women

Exploring the relationship between blood toxic metal(oid)s and serum insulin levels through benchmark modelling of human data: Possible role of arsenic as a metabolic disruptor

The major goal of this study was to estimate the correlations and dose-response pattern between the measured blood toxic metals (cadmium (Cd), mercury (Hg), chromium (Cr), nickel (Ni))/metalloid (arsenic (As)) and serum insulin level by conducting Benchmark dose (BMD) analysis of human data. The study involved 435 non-occupationally exposed individuals (217 men and 218 women). The samples were collected at health care institutions in Belgrade, Serbia, from January 2019 to May 2021. Blood sample preparation was conducted by microwave digestion. Cd was measured by graphite furnace atomic absorption spectrophotometry (GF-AAS), while inductively coupled plasma-mass spectrometry (ICP-MS) was used to measure Hg, Ni, Cr and As. BMD analysis of insulin levels represented as quantal data was done using the PROAST software version 70.1 (model averaging methodology, BMD response: 10%). In the male population, there was no correlation between toxic metal/metalloid concentrations and insulin level. However, in the female population/whole population, a high positive correlation for As and Hg, and a strong negative correlation for Ni and measured serum insulin level was established. BMD modelling revealed quantitative associations between blood toxic metal/metalloid concentrations and serum insulin levels. All the estimated BMD intervals were wide except the one for As, reflecting a high degree of confidence in the estimations and possible role of As as a metabolic disruptor. These results indicate that, in the case of As blood concentrations, even values higher than BMD (BMDL): 3.27 (1.26) (male population), 2.79 (0.771) (female population), or 1.18 (2.96) μg/L (whole population) might contribute to a 10% higher risk of insulin level alterations, meaning 10% higher risk of blood insulin increasing from within reference range to above reference range. The obtained results contribute to the current body of knowledge on the use of BMD modelling for analysing human data.

Human exposure to ochratoxin A and its natural occurrence in spices marketed in Chile (2016–2020): A case study of merkén

The potential ingestion of food products contaminated with ochratoxin A (OTA) is cause of concern for public health. Currently, several detection methods are available to detect OTA in singles spices but not in spice mixtures such as merkén. The present study modified, optimized, and validated a method for successful OTA quantification in merkén, paprika, and chili. A total of 321 merkén (n: 256), paprika (n: 39), and chili (n: 26) samples were collected from different retail locations in Chile over a 5-year period (2016–2020). OTA levels were determined by high performance liquid chromatography with fluorescence detection (HPLC-FLD). Validation parameters that included the limit of detection (LOD: 0.3 ng g−1), limit of quantification (LOQ: 1.0 ng g−1), linearity (0.9975), recovery in a fortified blank matrix (5 ng g−1: 81–105%), and relative standard deviation (RSD: 0.49–6.87%) were satisfactory. The presence of OTA in merkén, paprika, and chili samples was 66%, 59%, and 61%, respectively. Maximum OTA levels in merkén, paprika, and chili exceeded the limit established by national regulations of 5 ng g−1 by 77-fold (387.9 ng g−1), 59-fold (297 ng g−1), and 14-fold (71.6 ng g−1), respectively. The estimated daily intake (EDI) values were considerably higher in 2017 than 2020 (paprika ˃ chili ˃ merkén). The EDI values were also lower than the Benchmark dose level (BMDL10; 4730 ng kg−1 bw day) for non-neoplastic effects. Our study pinpointed the importance for continuously monitoring and regulating the OTA contamination in agricultural commodities such as spices. More investigations should be generated to modify the current regulation of OTA in spices.

Benchmark dose estimation based on Bayesian model averaging and its application to evaluation of cadmium exposure of population in Baiyin

Benchmark dose estimation based on Bayesian model averaging and its application to evaluation of cadmium exposure of population in Baiyin

P22-12 Benchmark dose response modelling of gene co-expression networks in hepatocytes exposed to known inducers of liver steatosis, cholestasis and necrosis

P22-12 Benchmark dose response modelling of gene co-expression networks in hepatocytes exposed to known inducers of liver steatosis, cholestasis and necrosis

Bayesian Concentration Ratio and Dissonance

We propose two new classes of Bayesian measure to investigate conflict among data sets from multiple studies. The first (“concentration ratio”) is used to quantify the amount of information provided by a single data set through the comparison of the prior and its posterior distribution, or two data sets according to their corresponding posterior distributions. The second class (“dissonance”) quantifies the extent of contradiction between two data sets. Both classes are based on volumes of highest density regions. They are well calibrated, supported by simulation, and computational algorithms are provided for their calculation. We illustrate these two classes in three real data applications: a benchmark dose toxicology study, a missing data study related to health effects of pollution, and a pediatric cancer study leveraging adult data.

Hematological Effects and Benchmark Doses of Long-Term Co-Exposure to Benzene, Toluene, and Xylenes in a Follow-Up Study on Petrochemical Workers.

Benzene, toluene, and xylenes (BTX) commonly co-exist. Exposure to individual components and BTX-rich mixtures can induce hematological effects. However, the hematological effects of long-term exposure to BTX are still unclear, and respective reference levels based on empirical evidence should be developed. We conducted a follow-up study in BTX-exposed petrochemical workers. Long-term exposure levels were quantified by measuring cumulative exposure (CE). Generalized weighted quantile sum (WQS) regression models and Benchmark Dose (BMD) Software were used to evaluate their combined effects and calculate their BMDs, respectively. Many hematologic parameters were significantly decreased at the four-year follow-up (p < 0.05). We found positive associations of CE levels of benzene, toluene, and xylene with the decline in monocyte counts, lymphocyte counts, and hematocrit, respectively (β > 0.010, Ptrend < 0.05). These associations were stronger in subjects with higher baseline parameters, males, drinkers, or overweight subjects (Pinteraction < 0.05). BTX had positive combined effects on the decline in monocyte counts, red-blood-cell counts, and hemoglobin concentrations (Ptrend for WQS indices < 0.05). The estimated BMDs for CE levels of benzene, toluene, and xylene were 2.138, 1.449, and 2.937 mg/m3 × year, respectively. Our study demonstrated the hematological effects of long-term BTX co-exposure and developed 8h-RELs of about 0.01 ppm based on their hematological effects.

Benchmark dose in the presence of coexposure to melamine and diethylhexyl phthalate and urinary renal injury markers in pregnant women

Environmental exposures to mixtures of toxic chemicals have potential interaction effects that may lead to hazard index values exceeding one. However, current regulation levels, such as tolerable daily intake (TDI), are mostly based on experimental studies conducted with a single chemical compound. In this study, we assessed the relationships between melamine and di-(2-ethylhexyl) phthalate (DEHP) exposure and their coexposure with the early renal injury markers N-acetyl -D-glucosaminidase (NAG), albumin/creatinine ratio (ACR), and microalbuminuria in 1236 pregnant women. Various generalized linear models with interaction terms and Bayesian kernel machine regression models were used for the (co-)exposure response associations. We derived the benchmark dose (BMD) and the corresponding one-sided 95% confidence bound BMDL based on the estimated (covariate-adjusted) average daily intake of melamine and DEHP metabolites measured in spot urine of the women collected during the third trimester. Given a benchmark response of 0.1, the BMDL level of melamine (DEHP) exposure on NAG (ACR, microalbuminuria) was 2.67 (11.20, 4.45) μg/kg_bw/day, and it decreased to as low as 1.46 (3.83, 2.73) μg/kg_bw/day when considering coexposure to DEHP (melamine) up to the 90th percentile. Both the exposure threshold levels of melamine and DEHP for early renal injuries in pregnant women were several-fold to one order lower than the current recommended TDIs by the WHO and the US FDA and EPA and were even lower considering coexposure. Because of concurrent exposures in real-world environments, more stringent regulation levels are recommended in susceptible populations, such as pregnant women, due to potential synergistic mixture effects.

Evaluating the influences of confounding variables on benchmark dose using a case study in the field of ionizing radiation

Purpose A vast amount of data regarding the effects of radiation stressors on transcriptional changes has been produced over the past few decades. These data have shown remarkable consistency across platforms and experimental design, enabling increased understanding of early molecular effects of radiation exposure. However, the value of transcriptomic data in the context of risk assessment is not clear and represents a gap that is worthy of further consideration. Recently, benchmark dose (BMD) modeling has shown promise in correlating a transcriptional point of departure (POD) to that derived using phenotypic outcomes relevant to human health risk assessment. Although frequently applied in chemical toxicity evaluation, our group has recently demonstrated application within the field of radiation research. This approach allows the possibility to quantitatively compare radiation-induced gene and pathway alterations across various datasets using BMD values and derive meaningful biological effects. However, before BMD modeling can confidently be used, an understanding of the impact of confounding variables on BMD outputs is needed. Methods To this end, BMD modeling was applied to a publicly available microarray dataset (Gene Expression Omnibus #GSE23515) that used peripheral blood ex-vivo gamma-irradiated at 0.82 Gy/min, at doses of 0, 0.1, 0.5 or 2 Gy, and assessed 6 hours post-exposure. The dataset comprised six female smokers (F-S), six female nonsmokers (F-NS), six male smokers (M-S), and six male nonsmokers (M-NS). Results A combined total of 412 genes were fit to models and the BMD distribution was noted to be bi-modal across the four groups. A total of 74, 41, 62 and 62 genes were unique to the F-NS, M-NS, F-S and M-S groups. Sixty-two BMD modeled genes and nine pathways were common across all four groups. There were no differential sensitivity of BMD responses in the robust common genes and pathways. Conclusion For radiation-responsive genes and pathways common across the study groups, the BMD distribution of transcriptional activity was unaltered by sex and smoking status. Although further validation of the data is needed, these initial findings suggest BMD values for radiation relevant genes and pathways are robust and could be explored further in future studies.

Benchmark dose modeling of transcriptional data: a systematic approach to identify best practices for study designs used in radiation research

Purpose Benchmark dose (BMD) modeling is a method commonly used in chemical toxicology to identify the point of departure (POD) from a dose-response curve linked to a health-related outcome. Recently, its application in the analysis of transcriptional data for quantitative adverse outcome pathway (AOP) development is being explored. As AOPs are informed by diverse data types, it is important to understand the impact of study parameters such as dose selection, the number of replicates and dose range on BMD outputs for radiation-induced genes and pathways. Materials and methods Data were selected from the Gene Expression Omnibus (GSE52403) that featured gene expression profiles of peripheral blood samples from C57BL/6 mice 6 hours post-exposure to 137Cs gamma-radiation at 0, 1, 2, 3, 4.5, 6, 8 and 10.5 Gy. The dataset comprised a broad dose range over multiple dose points with consistent dose spacing and multiple biological replicates. This dataset was ideal for systematically transforming across three categories: (1) dose range, (2) dose-spacing and (3) number of controls/replicates. Across these categories, 29 transformed datasets were compared to the original dataset to determine the impact of each transformation on the BMD outputs. Results Most of the experimental changes did not impact the BMD outputs. The transformed datasets were largely consistent with the original dataset in terms of the number of reproduced genes modeled and absolute BMD values for genes and pathways. Variations in dose selection identified the importance of the absolute value of the lowest and second dose. It was determined that dose selection should include at least two doses <1 Gy and two >5 Gy to achieve meaningful BMD outputs. Changes to the number of biological replicates in the control and non-zero dose groups impacted the overall accuracy and precision of the BMD outputs as well as the ability to fit dose-response models consistent with the original dataset. Conclusion Successful application of transcriptomic BMD modeling for radiation datasets requires considerations of the exposure dose and the number of biological replicates. Most important is the selection of the lowest doses and dose spacing. Reflections on these parameters in experimental design will provide meaningful BMD outputs that could correlate well to apical endpoints of relevance to radiation exposure assessment.

Development of a cell line-based in vitro assay for assessment of Diphtheria, Tetanus and acellular Pertussis (DTaP)-induced inflammasome activation

Safety and potency assessment for batch release testing of established vaccines still relies partly on animal tests. An important avenue to move to batch release without animal testing is the consistency approach. This approach is based on thorough characterization of the vaccine to identify critical quality attributes that inform the use of a comprehensive set of non-animal tests to release the vaccine, together with the principle that the quality of subsequent batches follows from their consistent production. Many vaccine antigens are by themselves not able to induce a protective immune response. The antigens are therefore administered together with adjuvant, most often by adsorption to aluminium salts. Adjuvant function is an important component of vaccine potency, and an important quality attribute of the final product. Aluminium adjuvants are capable of inducing NLRP3 inflammasome activation. The aim of this study was to develop and evaluate an in vitro assay for NLRP3 inflammasome activation by aluminium-adjuvanted vaccines. We evaluated the effects of Diphtheria-Tetanus-acellular Pertussis combination vaccines from two manufacturers and their respective adjuvants, aluminium phosphate (AP) and aluminium hydroxide (AH), in an in vitro assay for NLRP3 inflammasome activation. All vaccines and adjuvants tested showed a dose-dependent increase in IL-1β production and a concomitant decrease in cell viability, suggesting NLRP3 inflammasome activation. The results were analysed by benchmark dose modelling, showing a similar 50% effective dose (ED50) for the two vaccine batches and corresponding adjuvant of manufacturer A (AP), and a similar ED50 for the two vaccine batches and corresponding adjuvant of manufacturer B (AH). This suggests that NLRP3 inflammasome activation is determined by the adjuvant only. Repeated freeze-thaw cycles reduced the adjuvant biological activity of AH, but not AP. Inflammasome activation may be used to measure adjuvant biological activity as an important quality attribute for control or characterization of the adjuvant.

The Gut Microbial Metabolite Pyrogallol Is a More Potent Inducer of Nrf2-Associated Gene Expression Than Its Parent Compound Green Tea (-)-Epigallocatechin Gallate.

(-)-Epigallocatechin gallate (EGCG) has been associated with multiple beneficial effects. However, EGCG is known to be degraded by the gut microbiota. The present study investigated the hypothesis that microbial metabolism would create major catechol-moiety-containing microbial metabolites with different ability from EGCG to induce nuclear factor-erythroid 2-related factor 2 (Nrf2)-mediated gene expression. A reporter gene bioassay, label-free quantitative proteomics and reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) were combined to investigate the regulation of Nrf2-related gene expression after exposure of U2OS reporter gene or Hepa1c1c7 cells in vitro to EGCG or to its major microbial catechol-moiety-containing metabolites: (-)-epigallocatechin (EGC), gallic acid (GA) and pyrogallol (PG). Results show that PG was a more potent inducer of Nrf2-mediated gene expression than EGCG, with a 5% benchmark dose (BMD5) of 0.35 µM as compared to 2.45 µM for EGCG in the reporter gene assay. EGC and GA were unable to induce Nrf2-mediated gene expression up to the highest concentration tested (75 µM). Bioinformatical analysis of the proteomics data indicated that Nrf2 induction by PG relates to glutathione metabolism, drug and/or xenobiotics metabolism and the pentose phosphate pathway. Taken together, our findings demonstrate that the microbial metabolite PG is a more potent inducer of Nrf2-associated gene expression than its parent compound EGCG.

Reproductive and developmental toxicity of perfluorooctane sulfonate (PFOS) in the white-footed mouse (Peromyscus leucopus)

Concerns about per- and polyfluoroalkyl substances (PFAS) stem from their ubiquitous presence in the environment, bioaccumulation, resistance to degradation, and toxicity. Previously, toxicity data relevant to ecological risk assessment has largely been aquatic, terrestrial invertebrates, or avian in origin. In this study, repeated oral exposures of perfluorooctane sulfonate (PFOS) were administered to white-footed mice (Peromyscus leucopus) to evaluate effects on reproduction and development. Prenatal exposure to high doses of PFOS caused neonatal mortality, though growth and development were unaffected by low doses. Additionally, parental (P) generation animals exhibited increased liver:body weight, increased hepatocyte cytoplasmic vacuolization, and decreased serum thyroxine (T4) levels. Total litter loss was selected as the protective critical effect in this study resulting in a benchmark dose low (BMDL) of 0.12 mg/kg-d PFOS. Importantly, PFOS exposure has been linked to reduced adult recruitment in myriad species and at similar thresholds to this study. Similarities in critical/toxicologic effects across taxa may add confidence in risk assessments at sites with multiple taxa or environments.

Influence of mercury on thyroid hormone levels in the Serbian population - Benchmark dose approach

Influence of mercury on thyroid hormone levels in the Serbian population - Benchmark dose approach

Toxicity and toxicokinetics of the ethanol extract of Zuojin formula

BackgroundZuojin formula, a traditional Chinese medicine, comprises Coptis chinensis and Evodia rutaecarpa. In our previous study, the total alkaloid extract from Zuojin formula (TAZF) showed potent and improved efficacy. However, its safety and toxicokinetics remain unknown. The objective of this study was to evaluate the safety of repeated administrations of TAZF and investigate the internal exposure of the main components and its relationship with toxic symptoms.MethodsSprague–Dawley rats were orally administered TAZF at 0.4, 1.2 and 3.7 g/kg for 28 days, which was followed by a 14-day recovery period. The toxic effects were evaluated weekly by assessing body weight changes, food intake, blood biochemistry and haematological indices, organ weights and histological changes. A total of eight components were detected, including berberine, coptisine, epiberberine, palmatine, jatrorrhizine, columbamine, evodiamine, and rutaecarpine. The toxicokinetic profiles of the eight components were investigated after single and repeated administrations. Linear mixed effect models were applied to analyse the associations between internal exposure and toxic symptoms. Network pharmacology analysis was applied to explore the potential toxic mechanisms.ResultsCompared with the vehicle group, the rats in the low- and medium-dose groups did not show noticeable abnormal changes, while rats in the high-dose group exhibited inhibition of weight gain, a slight reduction in food consumption, abdominal bloating and atrophy of the splenic white pulp during drug administration. The concentration of berberine in plasma was the highest among all compounds. Epiberberine was found to be associated with the inhibition of weight gain. Network pharmacology analysis suggested that the alkaloids might cause abdominal bloating by affecting the proliferation of smooth muscle cells. The benchmark dose lower confidence limits (based on body weight inhibition) of TAZF were 1.27 g/kg (male) and 1.91 g/kg (female).ConclusionsTAZF has no notable liver or kidney toxicity but carries risks of gastrointestinal and immune toxicity at high doses. Alkaloids from Coptis chinensis are the main plasma components related to the toxic effects of TAZF.

Acute and sub-acute oral toxicity assessment of 5-hydroxy-1,4-naphthoquinone in mice

5-hydroxy-1,4-naphthoquinone (5NQ) or juglone is a bioactive molecule found in walnuts and has shown therapeutic effects in various disease models. Limited information is available regarding the toxicity of 5NQ, thereby limiting the clinical development of this drug. In the present study, oral acute (50, 300 and 2000 mg/kg) and sub-acute toxicity (5, 15 and 50 mg/kg) was assessed in mice to evaluate the safety of 5NQ. The acute toxicity study identified 118 mg/kg as the point-of-departure dose (POD) for single oral administration of 5NQ using benchmark dose modeling (BMD). Repeated administration of 5NQ at doses of 15 and 50 mg/kg/day caused reduction in food consumption and body weight of mice along with alterations in liver and renal function. Histopathological assessment revealed significant damage to hepatic and renal tissues at all doses in the acute toxicity study, and at higher doses of 15 and 50 mg/kg in the sub-acute toxicity study. We observed dose dependent mortality in sub-acute toxicity study and the no observed adverse effect level (NOAEL) was established as < 5 mg/kg/day. Modeling the survival response in sub-acute toxicity study identified 1.74 mg/kg/day as the POD for repeated administration of 5NQ. Serum levels of aspartate aminotransferase (AST) were most sensitive to 5NQ administration with a lower limit of BMD interval (BMDL) of 1.1 × 10−3 mg/kg/day. The benchmark doses reported in the study can be further used to determine a reference dose of 5NQ for human risk assessment.

Using the BMD Approach to Derive Acceptable Daily Intakes of Cannabidiol (CBD) and Tetrahydrocannabinol (THC) Relevant to Electronic Cigarette Liquids.

In the past 60 years, Cannabis sativa L. has been an object of increasing interest because of the psychotropic effects of some of its constituents. These effects mainly arise from the cannabinoid Δ9-tetrahydrocannabinol (Δ9-THC). C. sativa species also synthesize and accumulate the non-psychotropic compound cannabidiol (CBD). Due to their therapeutic potential, both cannabinoids are an object of medical research and drug development. More recently, CBD has received increasing interest as an ingredient in electronic cigarette liquids (e-liquids). This trend may have been reinforced by health and disease-related claims, often based on clinical studies, which are used to advertise CBD. CBD liquids may be based on full-spectrum hemp extracts, CBD isolates, or synthetic CBD, all of which may contain some residual levels of Δ9-THC from either natural content (in the extracts) or from possible degradation of CBD to Δ9-THC, which may occur during storage. There is uncertainty about safety regarding the consumption of CBD (and Δ9-THC) in e-liquids. The aim of this publication was to present an approach for a toxicological risk assessment of CBD and Δ9-THC relevant to e-liquids by using the benchmark dose (BMD) approach. Before an analysis to estimate a reference dose (RfD) for both cannabinoids, a systematic review of dose-response data was conducted. The data obtained were analyzed using the BMD approach to derive a benchmark dose lower confidence limit (BMDL). The BMDL was used as a point of departure to estimate the RfD. No adequate human data suitable for dose-response modeling were identified. Based on animal data, the RfD values for the most sensitive endpoints were selected. For CBD, an RfD for acute exposure of 1 mg/kg body weight (bw) was estimated. For Δ9-THC, an acute RfD was found to be 0.006 mg/kg bw. Additionally, the RfD for chronic exposure to CBD was estimated to be 4 mg/kg bw per day. The respective endpoints for CBD were a reduction in norepinephrine turnover and a reduction in uterus weight. The endpoint for Δ9-THC was a change in blood pressure. Because of the limited availability and quality of dose-response data, it cannot be excluded that the estimated RfD values might be afflicted with considerable uncertainties. Therefore, it is recommended to conduct further research on dose-response data, preferably from human studies.

A preliminary cumulative risk assessment of Diethylhexyl phthalate and Dibutyl phthalate based on the inhibition of embryonic development via the PPARγ pathway

BackgroundDiethylhexyl phthalate (DEHP) and dibutyl phthalate (DBP) are the two most widely used plasticizers (PAEs) that may act as endocrine disruptors and cause developmental toxicity. MethodsWe measured intrauterine exposure to DEHP and DBP which are the two most widely used phthalates (PAEs) in the cord blood of 50 postpartum women using ultra-HPLC-tandem mass spectrometry and solid-phase extraction. The embryotoxicity of DEHP and DBP was evaluated using the human embryonic stem cell test (hEST). Based on the intrauterine exposure concentration of DEHP and DBP in pregnant women and the reference point of toxic effects in hEST, we used the reference point index (RPI) method to assess the cumulative risk of DBP and DEHP. ResultsThe mean concentrations of DEHP and DBP were 99.9 μg/L and 24.7 μg/L, respectively. DEHP and DBP were weakly embryotoxic, and the benchmark dose lower confidence intervals were 29.99 and 0.99 μg/mL, respectively, as determined using hEST. Both DEHP and DBP inhibited embryonic development via PPAR/PTEN/Akt signal pathway. ConclusionThe findings suggest that the cumulative risk in pregnant women with a high level of exposure should receive more attention in the future.

Characterization of benzo[a]pyrene and colchicine based on an in vivo repeat-dosing multi-endpoint genotoxicity quantitative assessment platform.

Two prototypical genotoxicants, benzo[a]pyrene (B[a]P) and colchicine (COL), were selected as model compounds to deduce their quantitative genotoxic dose-response relationship at low doses in a multi-endpoint genotoxicity assessment platform. Male Sprague-Dawley rats were treated with B[a]P (2.5-80 mg/kg bw/day) and COL (0.125-2 mg/kg bw/day) daily for 28 days. The parameters included were as follows: comet assay in the peripheral blood and liver, Pig-a gene mutation assay in the peripheral blood, and micronucleus test in the peripheral blood and bone marrow. A significant increase was observed in Pig-a mutant frequency in peripheral blood for B[a]P (started at 40 mg/kg bw/day on Day 14, started at 20 mg/kg bw/day on Day 28), whereas no statistical difference for COL was observed. Micronucleus frequency in reticulocytes of the peripheral blood and bone marrow increased significantly for B[a]P (80 mg/kg bw/day on Day 4, started at 20 mg/kg bw/day on Days 14 and 28 in the blood; started at 20 mg/kg bw/day on Day 28 in the bone marrow) and COL (started at 2 mg/kg bw/day on Day 14, 1 mg/kg bw/day on Day 28 in the blood; started at 1 mg/kg bw/day on Day 28 in the bone marrow). No statistical variation was found in indexes of comet assay at all time points for B[a]P and COL in the peripheral blood and liver. The dose-response relationships of Pig-a and micronucleus test data were analyzed for possible point of departures using three quantitative approaches, i.e., the benchmark dose, breakpoint dose, and no observed genotoxic effect level. The practical thresholds of the genotoxicity of B[a]P and COL estimated in this study were 0.122 and 0.0431 mg/kg bw/day, respectively, and our results also provided distinct genotoxic mode of action of the two chemicals.

Arsenic species and their health risks in edible seaweeds collected along the Chinese coastline

Edible seaweeds with a relatively high total arsenic concentration have been a global concern. As the largest seaweed producer, China contributes about 60 % of the global seaweed production. The present study investigated 20 seaweed species collected from representative seaweed farming sites in the six provinces along the Chinese coastline, of which Saccharina japonica, Undaria pinnatifida, Neopyropia spp., Gracilaria spp., Sargassum fusiforme were listed as the most consumed seaweeds in Food and Agriculture Organization of the United Nations (FAO). The inorganic arsenic (iAs) concentration in most of the seaweeds was below maximum limits (0.3 mg iAs/kg) as seaweed additives for infant food in the National Food Safety Standard of Pollutants in China (GB2762-2017, 2017), except for the species Sargassum, in which the iAs concentration significantly exceeded the limit and ranged from 15.1 to 83.7 mg/kg. Arsenic speciation in 4 cultivated seaweeds grown in both temperate and subtropical zones is reported for the first time. No significant differences in total As and iAs concentration were identified, except slightly higher total As concentration were found in Saccharina japonica growing in the temperate zone. The estimated daily intake (EDI) of toxic iAs via seaweed consumption was generally below the EFSA CONTAM Panel benchmark dose lower confidence limit (0.3 μg/kg bw/day) except for all Sargassum species where the EDI was significantly higher than 0.3 μg/kg bw/day. Moreover, the first-ever reported data on As speciation indicated very high iAs concentrations in Sargassum hemiphyllum and Sargassum henslowianum. To minimize the food chain iAs exposure, reducing both human intake of Sargassum spp. and the used of Sargassum spp. for animal feed is highly recommended. CapsuleThis study showed that edible seaweed Sargassum spp. consumption may pose a health risk related to inorganic arsenic (iAs) exposure. The risk of iAs exposure via seaweed consumption or livestock is a concern that needs to be monitored. The arsenic accumulation and speciation may be predominantly species-dependent rather than environmental-dependent.