Benchmark Dose Lower Confidence Limit Research Articles

Update of the risk assessment of inorganic arsenic in food.

The European Commission asked EFSA to update its 2009 risk assessment on arsenic in food carrying out a hazard assessment of inorganic arsenic (iAs) and using the revised exposure assessment issued by EFSA in 2021. Epidemiological studies show that the chronic intake of iAs via diet and/or drinking water is associated with increased risk of several adverse outcomes including cancers of the skin, bladder and lung. The CONTAM Panel used the benchmark dose lower confidence limit based on a benchmark response (BMR) of 5% (relative increase of the background incidence after adjustment for confounders, BMDL05) of 0.06 μg iAs/kg bw per day obtained from a study on skin cancer as a Reference Point (RP). Inorganic As is a genotoxic carcinogen with additional epigenetic effects and the CONTAM Panel applied a margin of exposure (MOE) approach for the risk characterisation. In adults, the MOEs are low (range between 2 and 0.4 for mean consumers and between 0.9 and 0.2 at the 95th percentile exposure, respectively) and as such raise a health concern despite the uncertainties.

Risk Assessment of Isoeugenol in Food Based on Benchmark Dose-Response Modeling.

Isoeugenol has recently been evaluated as possibly carcinogenic (Group 2B) by the WHO International Agency for Research on Cancer (IARC). In light of this evaluation, an updated risk assessment of this common food constituent was conducted using the benchmark dose (BMD) approach as recommended by the European Food Safety Authority (EFSA) for point of departure (POD) determination, as an alternative to the no observed adverse effect level (NOAEL). This approach was specifically chosen, as for the relevant neoplastic endpoints only lowest observed adverse effect level (LOAEL) values are available. The toxicological endpoint from the animal studies with the most conservative BMD lower confidence limit (BMDL) value was identified. Using the obtained BMDL value of 8 mg/kg body weight/day as POD, an acceptable daily intake (ADI) of 16 µg/kg body weight/day was obtained, which-despite being more conservative than previous approaches-is still clearly above the estimated daily exposure level to isoeugenol in the USA and in Europe. These results confirm a low risk of the estimated daily exposure levels of isoeugenol.

Does Cannabidiol (CBD) in Food Supplements Pose a Serious Health Risk? Consequences of the European Food Safety Authority (EFSA) Clock Stop Regarding Novel Food Authorisation

In the European Union (EU), cannabidiol (CBD) products extracted from Cannabis sativa L. require pre-marketing authorisation under the novel food regulation. Currently, 19 CBD applications are being assessed by the European Food Safety Authority (EFSA). During the initial assessment of the dossiers, the EFSA Panel on Nutrition, Novel Foods, and Food Allergens (NDA) identified several knowledge gaps that need to be addressed before the evaluation of CBD can be finalised. The effects of CBD on the liver, gastrointestinal tract, endocrine system, nervous system, psychological function, and reproductive system need to be clarified. The contribution of this research is to provide an evidence-based assessment of the potential risks associated with CBD products, and to provide recommendations for risk management in the European Union while awaiting the finalisation of novel food applications. The available literature allows for a benchmark dose (BMD)–response modelling of several bioassays, resulting in a BMD lower confidence limit (BMDL) of 20 mg/kg bw/day for liver toxicity in rats. Human data in healthy volunteers showed increases in the liver enzymes alanine aminotransferase and aspartate aminotransferase in one study at 4.3 mg/kg bw/day, which was defined by the EFSA NDA panel as the lowest observed adverse effect level (LOAEL). The EFSA NDA panel recently concluded that the safety of CBD as a novel food cannot be assessed, resulting in a so-called clock stop for the applications until the applicants provide the required data. The authors suggest that certain CBD products still available on the EU market as food supplements despite the lack of authorisation should be considered “unsafe”. Products exceeding a health-based guidance value (HBGV) of 10 mg/day should be considered “unfit for consumption” (Article 14(1) and (2)(b) of Regulation No. 178/2002), while those exceeding the human LOAEL should be considered “injurious to health” (Article 14(1) and (2)(a) of Regulation No 178/2002).

Use of the benchmark-dose (BMD) approach to derive occupational exposure limits (OELs) for genotoxic carcinogens: N-nitrosamines.

N-Nitrosamines are potent carcinogens and considered non-threshold carcinogens in various regulatory domains. However, recent data indicate the existence of a threshold for genotoxicity, which can be adequately demonstrated. This aspect has a critical impact on selecting the methodology that is applied to derive occupational exposure limits (OELs). OELs are used to protect workers potentially exposed to various chemicals by supporting the selection of appropriate control measures and ultimately reducing the risk of occupational cancer. Occupational exposures to nitrosamines occur during manufacturing processes, mainly in the rubber and chemical industry. The present study derives OELs for inhaled N-nitrosamines, employing the benchmark dose (BMD) approach if data are adequate and read-across for nitrosamines without adequate data. Additionally, benchmark dose lower confidence limit (BMDL) is preferred and more suitable point-of-departure (PoD) to calculate human health guidance values, including OEL. The lowest OEL (0.2μg/m3 ) was derived for nitrosodiethylamine (NDEA), and nitrosopiperidine (NPIP) (OEL = 0.2μg/m3 ), followed by nitrosopyrrolidine (NPYR) (0.4μg/m3 ), nitrosodimethylamine (NDMA), nitrosodimethylamine (NMEA), and nitrosodipropylamine (NDPA) (0.5μg/m3 ), nitrosomorpholine (NMOR) (OEL = 1μg/m3 ), and nitrosodibutylamine (NDBA) (OEL = 2.5μg/m3 ). Limits based on "non-threshold" TD50 slope calculation were within a 10-fold range. These proposed OELs do not consider skin absorption of nitrosamines, which is also a possible route of entry into the body, nor oral or other environmental sources. Furthermore, we recommend setting a limit for total nitrosamines based on the occupational exposure scenario and potency of components.

First Report on the Presence of Toxic Metals and Metalloids in East Asian Bullfrog (Hoplobatrachus rugulosus) Legs.

We examined the presence of As, Cr, Cd, and Pb in 42 samples of farmed East Asian bullfrog (Hoplobatrachus rugulosus) from Vietnam and Thailand by inductively coupled plasma-mass spectrometry (ICP-MS). An estimation of the dietary intake and exposure to the toxic elements analysed was also carried out. The results showed very high As levels, with mean values of 0.094 ± 0.085 mg/Kg w.w. and a maximum of 0.22 mg/Kg. No significant differences were found for As contents between areas of production (p > 0.05). No detectable Cd contents were found in all the samples examined. The Pb concentrations of the East Asian bullfrog legs samples were below the European Commission’s permitted levels. The Cr and Pb contents of the East Asian bullfrog produced in Vietnam were significantly higher than that produced in Thailand (p < 0.05). The target hazard quotient (THQ) ratio for Cr was not exceeded for all the samples analysed. In contrast, the benchmark dose lower confidence limit (BMDL) and THQ ratios for As were exceeded, indicating carcinogenic and non-carcinogenic risks for those who consume this type of food. The results of this work confirm the role of As-contaminated water absorption as an important source of arsenic for these adult organisms.

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.

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.

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.

Trace elements in Foodstuffs from the Mediterranean Basin-Occurrence, Risk Assessment, Regulations, and Prevention strategies: A review.

Trace elements (TEs) are chemical compounds thatnaturally occur in the earth's crust and in living organisms at low concentrations. Anthropogenic activities can significantly increase the level of TEs in the environment and finally enter the food chain. Toxic TEs like cadmium, lead, arsenic, and mercury have no positive role in a biological system and cancause harmful effects on human health. Ingestion of contaminated food is a typical route of TEs intake by humans. Recent data about the occurrence of TEs in food available in the Mediterranean countries are considered in this review. Analytical methods are also discussed.Furthermore, a discussion of existing international agency regulations will be given. The risk associated with the dietary intake of TEs was estimated by considering consumer exposure and threshold values such as Benchmark dose lower confidence limit and provisional tolerable weekly intake established by the European Food Safety Authority and the Joint FAO/WHO Expert Committee on Food Additives, respectively. Finally, several remediation approaches to minimize TE contamination in foodstuffs were discussed including chemical, biological, biotechnological, and nanotechnological methods. The results of this study proved the occurrence of TEs contamination at high levels in vegetables and fish from some Mediterranean countries. Lead and cadmium are more abundant in foodstuffs than other toxic trace elements. Geographical variations in TE contamination of food crops clearly appear, with a greater risk in developing countries. There is still a need for the regular monitoring of these toxic element levels in fooditems to ensure consumer protection.

Health Safety Assessment of Ready-to-Eat Products Consumed by Children Aged 0.5-3 Years on the Polish Market.

Toxic elements have a negative impact on health, especially among infants and young children. Even low levels of exposure can impair the normal growth and development of children. In young children, all organs and metabolic processes are insufficiently developed, making them particularly vulnerable to the effects of toxic elements. The aim of this study is to estimate the concentration of toxic elements in products consumed by infants and young children. The health risk of young children due to consumption of ready-made products potentially contaminated with As (arsenic), Cd (cadmium), Hg (mercury), and Pb (lead) was also assessed. A total of 397 samples (dinners, porridges, mousses, snacks “for the handle”, baby drinks, dairy) were analyzed for the content of toxic elements. Inductively coupled plasma mass spectrometry (ICP-MS) was used to assess As, Cd, and Pb concentration. The determination of Hg was performed by atomic absorption spectrometry (AAS). In order to estimate children’s exposure to toxic elements, the content of indicators was also assessed: estimated daily intake (EDI), estimated weekly intake (EWI), provisional tolerable weekly intake (PTWI), provisional tolerable monthly intake (PTMI), the benchmark dose lower confidence limit (BMDL), target hazard quotient (THQ), hazard index (HI), and cancer risk (CR). The average content of As, Cd, Hg, and Pb for all ready-made products for children is: 1.411 ± 0.248 µg/kg, 2.077 ± 0.154 µg/kg, 3.161 ± 0.159 µg/kg, and 9.265 ± 0.443 µg/kg, respectively. The highest content As was found in wafer/crisps (84.71 µg/kg); in the case of Cd, dinners with fish (20.15 µg/kg); for Hg, dinners with poultry (37.25 µg/kg); and for Pb, fruit mousse (138.99 µg/kg). The results showed that 4.53% of the samples attempted to exceed Pb, and 1.5% exceeded levels of Hg. The highest value of THQ was made in the case of drinks, for Cd and Pb in mousses for children, and Hg for dairy products. The THQ, BMDL, and PTWI ratios were not exceeded. The analyzed ready-to-eat products for children aged 0.5–3 years may contain toxic elements, but most of them appear to be harmless to health.

Inter-individual variation in chlorpyrifos toxicokinetics characterized by physiologically based kinetic (PBK) and Monte Carlo simulation comparing human liver microsome and Supersome\u2122 cytochromes P450 (CYP)-specific kinetic data as model input

The present study compares two approaches to evaluate the effects of inter-individual differences in the biotransformation of chlorpyrifos (CPF) on the sensitivity towards in vivo red blood cell (RBC) acetylcholinesterase (AChE) inhibition and to calculate a chemical-specific adjustment factor (CSAF) to account for inter-individual differences in kinetics (HKAF). These approaches included use of a Supersome™ cytochromes P450 (CYP)-based and a human liver microsome (HLM)-based physiologically based kinetic (PBK) model, both combined with Monte Carlo simulations. The results revealed that bioactivation of CPF exhibits biphasic kinetics caused by distinct differences in the Km of CYPs involved, which was elucidated by Supersome™ CYP rather than by HLM. Use of Supersome™ CYP-derived kinetic data was influenced by the accuracy of the intersystem extrapolation factors (ISEFs) required to scale CYP isoform activity of Supersome™ to HLMs. The predicted dose–response curves for average, 99th percentile and 1st percentile sensitive individuals were found to be similar in the two approaches when biphasic kinetics was included in the HLM-based approach, resulting in similar benchmark dose lower confidence limits for 10% inhibition (BMDL10) and HKAF values. The variation in metabolism-related kinetic parameters resulted in HKAF values at the 99th percentile that were slightly higher than the default uncertainty factor of 3.16. While HKAF values up to 6.9 were obtained when including also the variability in other influential PBK model parameters. It is concluded that the Supersome™ CYP-based approach appeared most adequate for identifying inter-individual variation in biotransformation of CPF and its resulting RBC AChE inhibition.

Heavy Metals and the Occurrence of Ulcerative Dermal Necrosis (UDN) in Sea Trout from the RIVER REGA, Poland-Consumer Health Assessment.

Various factors, including heavy metals, can make fish more susceptible to disease. This study investigated, inter alia, the relationship between Pb, Cd, and Hg contamination of the organs and muscles of sea trout from the river Rega (Poland) and the occurrence of UDN (ulcerative skin necrosis) symptoms. Moreover, the dietary risk of Pb, Cd, and Hg uptake from the muscles of healthy sea trout was assessed based on estimated daily intake (EDI), target hazard quotient (THQ), benchmark dose lower confidence limits (BMDL01 and BMDL10), and tolerable weekly intake (TWI). The metal concentrations varied, depending on the fish organs and the fish condition. A significantly higher amount of Pb was found in the gonads, gills, and muscles, Cd in the kidneys, and Hg in the muscles of sea trout with UDN symptoms. The lowest concentrations of Pb and Cd were detected in the muscles, and of Hg in the gonads. Dietary exposure to Pb, Cd, and Hg accounted for: 0.4% of BMDL01 and 1.0% of BMDL10, 0.56% of TWI, and 16.5% of TWI, respectively. THQs for each metal and the HI value for combined metals were below 1. The weakening of fish due to UDN-like disease probably increased the accumulation of Pb in the gonads, gills, and muscles, and of Cd in the kidneys, of the sea trout. As regards the maximum levels (MRLs), the muscles of healthy sea trout are safe for consumption. The risk assessment suggests no concern for the health of consumers.

Cadmium and Lead Concentration in Drinking Instant Coffee, Instant Coffee Drinks and Coffee Substitutes: Safety and Health Risk Assessment

The presence of heavy metals in food is a global problem. The paper aimed to examine the content of cadmium (Cd) and lead (Pb) in instant coffee and instant coffee substitutes. The safety of consumption of the beverages by adult Poles was estimated based on the following parameters: tolerable weekly intake (TWI) %, benchmark dose lower confidence limit (BMDL) %, chronic daily intake (CDI), target hazard quotient (THQ) and hazard index (HI), for three beverage consumption patterns—one, two or three servings a day. Forty-nine samples of coffee, instant coffee drinks and coffee substitutes were analysed. The content of cadmium and lead was determined by ICP (inductively coupled plasma) analysis. The maximum level of Cd in the analysed beverages was 3.2 µg, and that of Pb was 82.6 µg per 1 kg. The tolerable level of intake of Cd (TWI) and Pb (BMDL) with the analysed beverages did not exceed 2.5%. The value of CDI, THQ and HI was not higher than 1, which means that the risk of diseases related to chronic exposure to Cd and Pb consumed with coffee should be evaluated as very low. However, special note should be taken of Pb, as the level of this metal was higher than that of Cd, and for beverages with a higher weight per serving (e.g. Cappuccino), the intake of Pb can exceed consumer-safe levels if they are consumed on a regular basis. Therefore, it should be considered whether it is advisable for flavoured multi-ingredient instant coffee drinks to be consumed from time to time only, and natural coffee with optional milk and/or sugar be the choice of regular coffee drinkers.

Acrylamide levels in smoke from conventional cigarettes and heated tobacco products and exposure assessment in habitual smokers

Acrylamide (AA) is a neurotoxic, genotoxic, and carcinogenic compound developed during heating at high temperatures. Foods such as potatoes, biscuits, bread and coffee are the main foodstuffs containing AA. Cigarette smoke may be a significant additional source of exposure. However, AA content may vary among different types of cigarettes. The study aimed to evaluate the AA content in conventional cigarettes (CC) and heated tobacco products (HTP) and its resulting exposure through their use. AA levels from the two types of cigarettes were determined by GC-MS and the daily exposure to AA was also ascertained. The margin of exposure (MOE) was calculated for neurotoxic and carcinogenic risk based on benchmark dose lower confidence limit for a 10% response (BMDL10) of 0.43 and 0.17, 0.30, and 1.13 mg/kgbw/day. AA level in CC ranged from 235 to 897 ng/cigarette, whereas HTP reported AA levels in the range of 99–187 ng/cigarette. The data showed a low neurotoxic risk for either CC or HTP, whereas a carcinogenic risk emerged through the smoking of CC based on different Benchmark doses. The carcinogenic risk for CC based on the highest Benchmark dose that was considered showed unsafe levels, as little as 10 CC cigarettes/day, whereas it was almost always of low concern for HTP. Another approach based upon the incremental lifetime cancer risk (ILCR) analysis led to similar results, exceeding, in some cases, the safety value of 10−4, as far as CC are concerned. Overall, the results confirmed that CC are a significant source of AA, and its levels were five times higher than in HTP.

Benchmark dose modelling in regulatory ecotoxicology, a potential tool in pest management

For several authorities, benchmark dose (BMD) methodology has become the recommended approach by which to derive reference values for risk assessment. However, in practice, the BMD approach is not standard use in risk assessment for pesticides where the no observed adverse effect level, lowest observed adverse effect level and effective dose (ED50 or EDx ) prevail. Regression-based BMD and the benchmark dose lower confidence limit (BMDL) have several advantages, such as utilizing more information from the generated data and being less dependent on tested dose levels. However, the BMD approach requires some degree of expert knowledge for defining an appropriate risk level for estimating the BMD and using more sophisticated statistical methods to calculate BMD and BMDL. The BMD approach is one way to move away from p value-based binary decision-making towards putting the weight on effect sizes. We review the advantages and disadvantages of focusing on the BMD approach for risk assessment of pesticides. Further, we discuss potential applications in efficacy trials for pest management purposes. © 2021 Society of Chemical Industry.

The content of lead, cadmium, arsenic, mercury and tin in fruit and their products based on monitoring studies - exposure assessment.

Fruit and fruit products are important part of our daily diet. In addition to the ingredients necessary for the proper functioning of the body, these products can also be a source of intake elements harmful to human health. Analysis of the results of monitoring studies conducted in Poland in 2015 concerning contamination of lead (Pb), cadmium (Cd), arsenic (As), mercury (Hg) and tin (Sn) in fruit and fruit products and exposure assessment. Approximately 600 samples of fresh, frozen, dried fruits, fruit preserves and canned fruits were tested. The laboratories of State Sanitary Inspection were involved in testing. Accredited and validated analytical methods were used. The test samples were prepared in accordance with the standard PN-EN 13804:2013. The contents of lead, cadmium and tin were determined by using flame atomic absorption spectrometry (FAAS) or flameless with electrothermal atomization spectrometry (GFAAS); arsenic by using hydride generation atomic absorption spectrometry method (HGAAS) and mercury the "cold vapor" atomic absorption spectrometry (CVAAS) method. Contamination of investigated samples with elements harmful to human health (Pb, Ca, As, Hg and Sn does not rise concern to human health and was in most cases comparable with contamination reported in other European Union countries. The estimated average exposure of adults and children to lead intake with fruit and fruit products ranged from 0.5% to 14.6% of the respective Benchmark Dose Lower Confidence Limit (BMDL) established by the European Food Safety Authority (EFSA). The mean intake of cadmium with these groups of foodstuffs was in the range 0.3 - 8.5% of the TWI value (Tolerable Weekly Intake) established by EFSA for adults and children (0.1 - 3.6% of the PTMI (Provisional Tolerable Monthly Intake) established by JECFA. In case of arsenic mean intake was in the range 0.5 - 1.6% BMDL whilst for mercury (inorganic form) intake represented 0.5 - 1.4% of TWI value established by JECFA and then confirmed by EFSA. Based on the obtained results, it was found that content of Pb, Cd, As, Hg and Sn in the tested samples of fruit and their products does not pose a risk to consumer health. Estimated exposure of consumers does not exceed tolerable doses established by EFSA and JECFA for these elements.

Ethyl carbamate in retail market condiments and risk assessment of its dietary exposure for the Korean population

ABSTRACT Ethyl carbamate (EC), a potential human dietary carcinogen, is found in fermented foods including the fermented soybean-based condiments, the major part of the Korean diet. Therefore, it is expected that their EC contents might pose health risks. Herein, we collected 111 condiments and estimated their EC contents via gas chromatography-mass spectrometry. Further, dietary intake of EC was evaluated, and the risk levels were assessed via the margin of exposure (MOE) approach and excess cancer risk assessment. EC contents of the condiments ranged from not detectable to 39.47 μg/kg, and the daily EC exposure ranged from 1.4 to 2.0 ng/kg BW per day, depending on gender and age groups in Korea. Of the condiments, soy sauce was the largest contributor to EC exposure. MOE and excess cancer risks for the average consumer were 166,300 and 9.0 × 10−8, respectively, and those for the consumers in the 95th percentiles (P95) were 53,504 and 2.8 × 10−7, respectively, indicating that the risk of exposure to EC is of lower concern in average consumers than heavy consumers. However, the EC exposure from condiments was higher than that in other Asian countries. Abbreviations: EC: ethyl carbamate; GC-MS: gas chromatography-mass spectrometry; MOE: margin of exposure; MRL: maximum residue level; IDL: instrumental detection level; IQL: instrumental quantification level; MDL: method detection level; MQL: method quantification level; EDI: estimated daily intakes; BMDL10: benchmark dose lower confidence limit

Estimation of Tolerable Daily Intake (TDI) for Immunological Effects of Aflatoxin.

Aflatoxins are toxic chemicals produced by the fungi Aspergillus flavus and Aspergillus parasiticus. In warm climates, these fungi frequently contaminate crops such as maize, peanuts, tree nuts, and sunflower seeds. In many tropical and subtropical regions of the world, populations are coexposed to dietary aflatoxin and multiple infectious pathogens in food, water, and the environment. There is increasing evidence that aflatoxin compromises the immune system, which could increase infectious disease risk in vulnerable populations. Our aim was to conduct a dose-response assessment on a noncarcinogenic endpoint of aflatoxin: immunotoxicological effects. We sought to determine a noncarcinogenic tolerable daily intake (TDI) of aflatoxin, based on the existing data surrounding aflatoxin and biomarkers of immune suppression. To conduct the dose response assessment, mammalian studies were assessed for appropriateness of doses (relevant to potential human exposures) as well as goodness of data, and two appropriate mouse studies that examined decreases in leukocyte counts were selected to generate dose response curves. From these, we determined benchmark dose lower confidence limits (BMDL) as points of departure to estimate a range of TDIs for aflatoxin-related immune impairment: 0.017-0.082 μg/kg bw/day. As aflatoxin is a genotoxic carcinogen, and regulations concerning its presence in food have largely focused on its carcinogenic effects, international risk assessment bodies such as the Joint Expert Committee on Food Additives (JECFA) have never established a TDI for aflatoxin. Our work highlights the importance of the noncarcinogenic effects of aflatoxin that may have broader public health impacts, to inform regulatory standard-setting.

Benchmark dose analysis for PAHs hydroxyl metabolites in urine based on mitochondrial damage of peripheral blood leucocytes in coke oven workers in China

ObjectivesThe aim was to explore the dose-response relationship between occupational polycyclic aromatic hydrocarbons (PAHs) exposure and mitochondrial damage in coke oven plants workers. Methods544 workers and 238 healthy people were recruited. The ultra-high performance liquid chromatography was used to determine the level of 1-hydroxypyrene, 1-hydroxynaphthalene, 2-hydroxynaphthalene and 3-hydroxyphenanthrene. The real-time fluorescence quantitative polymerase chain reaction was used to determine the mitochondrial DNA copy number (mtDNAcn). The benchmark dose software was used to analyze the benchmark dose. ResultsThe mtDNAcn in the exposure group was lower than that in the control group. The concentrations of 1-hydroxypyrene, 1-hydroxynaphthalene, 2-hydroxynaphthalene and 3-hydroxyphenanthrene in the exposure group were higher than those in the control group. There is a dose-response relationship between 1-hydroxypyrene, 3-hydroxyphenanthrene and mitochondrial DNA damage. The benchmark dose lower confidence limit (BMDL) of 1-hydroxypyrene were 0.045, 0.004, and 0.058 pg/μg creatinine in the total, male, and female population, respectively. The BMDL of 3-hydroxyphenanthrene were 5.142, 6.099, and 2.807 pg/μg creatinine in the total, male, and female population, respectively. ConclusionsThe BMDL of 1-hydroxypyrene and 3-hydroxyphenanthrene initially explored can provide a reference to establish occupational exposure biological limits.

Derivation of a Human In Vivo Benchmark Dose for Perfluorooctanoic Acid From ToxCast In Vitro Concentration-Response Data Using a Computational Workflow for Probabilistic Quantitative In Vitro to In Vivo Extrapolation.

A computational workflow which integrates physiologically based kinetic (PBK) modeling, global sensitivity analysis (GSA), approximate Bayesian computation (ABC), and Markov Chain Monte Carlo (MCMC) simulation was developed to facilitate quantitative in vitro to in vivo extrapolation (QIVIVE). The workflow accounts for parameter and model uncertainty within a computationally efficient framework. The workflow was tested using a human PBK model for perfluorooctanoic acid (PFOA) and high throughput screening (HTS) in vitro concentration–response data, determined in a human liver cell line, from the ToxCast/Tox21 database. In vivo benchmark doses (BMDs) for PFOA intake (ng/kg BW/day) and drinking water exposure concentrations (µg/L) were calculated from the in vivo dose responses and compared to intake values derived by the European Food Safety Authority (EFSA). The intake benchmark dose lower confidence limit (BMDL5) of 0.82 was similar to 0.86 ng/kg BW/day for altered serum cholesterol levels derived by EFSA, whereas the intake BMDL5 of 6.88 was six-fold higher than the value of 1.14 ng/kg BW/day for altered antibody titer also derived by the EFSA. Application of a chemical-specific adjustment factor (CSAF) of 1.4, allowing for inter-individual variability in kinetics, based on biological half-life, gave an intake BMDL5 of 0.59 for serum cholesterol and 4.91 (ng/kg BW/day), for decreased antibody titer, which were 0.69 and 4.31 the EFSA-derived values, respectively. The corresponding BMDL5 for drinking water concentrations, for estrogen receptor binding activation associated with breast cancer, pregnane X receptor binding associated with altered serum cholesterol levels, thyroid hormone receptor α binding leading to thyroid disease, and decreased antibody titer (pro-inflammation from cytokines) were 0.883, 0.139, 0.086, and 0.295 ng/ml, respectively, with application of no uncertainty factors. These concentrations are 5.7-, 36-, 58.5-, and 16.9-fold lower than the median measured drinking water level for the general US population which is approximately, 5 ng/ml.