Threshold Of Toxicological Concern Research Articles

FEMA GRAS assessment of natural flavor complexes: Asafetida oil, garlic oil and onion oil.

The Expert Panel of the Flavor and Extract Manufacturers Association (FEMA) applies its procedure for the safety evaluation of natural flavor complexes (NFCs) to re-evaluate the safety of Asafetida Oil (Ferula assa-foetida L.) FEMA 2108, Garlic Oil (Allium sativum L.) FEMA 2503 and Onion Oil (Allium cepa L.) FEMA 2817 for use as flavoring in food. This safety evaluation is part of a series of evaluations of NFCs for use as flavoring ingredients conducted by the Expert Panel that applies a scientific procedure published in 2005 and updated in 2018. Using a group approach that relies on a complete chemical characterization of the NFC intended for commerce, the constituents of each NFC are organized into well-defined congeneric groups and the estimated intake of each constituent congeneric group is evaluated using the conservative threshold of toxicological concern (TTC) concept. Data on the metabolism, genotoxic potential and toxicology for each constituent congeneric group are reviewed as well as studies on each NFC. Based on the safety evaluation, Asafetida Oil (Ferula assa-foetida L.), Garlic Oil (Allium sativum L.) and Onion Oil (Allium cepa L.) were affirmed as generally recognized as safe (GRASa) under their conditions of intended use as flavor ingredients.

Cytotoxicity, endocrine disrupting activity, and chemical analysis of 42 food contact silicone rubber products

After migration in 95 % ethanol (food simulant) at 70 °C for 2 h (accelerated conditions), the cytotoxicity and endocrine-disruption activity of 42 food contact silicone products (FCSPs) obtained from the Chinese market were studied. Of 31 kitchenwares, 96 % showed mild or above cytotoxicity (relative growth rate < 80 %) using the HeLa neutral red uptake test; and 84 % showed estrogenic (64 %), anti-estrogenic (19 %), androgenic (42 %), and anti-androgenic (39 %) activities by the Dual-luciferase reporter gene assay. The mold sample induced late phase HeLa apoptosis as detected by Annexin V-FITC/PI double staining flow cytometry, in addition, the migration of mold sample has a higher risk of endocrine disruption at high temperature usage. Encouragingly, 11 bottle nipples had neither cytotoxic nor hormonal activity. Utilizing multiple mass spectrometry techniques, non-intentionally added substances (NIASs) in 31 kitchenwares were analyzed, and the migration levels of 26 organic compounds and 21 metals were quantified, furthermore, the safe risk of single migrant was evaluated through their special migration limit (SML) or threshold of toxicological concern (TTC). Using “nchoosek” statement and Spearman's correlation analysis in MATLAB, the migration of 38 compounds or combinations including metals, plasticizers, methylsiloxanes, and lubricants, had strong correlation with cytotoxicity or hormonal activity. The coexistence of various chemical substances in migrants leads to complex biological toxicity of FCSPs, so it is very important to detect the toxicity of the final products. The combination of bioassays and chemical analyses are valuable tools to facilitate the identification and analyses of FCSPs and migrants that have potential safety risks.

Towards detecting genotoxic chemicals in food packaging at thresholds of toxicological concern using bioassays with high-performance thin-layer chromatography

High-performance thin-layer chromatography (HPTLC)-bioassays are promising new methods for detecting bioactive chemicals in food packaging. Here, we test whether direct-acting genotoxic chemicals are detectable in food contact materials (FCM) using HPTLC-bioassays. First, an interactive worksheet lays out steps to calculate needed detection limits in (bio)analytical methods from regulatory limits, including thresholds of toxicological concern (TTC). Second, we show that the sensitivity of a HPTLC-genotoxicity assay to low doses of chemicals, including food contact chemicals, is greater than a standardized microtiter plate version and in vitro assays already reported. Third, using HPTLC, we detected genotoxicity in extracts of FCM, and not in simulated migrates of FCM. Applying the worksheet to calculate needed detection limits in FCM migrates, we observed that seven of ten genotoxic chemicals would be detectable with HPTLC if present at the regulatory 10 ppb limit and two of ten at TTC for adults. With development, HPTLC-bioassays might become the best option for supporting safety assessment of genotoxicants in food packaging.

Elucidation of Non-Intentionally Added Substances from Plant Fiber/Plastic Composites by UPLC-QTOF/MS.

Plant fiber/plastic composites (PPCs) have been widely used in food contact materials (FCMs) for many benefits, such as their claimed better environmental footprint compared to conventional plastics. However, their safety is still not fully understood and must be comprehensively evaluated. Non-volatiles extracted from six PPCs with different plant fibers and polymer matrices were characterized by employing ultra-high-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry in combination with various spectral libraries and manual elucidation, taking into account spectral similarity and characteristic product ions. A total of 115 compounds were tentatively identified, 50 of which were oligomers or their derivatives from the sample with polylactic acid (PLA) and polybutylene adipate terephthalate (PBAT) as the polymer matrix, and some of them were Cramer rules class III substances based on the threshold of toxicological concern (TTC). Seven reaction products between PLA and PBAT monomers, as well as four derivatives of melamine, were elucidated and well detailed for the first time. In addition, bisphenol S was detected in all samples even though its origin remains to be further explored. Isoprothiolane, as an insecticide and fungicide used to control a range of rice pests, was identified in the sample with rice husk as fillers, experimentally confirming the presence of agrochemicals in samples containing plant fibers.

Safety assessment of the use of recycled high-density polyethylene in cosmetics packaging based on in silico modeling migration of representative chemical contaminants for dermal sensitization and systemic endpoints

A safety assessment of recycled high-density polyethylene (rHDPE) in cosmetic packaging was performed based on guidelines published by the European Food Safety Authority (EFSA) on the use of recycled plastics for food packaging. EFSA guidelines require demonstration that the concentration of selected representative chemical contaminants in recycled plastic resulting from exposure from food is lower than the threshold of toxicological concern (TTC) for genotoxic substances of 0.0025 µg/kg bw/day. To investigate the highest concentration (Cmod) of representative chemical contaminants, that would not exceed the genotoxic TTC, when migrating from rHDPE packaging to foodstuffs, used as cosmetic formulation surrogates, we used mathematical modeling software (MIGRATEST®EXP). The Cmod values of representative chemical contaminants were then compared with the EFSA-reported residual concentration (Cres) of each contaminant in the rHDPE. For each of the cosmetic product/packaging combinations evaluated, we found that the modeled values were clearly lower for Cmod than Cres, i.e., the recycling process could effectively reduce potential contaminants of rHDPE to levels that would not result in daily consumer exposure from cosmetic use exceeding the genotoxic TTC. For skin sensitization, we modeled a worst-case scenario and assumed 100 % of each representative chemical contaminant migrates into the cosmetic formulation from rHDPE. We then calculated the consumer exposure level for each contaminant based on the dose per unit area and compared it with the dermal sensitization threshold (DST) for reactive materials, which is 64 µg/cm2. In each case, we demonstrated that the migration of each representative chemical contaminant from rHDPE into each cosmetic formulation was far below the DST, confirming that there is no appreciable risk of sensitization for protein-reactive chemicals. In conclusion, these data support the safe use of rHDPE in the packaging of cosmetic products for leave-on and rinse-off applications.

Comparison of migration and cumulative risk assessment of antioxidants, antioxidant degradation products, and other non-intentionally added substances from plastic food contact materials

Antioxidants are used in the production of synthetic resins to prevent oxidative degradation. However, non-intentionally added substances (NIAS) and the degradation products of antioxidants may contaminate food contact materials (FCM) and migrate into food. Herein, NIAS and antioxidant degradation products in synthetic resins and their migration into food simulants under various conditions were evaluated. Risk assessment was performed based on the toxicity reference values or with threshold of toxicological concern (TTC) approach. The antioxidant degradation products migrated mainly to fatty-food simulants, with the highest migration in isooctane, followed by n-heptane (similar to or lower than isooctane) and 95 % ethanol. Especially, the migration of 2,4-di-tert-butylphenol was high when the FCM was used for the first time under daily use conditions such as ultraviolet sterilization or heating in a pot, oven, or microwave. In addition, 36 target substances were monitored in 142 products of 18 synthetic resins. Of these, 2,4-di-tert-butylphenol was most sensitively detected. Risk assessment demonstrated that all the investigated substances were below the toxicity reference values. However, the risk associated with polyethylene was relatively high compared to other synthetic resins. The cumulative risks of oxidizing Irgafos 168, (z)−9-octadecenamide, tri-o-tolyl phosphite, tri-p-tolyl phosphite, and 7,9-di-tert-butyl-1-oxaspiro(4,5)deca-6,9-diene-2,8-dione using the TTC approach were calculated to range from 34.81 % to 73.74 %, suggesting that the TTC is a more conservative risk assessment.

RIFM fragrance ingredient safety assessment, 2-tridecanone, CAS Registry Number 593-08-8.

The existing information supports the use of this material as described in this safety assessment. 2-Tridecanone was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, photoirritation/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analog 2-heptanone (CAS # 110-43-0) show that 2-tridecanone is not expected to be genotoxic and provide a calculated Margin of Exposure (MOE)>100 for the repeated dose toxicity and reproductive toxicity endpoints. Data from read-across analog 2-heptanone (CAS # 110-43-0) show that there are no safety concerns for 2-tridecanone for skin sensitization under the current declared levels of use. The photoirritation/photoallergenicity endpoints were evaluated based on ultraviolet/visible (UV/Vis) spectra; 2-tridecanone is not expected to be photoirritating/photoallergenic. The local respiratory toxicity endpoint was evaluated using the Threshold of Toxicological Concern (TTC) for a Cramer Class II material, and the exposure to 2-tridecanone is below the TTC (0.47mg/day). The environmental endpoints were evaluated; 2-Tridecanone was found not to be Persistent, Bioaccumulative, and Toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.

Developing an internal threshold of toxicological concern (iTTC)

BackgroundThreshold of Toxicological Concern (TTC) approaches are used for chemical safety assessment and risk-based priority setting for data poor chemicals. TTCs are derived from in vivo No Observed Effect Level (NOEL) datasets involving an external administered dose from a single exposure route, e.g., oral intake rate. Thus, a route-specific TTC can only be compared to a route-specific exposure estimate and such TTCs cannot be used for other exposure scenarios such as aggregate exposures.ObjectiveDevelop and apply a method for deriving internal TTCs (iTTCs) that can be used in chemical assessments for multiple route-specific exposures (e.g., oral, inhalation or dermal) or aggregate exposures.MethodsChemical-specific toxicokinetics (TK) data and models are applied to calculate internal concentrations (whole-body and blood) from the reported administered oral dose NOELs used to derive the Munro TTCs. The new iTTCs are calculated from the 5th percentile of cumulative distributions of internal NOELs and the commonly applied uncertainty factor of 100 to extrapolate animal testing data for applications in human health assessment.ResultsThe new iTTCs for whole-body and blood are 0.5 nmol/kg and 0.1 nmol/L, respectively. Because the iTTCs are expressed on a molar basis they are readily converted to chemical mass iTTCs using the molar mass of the chemical of interest. For example, the median molar mass in the dataset is 220 g/mol corresponding to an iTTC of 22 ng/L-blood (22 pg/mL-blood). The iTTCs are considered broadly applicable for many organic chemicals except those that are genotoxic or acetylcholinesterase inhibitors. The new iTTCs can be compared with measured or estimated whole-body or blood exposure concentrations for chemical safety screening and priority-setting.SignificanceExisting Threshold of Toxicological Concern (TTC) approaches are limited in their applications for route-specific exposure scenarios only and are not suitable for chemical risk and safety assessments under conditions of aggregate exposure. New internal Threshold of Toxicological Concern (iTTC) values are developed to address data gaps in chemical safety estimation for multi-route and aggregate exposures.

Estimating provisional margins of exposure for data-poor chemicals using high-throughput computational methods.

Current computational technologies hold promise for prioritizing the testing of the thousands of chemicals in commerce. Here, a case study is presented demonstrating comparative risk-prioritization approaches based on the ratio of surrogate hazard and exposure data, called margins of exposure (MoEs). Exposures were estimated using a U.S. EPA’s ExpoCast predictive model (SEEM3) results and estimates of bioactivity were predicted using: 1) Oral equivalent doses (OEDs) derived from U.S. EPA’s ToxCast high-throughput screening program, together with in vitro to in vivo extrapolation and 2) thresholds of toxicological concern (TTCs) determined using a structure-based decision-tree using the Toxtree open source software. To ground-truth these computational approaches, we compared the MoEs based on predicted noncancer TTC and OED values to those derived using the traditional method of deriving points of departure from no-observed adverse effect levels (NOAELs) from in vivo oral exposures in rodents. TTC-based MoEs were lower than NOAEL-based MoEs for 520 out of 522 (99.6%) compounds in this smaller overlapping dataset, but were relatively well correlated with the same (r 2 = 0.59). TTC-based MoEs were also lower than OED-based MoEs for 590 (83.2%) of the 709 evaluated chemicals, indicating that TTCs may serve as a conservative surrogate in the absence of chemical-specific experimental data. The TTC-based MoE prioritization process was then applied to over 45,000 curated environmental chemical structures as a proof-of-concept for high-throughput prioritization using TTC-based MoEs. This study demonstrates the utility of exploiting existing computational methods at the pre-assessment phase of a tiered risk-based approach to quickly, and conservatively, prioritize thousands of untested chemicals for further study.

Evaluating the utility of the Threshold of Toxicological Concern (TTC) and its exclusions in the biocompatibility assessment of extractable chemical substances from medical devices

The Threshold of Toxicological Concern (TTC) is a pragmatic approach used to establish safe thresholds below which there can be no appreciable risk to human health. Here, a large inventory of ∼45,000 substances (referred to as the LRI dataset) was profiled through the Kroes TTC decision module within Toxtree v3.1 to assign substances into their respective TTC categories. Four thousand and two substances were found to be not applicable for the TTC approach. However, closer examination of these substances uncovered several implementation issues: substances represented in their salt forms were automatically assigned as not appropriate for TTC when many of these contained essential metals as counter ions which would render them TTC applicable. High Potency Carcinogens and dioxin-like substances were not fully captured based on the rules currently implemented in the software. Phosphorus containing substances were considered exclusions when many of them would be appropriate for TTC. Refinements were proposed to address the limitations in the current software implementation. A second component of the study explored a set of substances representative of those released from medical devices and compared them to the LRI dataset as well as other toxicity datasets to investigate their structural similarity. A third component of the study sought to extend the exclusion rules to address application to substances released from medical devices that lack toxicity data. The refined rules were then applied to this dataset and the TTC assignments were compared. This case study demonstrated the importance of evaluating the software implementation of an established TTC workflow, identified certain limitations and explored potential refinements when applying these concepts to medical devices.

Prioritization of chemicals in food for risk assessment by integrating exposure estimates and new approach methodologies: A next generation risk assessment case study.

Next generation risk assessment is defined as a knowledge-driven system that allows for cost-efficient assessment of human health risk related to chemical exposure, without animal experimentation. One of the key features of next generation risk assessment is to facilitate prioritization of chemical substances that need a more extensive toxicological evaluation, in order to address the need to assess an increasing number of substances. In this case study focusing on chemicals in food, we explored how exposure data combined with the Threshold of Toxicological Concern (TTC) concept could be used to prioritize chemicals, both for existing substances and new substances entering the market. Using a database of existing chemicals relevant for dietary exposure we calculated exposure estimates, followed by application of the TTC concept to identify substances of higher concern. Subsequently, a selected set of these priority substances was screened for toxicological potential using high-throughput screening (HTS) approaches. Remarkably, this approach resulted in alerts for a selection of substances that are already on the market and represent relevant exposure in consumers. Taken together, the case study provides proof-of-principle for the approach taken to identify substances of concern, and this approach can therefore be considered a supportive element to a next generation risk assessment strategy.

Determination of Three Alkyl Camphorsulfonates as Potential Genotoxic Impurities Using GC-FID and GC-MS by Analytical QbD

Camphorsulfonic acid salts are commonly used in the manufacturing production of active pharmaceutical ingredients (APIs) and have the potential to form alkyl camphorsulfonates, which can be considered as potential genotoxic impurities (PGIs). Alkyl camphorsulfonates should be controlled using the Threshold of Toxicological Concern (TTC) when detected in APIs due to their genotoxicity. An in silico study utilizing the ICH M7 guideline was performed in order to classify the alkyl camphorsulfonates that can be produced from the reaction of camphorsulfonic acid salts with methanol, ethanol, and isopropyl alcohol, which are commonly used solvents in API manufacturing processes. Two sensitive, reproducible, and accurate analytical methods using GC-FID and GC-MS were developed using the analytical Quality By Design (QbD) approaches for the quantitation of three alkyl camphorsulfonates in APIs satisfying the control limit of PGIs according to the TTC. The detection limits of the GC-FID method were found to be between 1.5 to 1.9 ppm, and the detection limits of the GC-MS method were found to be between 0.055 to 0.102 ppm. The method was validated in terms of accuracy, linearity, precision, detection limit, quantitation limit, specificity and robustness.

RIFM fragrance ingredient safety assessment, geraniol, CAS registry number 106-24-1.

The existing information supports the use of this material as described in this safety assessment. Geraniol was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that geraniol is not genotoxic. Data on geraniol provide a calculated Margin of Exposure (MOE)>100 for the repeated dose toxicity and reproductive toxicity endpoints. Data provided geraniol a No Expected Sensitization Induction Level (NESIL) of 11000μg/cm2 for the skin sensitization endpoint. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet/visible (UV/Vis) spectra; geraniol is not expected to be phototoxic/photoallergenic. The local respiratory toxicity endpoint was evaluated using the Threshold of Toxicological Concern (TTC) for a Cramer Class I material, and the exposure to geraniol is below the TTC (1.4mg/day). The environmental endpoints were evaluated; geraniol was found not to be Persistent, Bioaccumulative, and Toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.

RIFM fragrance ingredient safety assessment, 3-Cyclohexene-1-carboxaldehyde, 1-ethenyl-, CAS Registry Number 1049017-63-1.

The existing information supports the use of this material as described in this safety assessment. 3-Cyclohexene-1-carboxaldehyde, 1-ethenyl- was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that 3-cyclohexene-1-carboxaldehyde, 1-ethenyl- is not genotoxic. Data on 3-cyclohexene-1-carboxaldehyde, 1-ethenyl- provide a calculated Margin of Exposure (MOE)>100 for the repeated dose toxicity endpoint. The reproductive and local respiratory toxicity endpoints were evaluated using the Threshold of Toxicological Concern (TTC) for a Cramer Class I material, and the exposure to 3-cyclohexene-1-carboxaldehyde, 1-ethenyl-is below the TTC (0.03mg/kg/day and 1.4mg/day, respectively). Data provided 3-cyclohexene-1-carboxaldehyde, 1-ethenyl- a No Expected Sensitization Induction Level (NESIL) of 1000μg/cm2 for the skin sensitization endpoint. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet/visible (UV/Vis) spectra; 3-cyclohexene-1-carboxaldehyde, 1-ethenyl- is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; 3-cyclohexene-1-carboxaldehyde, 1-ethenyl- was found not to be Persistent, Bioaccumulative, and Toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.

Wastewater-derived organic contaminants in fresh produce: Dietary exposure and human health concerns

Irrigation with reclaimed wastewater is a growing practice aimed at conserving freshwater sources, especially in arid and semiarid regions. Despite the apparent advantages to water management, the practice of irrigation with reclaimed wastewater exposes the agroenvironment to contaminants of emerging concern (CECs). In this report, we estimated the unintentional dietary exposure of the Israeli population (2808 participants) to CECs from consumption of produce irrigated with reclaimed wastewater using detailed dietary data obtained from a National Health and Nutrition Survey (Rav Mabat adults; 2014–2016). Human health risk analyses were conducted based on acceptable daily intake (ADI) and threshold of toxicological concern (TTC) approaches. The highest unintentional exposure to wastewater-borne CECs was found to occur through the consumption of leafy vegetables. All analyzed CECs exhibited hazard quotients <1 for the mean- and high-exposure scenarios, indicating no human health concerns. However, for the extreme exposure scenario, the anticonvulsant agents lamotrigine and carbamazepine, and the carbamazepine metabolite epoxide-carbamazepine exhibited the highest exposure levels of 29,100, 27,200, and 19,500 ng/person (70 kg) per day, respectively. These exposure levels exceeded the TTC of lamotrigine and the metabolite epoxide-carbamazepine, and the ADI of carbamazepine, resulting in hazard quotients of 2.8, 1.1, and 1.9, respectively. According to the extreme estimated scenario, consumption of produce irrigated with reclaimed wastewater (leafy vegetables in particular) may pose a threat to human health. Minimizing irrigation of leafy vegetables using reclaimed wastewater and/or improving the quality of the reclaimed wastewater using an advanced treatment would significantly reduce human dietary exposure to CECs.

Assessment of the applicability of the threshold of toxicological concern for per- and polyfluoroalkyl substances

While toxicity information is available for selected PFAS, little or no information is available for most, thereby necessitating a resource-effective approach to screen and prioritize those needing further safety assessment. The threshold of toxicological concern (TTC) approach proposes a de minimis exposure value based on chemical structure and toxicology of similar substances. The applicability of the TTC approach to PFAS was tested by incorporating a data set of no-observed-adverse-effect level (NOAEL) values for 27 PFAS into the Munro TTC data set. All substances were assigned into Cramer Class III and the cumulative distribution of the NOAELs evaluated. The TTC value for the PFAS-enriched data set was not statistically different compared to the Munro data set. Derived human exposure level for the PFAS-enriched data set was 1.3 μg/kg/day. Structural chemical profiles showed the PFAS-enriched data set had distinct chemotypes with lack of similarity to substances in the Munro data set using Maximum Common Structures. The incorporation of these 27 PFAS did not significantly change TTC Cramer Class III distribution and expanded the chemical space, supporting the potential use of the TTC approach for PFAS chemicals.

Updating the Dermal Sensitisation Thresholds using an expanded dataset and an in silico expert system

The Dermal Sensitisation Thresholds (DST) are Thresholds of Toxicological Concern, which can be used to justify exposure-based waiving when conducting a skin sensitisation risk assessment. This study aimed to update the published DST values by expanding the size of the Local Lymph Node Assay dataset upon which they are based, whilst assigning chemical reactivity using an in silico expert system (Derek Nexus). The potency values within the expanded dataset fitted a similar gamma distribution to that observed for the original dataset. Derek Nexus was used to classify the sensitisation activity of the 1152 chemicals in the expanded dataset and to predict which chemicals belonged to a High Potency Category (HPC). This two-step classification led to three updated thresholds: a non-reactive DST of 710 μg/cm2 (based on 79 sensitisers), a reactive (non-HPC) DST of 73 μg/cm2 (based on 331 sensitisers) and an HPC DST of 1.0 μg/cm2 (based on 146 sensitisers). Despite the dataset containing twice as many sensitisers, these values are similar to the previously published thresholds, highlighting their robustness and increasing confidence in their use. By classifying reactivity in silico the updated DSTs can be applied within a skin sensitisation risk assessment in a reproducible, scalable and accessible manner.

Alternaria mycotoxins in food commodities marketed through e-commerce stores in China: Occurrence and risk assessment

The natural occurrence of mycotoxins like Alternaria mycotoxins in food commodities is concerning in terms of health risks for humans. Currently, detailed investigations of Alternaria mycotoxins, such as alternariol (AOH), alternariol methyl ether (AME), tenuazonic acid (TeA), tentoxin (TEN), and altenuene (ALT) in food commodities marketed through e-commerce stores in China remains scarce. In addition, not many studies have focused on the associated dietary risk of these mycotoxins. This study conducted a survey (486 samples) for five Alternaria mycotoxins using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) methods. Among five Alternaria mycotoxins, TeA had the highest occurrence rate (51.0%) and concentration (average concentration of 40.6 μg/kg) in food commodities, followed by TEN, AOH, AME, and ALT. Millet and tomato products were contaminated with higher levels of TeA than other types of food commodities. The combination of TeA + TEN and AME + TeA + TEN were the predominant two contamination patterns detected in cereal and fruit products. Chronic dietary exposures to Alternaria mycotoxins were performed by the threshold of toxicological concern (TTC) approach. The mean and 95th percentile chronic dietary exposures to AOH and AME indicated different risk levels for consumers in China, with the highest exposure observed in the 2–7 years group, indicating potential dietary health concern. The mean chronic dietary exposures to TeA and ALT did not indicate a risk for the consumers, but the exposure to TeA through cereal product consumption exceeded the TTC value in the 2–12 years group at 95th percentile evaluation. Therefore, strategies should be continuously adopted to decrease or eliminate the occurrence of Alternaria mycotoxins in food commodities in order to reduce the dietary risks for humans.

A simple approach to assess the cancer risk of occupational exposure to genotoxic drugs in healthcare settings

BackgroundSeveral drugs for human use possess genotoxic properties as a necessary consequence of their intended therapeutic effect (e.g. antineoplastics). Health workers may be exposed to these chemicals in various occupational settings such as dose preparation and administration. To date, there are no quantitative risk assessment models to estimate the cancer risk of health workers due to the handling of genotoxic drugs. We therefore developed a quantitative risk assessment model to assess the cancer risk of occupational exposure to genotoxic drugs in healthcare settings based on the threshold of toxicological concern (TTC) concept. This model was used to evaluate the cancer risk of health workers due to the handling of genotoxic drugs in modern health care facilities.MethodsWe modified the threshold of toxicological concern (TTC) concept to fit the purpose of occupational cancer risk assessment. The risk model underlying ICH guideline M7 (R1): “assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk” was used as a starting point for our model. We conducted a short review of studies on the occupational exposure of health workers to genotoxic drugs. These occupational exposure data were compared to the acceptable exposure levels resulting from our TTC based risk model.ResultsBased on the threshold of toxicological concern (TTC) concept, we defined an acceptable daily intake (ADI) of 4 μg/day as threshold of no concern for the exposure of health workers to genotoxic drugs. Regarding the dermal exposure of health workers to genotoxic drugs, we derived a corresponding acceptable surface contamination level (ASCL) of 20 ng/cm2. Both ADI and ASCL are usually not exceeded in modern healthcare settings. Current safety precautions provide sufficient protection to health workers.ConclusionsThe application of our model indicates that workers in modern healthcare facilities are not at risk of developing work related cancer above widely accepted cancer risk levels due to the occupational exposure to genotoxic drugs. Hence, the present study may assist employers and public authorities to make informed decisions concerning the need for (further) protective measures and during risk communication to health workers.

RIFM fragrance ingredient safety assessment, l-carvone, CAS Registry Number 6485-40-1

l-Carvone was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that l-carvone is not genotoxic and provided a No Expected Sensitization Induction Level (NESIL) of 2600 μg/cm2 for the skin sensitization endpoint. Data on l-carvone provided a calculated Margin of Exposure (MOE) >100 for the repeated dose toxicity and reproductive toxicity endpoints. The phototoxicity/photoallergenicity endpoint was completed based on data and ultraviolet/visible (UV/Vis) spectra; l-carvone is not phototoxic/photoallergenic. The local respiratory toxicity endpoint was evaluated using the Threshold of Toxicological Concern (TTC) for a Cramer Class II material (0.47 mg/day); the exposure to l-carvone is below the TTC. The environmental endpoints were evaluated; l-carvone was found not to be persistent, bioaccumulative, and toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.