Breast imaging in focus: A bibliometric overview of visual quality, modality innovations, and diagnostic performance.

INTRODUCTION: Breast imaging plays a crucial role in the early detection and management of breast cancer, with visual quality, modality innovation and diagnostic performance being key factors in achieving accurate diagnoses and optimal patient outcomes. This paper presents a comprehensive bibliometric analysis of the literature on the three above elements focusing on breast imaging, aiming to uncover publication trends, identify influential works and authors, and highlight future research directions. METHODS: We employed a methodical bibliometric approach, making use of Scopus and Web of Science (WoS) databases for gathering literatures. We planned our search strategy, concentrating on terms linked to "breast imaging," "image quality," and "diagnostic accuracy" to ensure a systematic examination of the subject. The enhanced search functions in these databases enabled us to narrow down and improve our findings, choosing only the articles, conference papers, and book sections that are most relevant. After conducting a thorough screening process to remove duplicates and evaluate significance, we utilized ScientoPy and VOSviewer software for an in-depth bibliometric analysis. This helped to explore trends in publications, patterns of citations, and thematic groups, giving us a better understanding of how the field has changed and where it currently stands. Our approach prioritized assessing methodological quality and bias in the studies we included, guaranteeing the reliability of our findings. RESULTS: We reviewed 2984 relevant publications, revealing a consistent annual growth rate of 2.8% in breast imaging research, with the United States and Europe leading in contributions. The study found that advancements in radiological technologies and international collaboration are driving forces behind the field's expansion. Key subject areas such as 'Radiology, Nuclear Medicine, and Medical Imaging' dominated, underscoring their impact on diagnostic quality. Notable authors and institutions have been identified for their influential research, characterized by high citation metrics and significant scholarly impact. CONCLUSION: The study shows a continuous increase in research on breast imaging, considered by new technologies and teamwork defining the present time. The assessment highlights a key move towards utilizing digital imaging methods and computational analysis, affecting the improvement of future diagnostic procedures and patients' results. The study highlights the importance of continued international collaborations to tackle the new barriers in breast imaging and make the most of technological progress. IMPLICATIONS FOR PRACTICE: This study shows a focus on using interdisciplinary methods and cutting-edge technology in breast imaging to help healthcare professionals improve their performance and accuracy in diagnosis. Recognizing vital research and emerging trends should guide clinical guidelines, radiology training, and patient care plans to encourage the use of effective techniques and stimulate innovation in diagnostic approaches.

Carcinogenicity testing in drug development: Getting it right.

For a pharmaceutical drug, carcinogenicity testing occurs in rodents to identify its tumorigenic potential to allow assessment of the risk from its use in humans. Testing takes the form of 2-year studies in mice and rats and/or more recently, a 6-month study in transgenic mice. This paper examines the process of regulatory interaction regarding carcinogenicity testing, notably through the United States (US) Food and Drug Administration (FDA) Special Protocol Assessment (SPA) process to seek Executive Carcinogenicity Assessment Committee (ECAC) approval. The content of 37 submissions to CAC were examined. The paper also examines the outcome from such agency engagement, notably around study dose level selection as well as looking at the design of proposed carcinogenicity study protocols used in submissions (including numbers of animals, control group aspects and toxicokinetic [TK] evaluation). Overall, it was shown that the current process of regulatory interaction allows for studies acceptable to support eventual drug approval and marketing. However, it was established that areas exist to improve the content of submission documents and study design aspects.

Preventive Pharmacovigilance: timely and precise prevention of adverse events through person-level patient screening and dose-level product surveillance.

The goal of pharmacovigilance (PV) is to prevent adverse events (AEs) associated with drugs and vaccines. Current PV programs are of a reactive nature and rest entirely on data science, i.e., detecting and analyzing AE data from provider/patient reports, health records and even social media. The ensuing preventive actions are too late for people who have experienced AEs and often overly broad, as responses include entire product withdrawals, batch recalls, or contraindications of subpopulations. To prevent AEs in a timely and precise manner, it is necessary to go beyond data science and incorporate measurement science into PV efforts through person-level patient screening and dose-level product surveillance. Measurement-based PV may be called 'preventive pharmacovigilance', the goal of which is to identify susceptible individuals and defective doses to prevent AEs. A comprehensive PV program should contain both reactive and preventive components by integrating data science and measurement science.

Comparison of design methods for a safety run-in phase of a phase II clinical trial.

BACKGROUND/AIMS: In pediatric oncology, a Phase II trial often utilizes a safety run-in phase followed by an efficacy phase that enrolls at the dose level selected based on the safety run-in. Different from a Phase I trial, a Phase II safety run-in often assesses a very small number of dose levels. In the context of a safety run-in that assesses two or three dose levels, this article aims to compare three design methods, including the algorithm-based designs 3 + 3 and Rolling 6, and the model-assisted designs such as the Bayesian optimal interval design. METHODS: Extensive simulations were conducted to evaluate and compare operating characteristics of the three design methods for a safety run-in with two or three dose levels, varying the starting dose level. RESULTS: The performance of algorithm-based and model-assisted designs can be influenced by selection of the starting dose level, with trials starting at a lower dose level having a higher probability of selecting a low dose or considering all doses as toxic. The impact is larger for 3 + 3 and Rolling 6 but to a lesser extent for Bayesian optimal interval design. For a safety run-in with two dose levels, using 3 + 3 or Rolling 6 and starting at the higher dose often lead to similar performance to Bayesian optimal interval design. For safety run-in with three dose levels, starting at the middle dose with 3 + 3, Rolling 6 or Bayesian optimal interval design is a good compromise between improving correct dose selection and imposing a toxic dose to less patients. CONCLUSIONS: Despite being sensitive to the starting dose level, the 3 + 3, Rolling 6 and Bayesian optimal interval designs overall demonstrate reasonable performance, which can be further improved with wise selection of the starting dose level. The Rolling 6 design remains the recommended design method especially if pharmacokinetics is important or required with this design having the feature of treating six patients per dose level. When designing a safety run-in, selection of a design method or selection of a starting dose should consider both the performance of the design approaches with different choices of a starting dose level and the magnitude of safety concerns with the dose levels under investigation.

Computed Tomography Dose Level in Selected Five Principal Hospitals in Ethiopia.

Background: X-ray Computed Tomography dose levels have been varying among modalities and scanning body regions due to the absence of incessant routine follow-up. Thus, the study aimed to compute the dose index discrepancies in Ethiopia for the most recurring scan protocols (head, chest, abdomen, and pelvis). Methods: A purposive sampling method was employed to select the hospitals due to the rare existence of functional CT scanners in Ethiopia. From the selected hospitals, a total of 1,385 (249 heads, 804 chests, 132 abdomens, and 200 pelvis) were collected in terms of standard dose metric values in the period of December 2019-March 2020. Patients' DLP was computed into mean value using IBM SPSS Statistics 20 software. From the mean DLP, we can compute the effective dose. Results: Patients' dose level disparity was observed in this study though it is below the ICRP standard level for all body regions except for pelvis DLP (593.37 mGy-cm) at Black Lion. The dose level for the head and chest are computed within the recommended level at all hospitals. Effective doses for the pelvis at four hospitals (Teklehaimanot, Black Lion, ALERT, Paul's, and Ayder hospitals) were computed as 6.45, 8.90, 5.08, 6.54, and 6.84 mSv respectively, and the effective doses for abdomen at Ayder Hospital was obtained to be 8.90 mSv, which is above the recommended value. Conclusion: X-ray CT scanners are somewhat properly functioning although some sort of justification and optimization for pelvis and abdomen examinations are strongly recommended to implement as low as reasonably achievable principle.

A Phase 1 Dose-Escalation Study of the Cardiac Myosin Inhibitor Aficamten in Healthy Participants.

This phase 1, randomized, double-blind, placebo-controlled study of aficamten (formerly CK-3773274) in healthy adults identified a pharmacologically active range of doses and exposures. At doses that were pharmacologically active (single doses of ≤50 mg or daily dosing of ≤10 mg for 14 or 17 days), aficamten appeared to be safe and well tolerated. Adverse events were generally mild and no more frequent than with placebo. Pharmacokinetic assessments showed dose proportionality over the range of single doses administered, and pharmacokinetics were not affected by administration with food or in otherwise healthy individuals with a cytochrome P450 2D6 poor metabolizer phenotype. (A Single and Multiple Ascending Dose Study of CK-3773274 in Health Adult Subjects; NCT03767855).

Technical note: Relationship between peak skin dose and fluoroscopic Ka,r : Clinical variations and application in establishing substantial radiation dose levels.

BACKGROUND: The reference point cumulative air kerma (Ka,r ) is a commonly used dose quantity for establishing substantial radiation dose levels (SRDLs) that can provide guidance for patient dose management actions following fluoroscopically guided procedures. However, the Ka,r may not correlate well with the patient peak skin dose (Dskin,max ) because the relationship between Ka,r and Dskin,max may vary widely due to clinical variations. Therefore, it may be prudent for institutions to establish different Ka,r -based SRDL values based on the clinical procedure type. PURPOSE: The present study investigates the relationship between Ka,r and Dskin,max for different clinical services and how that variation may overestimate or underestimate the need for patient follow-up. Additionally, the study suggests a possible framework for establishing Ka,r SRDLs based on the clinical data analysis. METHODS: A retrospective analysis was performed for fluoroscopically guided interventions exceeding 5 Gy Ka,r . For each procedure, the patient Dskin,max was estimated and the ratio of Dskin,max to Ka,r (DKR) was calculated. Results were pooled into one of three clinical service categories: body interventions (n = 33), cardiac interventions (n = 81), or neurological (neuro) interventions (n = 44). The distributions in Ka,r , Dskin,max , and DKR were analyzed in aggregate and by the clinical service category. RESULTS: The median Ka,r values for procedures exceeding 5 Gy were 6.0 Gy (95% CI [5.6, 6.4]) for body interventions, 5.8 Gy (95% CI [5.5, 6.0]) for cardiac interventions, and 6.3 Gy (95% CI [5.9, 6.6]) for neuro interventions. Dskin,max for the same procedure data sets were 5.0 Gy (95% CI [4.4, 5.6]) for body interventions, 5.5 Gy (95% CI [5.2, 5.8]) for cardiac interventions, and 3.7 Gy (95% CI [3.4, 4.0]) for neuro interventions. This resulted in median DKR values of 0.81 for body interventions, 0.91 for cardiac interventions, and 0.59 for neuro interventions. CONCLUSIONS: This study illustrates the need to understand the relationship between the reported Ka,r and the patient Dskin,max for different types of interventional procedures. This is especially important when an institution uses Ka,r as the parameter for establishing an SRDL threshold to identify patients who may require clinical follow-up. The implications of this research and a guide for how to implement these findings are elaborated on in the Discussion.

Dose level of pediatric CT scanning in a hospital / 中国辐射卫生

@#<b>Objective</b> To investigate the dose level of pediatric CT scan in one hospital, and to provide recommendations for optimized scanning. <b>Methods</b> The CT scan data of children were collected from this hospital to analyze the differences in typical dose values and typical scanning parameters between different age groups and different scanning parts. <b>Results</b> The sample size was >10 for routine cranial scan, routine maxillary sinus scan, and routine chest scan in each age group, and the 1-year-old group and the 5-year-old group had the same kV, mA, and CTDIvol values of routine cranial scan and maxillary sinus scan, but with relatively great differences in the parameters of chest scan. <b>Conclusion</b> Scanning parameters in this hospital can be further optimized, and optimization measures should be adopted continuously.

Toward a comparison and an optimization of CT protocols using new metrics of dose and image quality part I: prediction of human observers using a model observer for detection and discrimination tasks in low-dose CT images in various scanning conditions.

In the context of reducing the patient dose coming from CT scanner examinations without penalizing the diagnosis, the assessment of both patient dose and image quality (IQ) with relevant metrics is crucial. The present study represents the first stage in a larger work, aiming to compare and optimize CT protocols using dose and IQ new metrics. We proposed here to evaluate the capacity of the Non-PreWhitening matched filter with an eye (NPWE) model observer to be a robust and accurate estimation of IQ. We focused our work on two types of clinical tasks: a low contrast detection task and a discrimination task. We designed a torso-shaped phantom, including Plastic Water®slabs with cylindrical inserts of different diameters, sections and compositions. We led a human observer study with 13 human observers on images acquired in multiple irradiation and reconstruction scanning conditions (voltage, pitch, slice thickness, noise level of the reconstruction algorithm, energy level in dual-energy mode and dose), to evaluate the behavior of the model observer compared to the human responses faced to changing conditions. The model observer presented the same trends as the human observers with generally better results. We rescaled the NPWE model on the human responses by scanning conditions (kVp, pitch, slice thickness) to obtain the best agreement between both observer types, estimated using the Bland-Altman method. The impact of some scanning parameters was estimated using the correct answer rate given by the rescaled NPWE model, for both tasks and each insert size. In particular, the comparison between the dual-energy mode at 74 keV and the single-energy mode at 120 kVp showed that, if the 120 kVp voltage provided better results for the smallest insert at the lower doses for both tasks, their responses were equivalent in many cases.

Measurement of dose field distribution around mobile cone beam computed tomography (CBCT) / 中国辐射卫生

Objective To measure the peripheral dose distributions of the mobile head cone beam computed tomography (CBCT) and evaluate the impact of CBCT on the surrounding personnel and environment, and provide data support for clinical radiation protection management. Methods Combined with the structural characteristics of CBCT, AT1123 was used in the direction of 0° (counterclockwise), 45°, 90°, 135°, 180°, 225°, 270° and 315° in front of CBCT to measure the ambient dose equivalent rate of 30 cm, 80 cm and 130 cm away from the ground when the equipment was normally out of the beam, and the boundary of the temporary control area was drawn. At the same time, the dose level behind the lead screen 1 m away from the external surface of the equipment was measured and analyzed. Results The dose field around CBCT was symmetrically distributed with the dividing line of 0° and 180°, and the radiation dose level of 5.5 m in the direction of 0°, 3.5 m in the direction of 45°, 0.5 m in the direction of 90° and within 1.0 m in the direction of 180° (inside the "spoon" type) was higher than 2.5 μSv/h. The radiation dose levels of CT aperture 0° (straight forward), 45° and 315° behind the lead screen 1 m away from the equipment surface were 0.37 μSv/h, 0.22 μSv/h and 0.54 μSv/h, respectively. Conclusion The results show that the radiation dose around the mobile head cone beam CT is in a low dose level, the distribution of the dose field can provide necessary reference for the administrative and medical personnel to strengthen the radiation safety management. At the same time, it is suggested that lead screens should be set up in the clinical use of mobile CT to ensure the health and safety of the surrounding people and the environment.

Plasma, liver, and kidney exposures in rats after oral doses of industrial chemicals predicted using physiologically based pharmacokinetic models: A case study of perfluorooctane sulfonic acid.

A simplified physiologically based pharmacokinetic (PBPK) model consisting of chemical receptor, metabolizing and/or excreting, and central compartments was recently proposed. In the current study, this type of PBPK model was set up for perfluorooctane sulfonate, an environmental toxicant with liver effects, as a model compound; the model was then used to estimate tissue concentrations. The pharmacokinetic parameter input values for the model were calculated to give the best fit to reported/measured blood substrate concentrations in rats. The maximum concentrations and areas under the concentration versus time curves in plasma, liver, and kidney extrapolated using PBPK models for perfluorobutane sulfonic acid, perfluorohexane sulfonic acid, and perfluorooctane sulfonic acid were consistent with the reported mean values in rats. Using the rat models and scaled-up human PBPK models, some accumulation of perfluorooctane sulfonic acid in plasma and liver was seen after repeated doses. The reported 50th and 95th percentile concentrations of perfluorooctane sulfonic acid in human blood (0.0048 and 0.0183 ng/mL, respectively) in the general population underwent reverse dosimetry analysis using our PBPK models. These human blood concentrations potentially imply exposures of 0.041 and 0.16 µg/kg/day, respectively, for 90 days, values that are roughly similar to the reference dose (0.02 µg/kg/day) with an uncertainty factor of 30. These results indicate the relatively good estimates for tissue and blood exposures of chemical substrates after oral doses generated using the latest PBPK models.

Exposure to environmentally-relevant concentrations of hexavalent chromium does not induce ovarian toxicity in mice.

Exposure to high concentrations of hexavalent chromium [Cr(VI)] in drinking water (≥250 ppm) is reported to decrease ovarian follicle counts and increase follicular atresia in mice. To assess effects at lower concentrations, herein we exposed B6C3F1 mice to 0.1-150 ppm Cr(VI) in drinking water for 90 days in a GLP-compliant study. Ovarian follicular counts, differentiation, and degeneration were assessed from every 10th serial section (up to 14 sections per ovary). Ovarian follicular counts, differentiation, and rate of atresia were not altered in any exposure group. Gross and microscopic changes were not apparent in any of the evaluated reproductive or glandular organs. The no observable adverse effect level (NOAEL) for follicular effects was 150 ppm. In addition to these findings, published Cr(VI) studies examining follicles were scored using two methods for assessing study quality for use in risk assessment-including the Toxic Substance Control Act (TSCA) scoring method. Both methods revealed that studies reporting adverse effects on follicles generally received low scores. Overall, the current study indicates no/low potential for Cr(VI) to induce follicular toxicity in mice below 150 ppm Cr(VI) in drinking water (17.7 mg/kg bodyweight).

A survey of computed tomography dose index and dose length product level in usual computed tomography protocol.

BACKGROUND: Nowadays, the use of computed tomography (CT) as a diagnostic tool has been considerably increased. Therefore, implementation of the program to conform the protection regulations on the CT scan is necessary to reduce the detrimental effects of radiation. OBJECTIVE: This study was performed to measure weighted CT dose index (CTDIW) and dose length product (DLP) in routine CT protocols of the adult patients. METHODS: In this study, the patient dose was determined in routine CT protocols. The CT scanner used in this study was a single-slice Toshiba model. Scan parameters for each protocol were registered for 10 standard sized patients and then by applying it to the CT system, CTDIw and DLP mean values were calculated and finally the values of dose were compared with the reference dose limit. RESULTS: The mean values of CTDIw and DLP for head, para nasal sinuses, chest, abdomen, and pelvis protocols were 34.11, 19.67, 15.47, 13.95, 10.08 mGy and 362.67, 153.97, 307.33, 346.07, 189.37 mGy.cm, respectively. The mean values of CTDIW and DLP obtained in all of the protocols were less and even less than half in some of the protocols compared with the European guidelines and the UK reference values. However, mean values of CTDIw in the Chest and Abdomen protocols, were greater than IAEA reported values. CONCLUSIONS: Using lower milli Amperes and higher kilo voltage peak as well as minimizing scan area and number of slices should be considered for more reduction in patients' dose.

Mycophenolate mofetil following glucocorticoid treatment in Henoch-Schönlein purpura nephritis: the role of early initiation and therapeutic drug monitoring.

BACKGROUND: Henoch-Schönlein purpura (HSP) is the most common vasculitis in childhood and traditionally considered as a self-limiting disease. However, renal involvement can unfavorably determine long-term prognosis. The reported regimens to treat HSP nephritis (HSPN) are diverse, indicating that the most effective treatment remains controversial. METHODS: This retrospective, single-center study involved 18 patients presenting with HSPN and nephrotic-range proteinuria. We aimed to investigate the efficacy and safety of mycophenolate mofetil (MMF) and identify a cut-off level for estimated mycophenolic acid area under the curve (eMPA-AUC0-12h) values, which can predict complete remission with high sensitivity. RESULTS: Despite prior insufficient therapeutic response to corticosteroids, 89% of patients showed a significant decrease in proteinuria after 1 month of MMF treatment. None of them relapsed during treatment; however, two children relapsed after discontinuation. Based on results of a receiver operating characteristic (ROC) analysis, an eMPA-AUC0-12h >56.4 mg*h/l was a predictor for complete remission within 3 months (80% sensitivity, 83.3% specificity, p = 0.035). During MMF administration, we encountered no adverse event requiring discontinuation of treatment. CONCLUSION: Our study demonstrates that MMF is a safe and potentially effective secondary treatment option for children with HSPN to achieve and maintain long-term remission without serious side effects. To achieve complete remission within 3 months, resolve severe inflammatory glomerular lesions, and avoid progression to chronic kidney disease, we propose timely diagnosis and early initiation of MMF with an eMPA-AUC0-12h value of 56.4 mg*h/l.

Derivation of an oral Maximum Allowable Dose Level for Bisphenol A.

Bisphenol A (BPA) is a high production volume chemical that is used in plastics and epoxy coatings. In 2015, California's Office of Environmental Health Hazard Assessment (OEHHA) added BPA to the Proposition 65 list of chemicals "known to cause reproductive toxicity" based on its Developmental and Reproductive Toxicant Identification Committee's (DART-IC) conclusion that BPA has been shown to cause female reproductive toxicity. A critical factor in determining compliance with Proposition 65 is a Maximum Allowable Dose Level (MADL), which is the exposure level at which a chemical would have no observable reproductive effect even if a person were exposed to 1000 times that level. We performed a comprehensive review of the literature, including the studies reviewed by DART-IC, and derived an oral MADL. Of all the studies we identified, Delclos et al. (2014) is of sufficient quality, has the lowest no observed effect level (NOEL), and results in the most conservative MADL of 157 µg/d. This is generally supported by other studies, including those that were considered by DART-IC. Also, the oral MADL provides a similar margin of safety as OEHHA's dermal MADL and other regulatory guidelines. Taken together, the scientific data support an oral MADL of 157 µg/d.

Subchronic Toxicological Assessment of Diosgenin in Kunming Mice / 世界科学技术-中医药现代化

This study was aimed to evaluate the subchronic toxicity of diosgenin in mice. A total of 80 mice were divided into 4 groups, which were 0 (control), 100, 200, and 400 mg·kg-1 by the random number table. Intragastric administration was given once a day for 90 days in the assessment of subchronic toxicity of diosgenin among mice. The observed indexes contained body weight, fur color, diet, feces, and etc. The detected indexes contained blood routine analysis, blood biochemistry and pathological examination. The results showed that compared with the control group, the body weights of mice in the male medication group were slight reduced. There were no significant hematologic and pathologic abnormalities. It was concluded that the subchronic toxicity of diosgenin with no observed adverse effect dose level was more than 400 mg·kg-1. The oral administration was relatively safe.

Preliminary study on the radiological and physicochemical quality of the Umgeni Water catchments and drinking water sources in KwaZulu-Natal, South Africa.

Raw and potable water sample sources, from the Umgeni Water catchment areas (rivers, dams, boreholes) in central KwaZulu-Natal (South Africa), were screened for Uranium concentration and alpha and beta radioactivity. Test methods used were gas flow proportional counting for alpha-beta radioactivity, and kinetic phosphorescence analysis (KPA), for Uranium. The uranium levels (median = 0.525 µg/L, range = <0.050-5.010) were well below the international World Health Organization (WHO) (2011) guideline for drinking-water quality (≤15 µg/L). The corresponding alpha and beta radioactivity was ≤0.5 Bq/L (median = 0.084, Interquartile Range (IR) = 0.038, range = 0.018-0.094), and ≤1.0 Bq/L (median = 0.114, IR = 0.096, range = 0.024-0.734), respectively, in compliance with the international WHO limits. For uranium radionuclide, the average dose level, at uranium level of ±0.525 µg/L, was 0.06 µSv/a, which complies with the WHO reference dose level for drinking water (<0.1 mSv/a). There was a distinct trend of cluster of relatively higher Uranium levels of some sources that were found to be associated with the geology/geography and groundwater sources. Overall, the radiological water quality classification, with respect to WHO, is "Blue" - ideal; additional physicochemical analyses indicated good water quality. The analytical test methods employed were found to be suitable for preliminary screening for potential radioactive "hot spots". The observed Uranium levels, and the alpha/beta radioactivity, indicate contribution largely from Naturally Occurring Radioactive Material (NORM), with no significant health risk to humans, or to the environment.

Estimation of health risk by using toxicokinetic modelling: a case study of polychlorinated biphenyl PCB153.

To assess potential PCB153-associated human health effects and risks, it is necessary to model past exposure. PCB153 blood concentrations, obtained from the AMAP biomonitoring programme, in Inuit women covering the years 1994-2006 at Disko Bay, 1999-2005 at Nuuk, and 1992-2007 at Nunavik were used to extrapolate body burden and exposure to the whole lifespan of the population by the one-compartment toxicokinetic model. By using risk characterisation modelling, calculated Hazard Quotients were higher than 1 between the years 1955 and 1987 for the 90th population percentile and during 1956-1984 for the 50th population percentile. Cancer risk for overall exposure of PCB153 ranged from 4.6×10(-5) to 1.8×10(-6) for the 90th percentile and 3.6×10(-5) to 1.4×10(-10) for the 50th percentile between 1930 and 2049, when central estimates or upper-bound slope factors were applied. Cancer risk was below 1×10(-6) for the same time period when a lower slope factor was applied. Significant future research requirements to improve health risk characterisation include, among others, larger sample sizes, better analytical accuracy, fewer assumptions in exposure assessment, and consequently, a better choice of the toxicity benchmark used to develop the hazard quotient.

Complex mixtures: relevance of combined exposure to substances at low dose levels.

Upon analysis of chemically complex food matrices a forest of peaks is likely to be found. Identification of these peaks and concurrent determination of the toxicological relevance upon exposure is very time consuming, expensive and often requires animal studies. Recently, a safety assessment framework based on the Threshold of Toxicological Concern (TTC) was published to assess the safety of chemically complex matrices more efficiently. In this safety assessment framework, the toxicological relevance of exposure to unidentified substances in chemically complex food matrices can be related to the Cramer class III TTC threshold, currently set at 90 µg/day. However, possible additive or synergistic effects of combined exposure is not covered. The current evaluation describes the relevance of combined low dose exposure to unidentified substances in chemically complex food matrices. It is concluded that to some extent cumulative effects at exposure levels for each substance at or below the Cramer class III TTC threshold, being present in a complex mixture including food, might occur. However the health relevance of possible cumulative effects at this dose level is considered to be that low that a need for a correction factor to cover possible cumulative effects is very low to absent.