Guidance on the use of the benchmark dose approach in risk assessment

More, Simon John; Bampidis, Vasileios; Benford, Diane; Bragard, Claude; Halldórsson, Thorhallur I.; Hernández‐Jerez, Antonio F; Bennekou, Susanne Hougaard; Koutsoumanis, Kostas; Lambré, Claude; Machera, Kyriaki; Mennes, Wim; Mullins, Ewen; Nielsen, S. S.; Schrenk, Dieter; Turck, Dominique; Younes, Maged; Aerts, Marc; Edler, Lutz; Sand, Salomon; Wright, Matthew; Binaglia, Marco; Bottex, Bernard; Abrahantes, José Cortiñas; Schlatter, Josef Rudolf

doi:10.2903/j.efsa.2022.7584

Cited by 62 publications

(102 citation statements)

References 50 publications

(63 reference statements)

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“…Benchmark dose (BMD) analysis was carried out using the PROAST software package developed by RIVM (version 70.0) on the web‐app ‘EFSA‐Proastplatform’ based on the EFSA Scientific Committee guidance ( 2017a ). To judge the width of the BMD credible interval, the set of criteria and cut‐off values described in the latest EFSA Guidance on BMD modelling (EFSA Scientific Committee, 2022 ) were applied. 10…”

Section: Data and Methodologiesmentioning

confidence: 99%

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Risks for human health related to the presence of grayanotoxins in certain honey

Schrenk¹,

Bignami²,

Bodin³

et al. 2023

EFS2

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The European Commission asked EFSA for a scientific opinion on the risks for human health of the presence of grayanotoxins (GTXs) in ‘certain honey’ from Ericaceae plants. The risk assessment included all structurally related grayananes occurring with GTXs in ‘certain’ honey. Oral exposure is associated with acute intoxication in humans. Acute symptoms affect the muscles, nervous and cardiovascular systems. These may lead to complete atrioventricular block, convulsions, mental confusion, agitation, syncope and respiratory depression. For acute effects, the CONTAM Panel derived a reference point (RP) of 15.3 μg/kg body weight for the sum of GTX I and III based on a BMDL 10 for reduced heart rate in rats. A similar relative potency was considered for GTX I. Without chronic toxicity studies, an RP for long‐term effects could not be derived. There is evidence for genotoxicity in mice exposed to GTX III or honey containing GTX I and III, showing increased levels of chromosomal damage. The mechanism of genotoxicity is unknown. Without representative occurrence data for the sum of GTX I and III and consumption data from Ericaceae honey, acute dietary exposure was estimated based on selected concentrations for GTX I and III reflecting concentrations measured in ‘certain’ honeys. Applying a margin of exposure (MOE) approach, the estimated MOEs raised health concerns for acute toxicity. The Panel calculated the highest concentrations for GTX I and III below which no acute effects would be expected following ‘certain honey’ consumption. The Panel is 75% or more certain that the calculated highest concentration of 0.05 mg for the sum of GTX I and III per kg honey is protective for all age groups regarding acute intoxications. This value does not consider other grayananes in ‘certain honey’ and does not cover the identified genotoxicity.

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Section: Data and Methodologiesmentioning

confidence: 99%

“…injection of GTX III in rats (Turkmen et al., 2013 ), using model averaging. BMD analysis was performed according to the EFSA guidance (EFSA Scientific Committee, 2017a and 2022 ).…”

Section: Appendix C – Bmd Analysismentioning

confidence: 99%

Risks for human health related to the presence of grayanotoxins in certain honey

Schrenk¹,

Bignami²,

Bodin³

et al. 2023

EFS2

Self Cite

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“…The toxicity studies that are to be used in the assessment should be designed in such a way that they provide a reliable and useful lower confidence limit of the benchmark dose (BMDL)–upper confidence limit of the benchmark dose (BMDU) intervals 27 in accordance with the EFSA Guidance on Dose Response Modelling (EFSA Scientific Committee, 2022 ) or with the most recent version thereof. For all parameters studied, as specified in the respective OECD TGs, the data should be submitted in an appropriate electronic format (i.e.…”

Section: Safety Datamentioning

confidence: 99%

“…parameters for which a dose‐related effect is observed, including those for which effects are observed only at the top dose) because the results of this analysis are part of the evaluation in Tier II. The reporting of the dose–response modelling should include its results and the information as specified in Appendix E of the EFSA Guidance on Dose Response Modelling (EFSA Scientific Committee, 2022 ).…”

Section: Safety Datamentioning

confidence: 99%

“…The same cut‐off value will be applied for flavouring substances . This criterion would not only apply to an MOE based on a no‐observed‐adverse‐effect level (NOAEL) as reference point, but also to an MOE which is calculated from a BMDL, provided that the benchmark response (BMR) on which this BMDL is based, can be considered of toxicological significance (EFSA Scientific Committee, 2022 ).…”

Section: Safety Datamentioning

confidence: 99%

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Scientific Guidance on the data required for the risk assessment of flavourings to be used in or on foods

Younes¹,

Aquilina²,

Castle³

et al. 2022

EFS2

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Following a request from the European Commission, EFSA developed a new scientific guidance to assist applicants in the preparation of applications for the authorisation of flavourings to be used in or on foods. This guidance applies to applications for a new authorisation as well as for a modification of an existing authorisation of a food flavouring, submitted under Regulation (EC) No 1331/2008. It defines the scientific data required for the evaluation of those food flavourings for which an evaluation and approval is required according to Article 9 of Regulation (EC) No 1334/2008. This applies to flavouring substances, flavouring preparations, thermal process flavourings, flavour precursors, other flavourings and source materials, as defined in Article 3 of Regulation (EC) No 1334/2008. Information to be provided in all applications relates to: (a) the characterisation of the food flavouring, including the description of its identity, manufacturing process, chemical composition, specifications, stability and reaction and fate in foods; (b) the proposed uses and use levels and the assessment of the dietary exposure and (c) the safety data, including information on the genotoxic potential of the food flavouring, toxicological data other than genotoxicity and information on the safety for the environment. For the toxicological studies, a tiered approach is applied, for which the testing requirements, key issues and triggers are described. Applicants should generate the data requested in each section to support the safety assessment of the food flavouring. Based on the submitted data, EFSA will assess the safety of the food flavouring and conclude whether or not it presents risks to human health and to the environment, if applicable, under the proposed conditions of use.

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Interpretation of in vitro concentration‐response data for risk assessment and regulatory decision‐making: Report from the 2022 IWGT quantitative analysis expert working group meeting

Beal,

Chen,

Dearfield

et al. 2024

Environ and Mol Mutagen

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Quantitative risk assessments of chemicals are routinely performed using in vivo data from rodents; however, there is growing recognition that non‐animal approaches can be human‐relevant alternatives. There is an urgent need to build confidence in non‐animal alternatives given the international support to reduce the use of animals in toxicity testing where possible. In order for scientists and risk assessors to prepare for this paradigm shift in toxicity assessment, standardization and consensus on in vitro testing strategies and data interpretation will need to be established. To address this issue, an Expert Working Group (EWG) of the 8th International Workshop on Genotoxicity Testing (IWGT) evaluated the utility of quantitative in vitro genotoxicity concentration‐response data for risk assessment. The EWG first evaluated available in vitro methodologies and then examined the variability and maximal response of in vitro tests to estimate biologically relevant values for the critical effect sizes considered adverse or unacceptable. Next, the EWG reviewed the approaches and computational models employed to provide human‐relevant dose context to in vitro data. Lastly, the EWG evaluated risk assessment applications for which in vitro data are ready for use and applications where further work is required. The EWG concluded that in vitro genotoxicity concentration‐response data can be interpreted in a risk assessment context. However, prior to routine use in regulatory settings, further research will be required to address the remaining uncertainties and limitations.This article is protected by copyright. All rights reserved.

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Guidance on the use of the benchmark dose approach in risk assessment

Cited by 62 publications

References 50 publications

Risks for human health related to the presence of grayanotoxins in certain honey

Risks for human health related to the presence of grayanotoxins in certain honey

Scientific Guidance on the data required for the risk assessment of flavourings to be used in or on foods

Interpretation of in vitro concentration‐response data for risk assessment and regulatory decision‐making: Report from the 2022 IWGT quantitative analysis expert working group meeting

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