Development of the Threshold of Toxicological Concern Concept and its Relationship to Duration of Exposure

Brigo, Alessandro; Müller, Lutz

doi:10.1002/9780470929377.ch2

Cited by 8 publications

(7 citation statements)

References 52 publications

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“…Examples of classspecific AIs are the monofunctional alkyl chloride and bromide compounds. 3,6,26 ICH Q3A/Q3B thresholds. Depending on the source of the impurity (process impurity or storage degradant), if nonmutagenic, application of the default ICH Q3A or Q3B qualification thresholds is appropriate.…”

Section: Approaches To Consider When There Is No Toxicology Data Available To Establish a Pde Or Aimentioning

confidence: 99%

Deriving Compound-Specific Exposure Limits for Chemicals Used in Pharmaceutical Synthesis: Challenges in Expert Decision-Making Exemplified Through a Case Study-Based Workshop

et al. 2021

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A workshop entitled “Deriving Compound-Specific Exposure Limits for Chemicals Used in Pharmaceutical Synthesis” was held at the 2018 Genetic Toxicology Association annual meeting. The objectives of the workshop were to provide an educational forum and use case studies and live multiple-choice polling to establish the degree of similarity/diversity in approach/opinion of the industry experts and other delegates present for some of the more challenging decision points that need to be considered when developing a compound-specific exposure limit (ie, acceptable intake or permissible or permitted daily exposure). Herein we summarize the relevant background and case study information for each decision point topic presented as well as highlight significant polling responses and discussion points. A common observation throughout was the requirement for expert judgment to be applied at each of the decision points presented which often results in different reasoning being applied by the risk assessor when deriving a compound-specific exposure limit. This supports the value of precompetitive cross-industry collaborations to develop compound-specific limits and harmonize the methodology applied, thus reducing the associated uncertainty inherent in the application of isolated expert judgment in this context. An overview of relevant precompetitive cross-industry collaborations working to achieve this goal is described.

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Section: Approaches To Consider When There Is No Toxicology Data Available To Establish a Pde Or Aimentioning

confidence: 99%

Deriving Compound-Specific Exposure Limits for Chemicals Used in Pharmaceutical Synthesis: Challenges in Expert Decision-Making Exemplified Through a Case Study-Based Workshop

et al. 2021

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“…The most common classes of structurally alerting potential impurities are alkylating agents and aromatic amines (see for example Delaney, []; Galloway et al, []). Based on the analysis by Brigo and Müller [] of the potency of alkyl halides, a class limit for monofunctional alkyl chlorides was adopted in ICH M7, recommending that limits 10 times the default TTC‐based ADI were acceptable for alkyl chlorides that did not have carcinogenicity data. Discussion continues on aromatic amines which have a very wide range of carcinogenic potencies, (see for example Brigo and Müller []).…”

Section: Ich M7: Assessment and Control Of Dna Reactive (Mutagenic) Imentioning

confidence: 99%

“…Based on the analysis by Brigo and Müller [] of the potency of alkyl halides, a class limit for monofunctional alkyl chlorides was adopted in ICH M7, recommending that limits 10 times the default TTC‐based ADI were acceptable for alkyl chlorides that did not have carcinogenicity data. Discussion continues on aromatic amines which have a very wide range of carcinogenic potencies, (see for example Brigo and Müller []). Class‐specific limits were not adopted for aromatic amines in ICH M7 and further analysis is needed, but based on existing data with the classes of aromatic amines used in drug syntheses, an argument can be made that the structural characteristics of the most potent are identifiable, and for aromatic amines without those structures a class limit 5X the default may be appropriate [Galloway et al, ].…”

Section: Ich M7: Assessment and Control Of Dna Reactive (Mutagenic) Imentioning

confidence: 99%

International regulatory requirements for genotoxicity testing for pharmaceuticals used in human medicine, and their impurities and metabolites

Galloway

2017

Environ and Mol Mutagen

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The process of developing international (ICH) guidelines is described, and the main guidelines reviewed are the ICH S2(R1) guideline that includes the genotoxicity test battery for human pharmaceuticals, and the ICH M7 guideline for assessing and limiting potentially mutagenic impurities and degradation products in drugs. Key aspects of the guidelines are reviewed in the context of drug development, for example the incorporation of genotoxicity assessment into non-clinical toxicity studies, and ways to develop and assess weight of evidence. In both guidelines, the existence of "thresholds" or non-linear dose responses for genotoxicity plays a part in the strategies. Differences in ICH S2(R1) protocol recommendations from OECD guidelines are highlighted and rationales explained. The use of genotoxicity data during clinical development and in assessment of carcinogenic potential is also described. There are no international guidelines on assessment of potentially genotoxic metabolites, but some approaches to safety assessment are discussed for these. Environ. Mol. Mutagen. 58:296-324, 2017. © 2017 Wiley Periodicals, Inc.

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“…Chemicals may induce DNA damage by directly interacting with it (e.g., alkylating agents) or by acting on non-DNA targets (e.g., mitotic spindle poisons, inhibitors of topoisomerase, etc.). For DNA-reactive genotoxins, the mechanism by which they induce genetic damage is assumed to follow a linear no-threshold model; on the other hand, for molecules not interacting directly with DNA, the existence of a threshold concentration required to induce the damage is by and large accepted [ 44 ]. Impurities that belong to the second category of substances can be regulated according to the ICH Quality Guideline Q3C [ 45 ] which includes class 2 solvents.…”

Section: Assessment Of Potential Genotoxic Impuritiesmentioning

confidence: 99%

The Use of In Silico Models Within a Large Pharmaceutical Company

Brigo¹,

Muster²

2016

Methods in Molecular Biology

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The present contribution describes how in silico models are applied at different stages of the drug discovery process in the pharmaceutical industry. A thorough description of the most relevant computational methods and tools is given along with an in-depth evaluation of their performance in the context of potential genotoxic impurities assessment.The challenges of predicting the outcome of highly complex studies are discussed followed by considerations on how novel ways to manage, store, share and analyze data may advance knowledge and facilitate modeling efforts.

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Development of the Threshold of Toxicological Concern Concept and its Relationship to Duration of Exposure

Cited by 8 publications

References 52 publications

Deriving Compound-Specific Exposure Limits for Chemicals Used in Pharmaceutical Synthesis: Challenges in Expert Decision-Making Exemplified Through a Case Study-Based Workshop

Deriving Compound-Specific Exposure Limits for Chemicals Used in Pharmaceutical Synthesis: Challenges in Expert Decision-Making Exemplified Through a Case Study-Based Workshop

International regulatory requirements for genotoxicity testing for pharmaceuticals used in human medicine, and their impurities and metabolites

The Use of In Silico Models Within a Large Pharmaceutical Company

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