Bioavailability adjustments for parenteral leachables

When assessing chemical safety, toxicologists often need to use data from one route of administration to assess the risk of exposure via another. A recent publication has presented a workflow for how to make such a bioavailability adjustment when deriving Permitted Daily Exposure (PDE) values for leachables in parenteral drug products.

A database of 60 potential leachables was analysed, using three methods to derive a Bioavailability Adjustment Factor (BAF): (i) using available experimental bioavailability data for the leachable itself; (ii) applying read-across to a suitably similar surrogate with bioavailability data; and (iii) estimating bioavailability from physicochemical properties. In each case, key factors were outlined to help experts review the reliability of the bioavailability values derived in a weight-of-evidence assessment, providing more reliable BAFs.

The resulting workflow recommends that toxicologists carefully assess the reliability of any data used to directly derive BAFs, by considering the type of study, tested species, and first-pass metabolism. For BAFs determined using read-across, it is important to ensure the surrogate has sufficient structural, physicochemical and metabolic similarity. Finally, when data are lacking and physicochemical properties are used to estimate bioavailability, there is a need to consider if lipophilicity can be estimated, and whether the substance contains any metabolically labile groups.

Overall, it is hoped that this work will promote harmonisation between toxicologists and reduce the need for animal testing when using oral toxicity data to assess parenteral exposure to chemicals.

Reference: Regulatory Toxicology and Pharmacology

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EFSA evaluation of aspartame-acesulfame salt

The EFSA FAF Panel has re-evaluated the safety of aspartame-acesulfame salt (E 962) as a food additive, previously considered in 2000 by the Scientific Committee on Food (SCF). No biological or toxicological data specific to the salt were identified but, given that it dissociates upon ingestion into the ions of the authorised sweeteners aspartame (E 951) and acesulfame K (E 950), the Panel assessed its safety based on the available information on these two sweeteners. It used the 2025 EFSA evaluation of acesulfame K (which established an Acceptable Daily Intake (ADI) of 15 mg/kg bw), and updated the 2013 EFSA evaluation of aspartame (both the exposure and toxicology data, with no change in its ADI of 40 mg/kg bw). The Panel concluded that the estimated dietary exposures to both substances, including from the aspartame-acesulfame salt, were below their respective ADIs across all population groups, and that there is no safety concern at the reported uses and use levels for all three substances. It recommended that the EU specifications for the aspartame-acesulfame salt be updated, including an assurance that the sweeteners it is produced from comply with their respective specifications.

Reference: EFSA

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JRC releases report on Artificial Intelligence (AI) for biological research

In a rather timely release, the European Commission’s Joint Research Centre has published an overview of the current landscape of AI in the life sciences. Following a review of the capabilities and trends of over 450 biological AI models, including for the prediction of toxicity and Absorption, Distribution, Metabolism and Excretion (ADME), it was noted that these models can bring significant benefits in research areas such as protein design, genome analysis and drug discovery. However, the use of AI also raises important questions and challenges, particularly since frameworks for assessing the readiness, misuse potential, and deployment risk of the models are still being developed. The main review findings and key conclusions are presented, along with salient objectives including the need to set realistic expectations of AI models, inform on current (and future) research trends, and support informed policy and governance decisions with regard to AI in biology.

Reference: European Commission

FDA updates nitrosamine guidance to allow the use of LTL adjustments

The ICH M7(R2) guideline on the “Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk” allows Acceptable Intake (AI) limits to be adjusted when the duration of drug treatment is Less-Than-Lifetime (LTL). However, global regulatory agencies have previously not recommended the use of LTL adjustments for nitrosamine AI limits due to several data gaps for this potent class of genotoxic carcinogens.

Based on recently published research from the Health and Environmental Sciences Institute (HESI), which addressed those data gaps, the FDA’s Center for Drug Evaluation and Research (CDER) has released a non-binding guidance document which states that there is now scientific support for the use of LTL approaches for nitrosamine impurities. The use of these adjustments, however, is not recommended for any interim nitrosamine AI limits. Any applications to the Agency using LTL-adjusted AI limits should contain a scientific rationale for their use and will be assessed on a case-by-case basis.

Reference: FDA

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European Parliament reports on the health effects of fine particulate matter

A recent review from two Committees of the European Parliament showed consistent health effects resulting from exposure to fine particulate matter, PM2.5 and PM10, across multiple disease categories. Effects include heart attacks and strokes, lung disease (including asthma, chronic obstructive pulmonary disease (COPD) and cancer), cognitive impairment, depression and neurodevelopmental conditions. No safe threshold for exposure could be identified. Consideration of the literature, quantitative analysis of exposure trends, stakeholder interviews, and comparative case studies across EU Member States indicate that air quality has improved significantly across the EU since 2005, with overall PM2.5-attributable premature deaths having fallen by approximately 57% over this period. However, persistent inequalities in exposure were identified across populations (older adults having greater cumulative lifetime exposure) and regions (the poorest fifth of EU regions were exposed to around 30% more PM2.5 than the wealthiest). The overall downward exposure trend was considered to be a direct result of EU and national legislation covering vehicle emissions, industrial processes and fuel standards, but significant legislative gaps were identified, including those concerning exposure through agricultural emissions (specifically ammonia), residential wood-burning and emissions from domestic heating appliances. The review also outlined evidence-based policy recommendations to further reduce the health impacts of exposure to fine particulate matter across the EU. 

Reference: European Union

Written by

Craig Freeman

Craig Freeman

Senior Toxicologist

Qualifications

BSc in Biological and Medicinal Chemistry

UK Registered Toxicologist (UKRT)

European Registered Toxicologist (ERT)

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