It is a truth not always recognised that toxicological hazard and risk assessment as currently practiced is a ball-park science, and a health criteria value – a Tolerable Daily Intake (TDI), a Permitted Daily Exposure (PDE) or similar – quoted to 2 significant figures is probably one significant figure more than the data really can confidently support. Occasionally practitioners will let the mask slip. A recent exercise from a group of scientists from the pharmaceutical sector was commendably open when they compared their companies’ attempts to develop PDEs for five marketed Active Pharmaceutical Ingredients (APIs) (amlodipine, hydrochlorothiazide, metformin, morphine, and omeprazole). They noted that inter-company bottom lines of “up to 3-fold are normal, and between 3 and 10-fold may be justified and should not be of concern on a regulatory perspective” (Sehner et al., 2024).

With this in mind, we would have been sanguine if there was not total Expert Group agreement on the amount of bisphenol A (BPA) we could tolerate daily before our health was threatened, even if said experts were looking at essentially the same dataset. Sadly, the current BPA saga risks undermining the very credibility of applied toxicology, as Expert Group differences of opinion on what constitutes a tolerable level of ingested BPA has stretched way beyond breaking point. Whilst a Panel of the European Food Safety Authority (EFSA) favoured 0.2 ng/kg bw/day (EFSA, 2023), the German Federal Institute for Risk Assessment (BfR), although fully aware of the EFSA opinion, felt that 0.2 µg/kg bw/day (three orders of magnitude higher than the EFSA figure) was more appropriate. Subsequent discussions between EFSA and the BfR gave little indication that either party wanted to alter its position (EFSA/BfR, 2023). The European Medicines Agency (EMA) has weighed into the debate, essentially disagreeing with most of the major EFSA decisions involved in the derivation of the ng/kg bw TDI (EFSA/EMA, 2022), as have the Senate Commission on Food Safety of the German Research Foundation (Leist et al., 2024), and the UK Committee on Toxicity (COT, 2024). The COT, keen not to duplicate effort, particularly with a database this large, has decided “to adopt the TDI derived by the BfR” (COT, 2024).

There is some pretty heavy science involved here, and the breadth of commitment among the members of the EFSA Panel to the bottom line is unknown. The German, UK and EMA opposition though is united in one general criticism of the EFSA effort, the Panel’s confidence that an upstream finding, a BPA-related, subtle change in one immune system cell type in the cellular profile of mice, will likely result in an adverse health impact in the real world. We must be fair to the EFSA Panel and note that a group of about 40 academics “strongly support” EFSA’s BPA endeavours. The 40 include several very vocal critics of the current means of evaluating endocrine disruptors, and this is reflected in their final conclusion that “additional giant steps are needed to completely redesign the methods used to regulate exposure to tens-of-thousands of untested chemicals in food, beverages, and household products” (vom Saal et al., 2024). Is the EFSA Panel’s view on BPA the first sign that at least some of the previously more conservative toxicologists that inhabit the regulatory scene are ready to embark on this uncharted voyage? The EFSA Panel reported that both the mean and the 95th percentile dietary BPA exposures, as estimated in their 2015 report, exceed the new TDI by two to three orders of magnitude in all age groups, including all infant and toddler groups (EFSA, 2023). However, the exposure estimates are below or around the BfR tolerable figure. Thus, the difference in Expert Group views is not merely academic. The debate continues…

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