Official enthusiasm for the Threshold of Toxicological Concept (TTC) is maintained. That is the tenor of the latest EFSA draft guidance document on this important topic ( If you have any comments to make you have until 8th January 2019 as that is when public consultation of the draft closes.

The draft provides encouragement for those of us who have sought TTC succour when we have needed to evaluate health risks from unknown (unidentified) chemicals. This comes from EFSA’s general approval of a TTC approach in the assessment of mixtures – which presumably could include not only dietary components and migrants from food-contact materials, but also extractables and leachables profiles generally. Of course, the assessor must have sufficient analytical information to be sure that the uncharacterised substances are not beyond the TTC pale, such as the highly potent toxins and carcinogens that make up the Cohorts of Concern. Our analyst colleagues assure us these are relatively easy to spot. Once satisfied on that score, any unknowns can be viewed as mutagens and the lifetime TTC (0.0025 μg/kg bw/day) would apply to their summed exposure. If there are no concerns for genotoxicity, and OPs or carbamates can also be eliminated as possibilities, then the benchmark of safety would be that considered appropriate for Cramer Class III structures, and we would have 1.5 µg/kg bw/day to benchmark oral exposures. We can expect to see similar approaches being more explicitly approved when the new ISO 10993-17 guidance is published (imminently). EFSA rightly reminds us that, as always, case-by-case is the golden rule, always good news for an expert risk assessor. It is also good in a scientific sense to see Expert Groups steering the community towards TTC values based on body weight rather than per capita, albeit all these extra noughts are going to challenge the fact checkers.

The draft confirms EFSA’s 2016 view that hydrazines (once prominent members of the Cohort of Concern) do not in fact merit a position on the naughty step. They are no longer excluded from the TTC approach because only 4% (2 out of 57) of tested hydrazines pose a cancer risk of >1 in 1 million at 0.0025 µg/kg bw/day. Not so good news though for organosilicon substances. EFSA has noted that they are not represented in the toxicity database of Munro et al. so should be added to the short list of the excluded chemical classes that are not worthy of TTC assistance.

The TTC bandwagon continues to roll. The ongoing CEFIC-LRI-sponsored project to generate a curated and quality-controlled database on genotoxic and non-genotoxic carcinogens is something to anticipate. Perhaps even more exciting is the US FDA’s Expanded Decision Tree (EDT) Project that is about to burst onto the scene. This effort involves >18,000 studies and will provide NOAELs for some 2000 substances that will be organized according to their structure, metabolic fate and toxic potential. The hope is that this will strengthen the robustness of the Cramer I, II and III default figures. FDA is also in the process of developing an EDT software and we wait to learn how well its Cramer Class assignations align with those of Toxtree and OECD Toolbox. EFSA acknowledged that software programmer decisions mean Toxtree and Toolbox do not always yield the same Class assignations, a source of frustration to many of us; will EDT add to the mix? We routinely encounter errors in Toxtree and it would make a lovely seasonal gift if we could manually reverse YES/NO answers to allow an analysis to continue on its merry way. It’s worth checking any controversial predictions against the published paper and assessing how the rule changes might affect the classification.

A major challenge for health risk assessors is the fact that Expert Groups tend to focus on deriving default figures for exposures that occur daily for 70 years, which is far from the reality of life. If you are involved in ISO 10993-17-based toxicological risk assessments (TRAs) of extractables from Medical Devices, you’ll be familiar with the concept of deriving Tolerable Intake (TI) figures for the different use duration categories (up to 24 hours, 1-30 days and >30 days), and it would be good to see some intellectual investment in the derivation of tolerable default figures for short-term and intermittent exposures. EFSA continues the traditional practice in the recent draft, saying that “There are currently insufficient data to establish TTC values specifically for short‑term exposure” and concludes that less-than-lifetime exposure should be addressed case-by-case. That’s never bad advice (though not very helpful advice), but is it really such a difficult process? ICH, ECHA, FDA, EPA etc., have all suggested default factors for converting a subacute NOAEL to a subchronic NOAEL and the latter to a chronic equivalent. Is any Expert Group willing to reverse the logic and say that a lifetime ADI could be increased perhaps 2-5-fold to generate an ADI for short-term human exposure? At least as a working value?

EFSA provides some useful guidance on how TTC might be applied to infants, a time of life where some enzyme activities and kidney function are sub-optimal. For infants <16 weeks of age, the recommendation is for an additional uncertainty factor (UF) of 3, increasing the standard UF for inter-individual human variability to 30.

Advice on predicting the mutagenic potential of untested compounds of known structure remains essentially unchanged. To optimise sensitivity/specificity in predicting mutagenicity, at least two independent (Q)SAR models should be used (alert and statistically-based models, respectively). Wise words, especially when you think of the problems certain Toxtree alerts such as the ‘H-acceptor-path3-H-acceptor’ have caused. At bibra, we routinely apply Leadscope, Toxtree and Toolbox, and have expert partners who can run DEREK analyses, but expert judgement still plays an important role.

In a world where the analysts are getting ever more capable of finding compounds at increasingly low levels, the value of TTC as both a priority-setting tool and a health-risk assessment methodology has never been higher. A read through this draft and the earlier, referenced material, is highly recommended.



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