A toxicological risk assessment (TRA) is a phrase used in many industries e.g. food, cosmetics, nicotine etc, and typically there is no exact definition of what it might comprise of. It is defined as “an expert toxicological assessment demonstrating that the ingredients and foreseeable use of the product do not present an unacceptable risk.” Where the product requires a submission and an approval, there is typically guidance and ‘attained’ knowledge on what to include, at what depth, and how the assessment is structured, however, in cases where approval is not required and we do not have the benefit of regulatory scrutiny, it is not so clear.
This is most apparent in the nicotine industry where large wholesale sellers request TRAs before they will sell a new brand of nicotine pouches. Effectively, they are asking for a toxicologist to make a statement saying the ingredients within a product, both individually and collectively, when consumed, will not be an unacceptable risk. To the toxicologist, this is largely seen as the risk to the user/consumer. To the wholesaler, this has an added dimension, the risk to their reputation.
To the manufacturer of the product who needs the switch to large wholesalers to realise their product's sales potential, this is a necessary but often unexpected step and, without the benefit of the reasons behind the request, feels like arbitrary red tape as opposed to a defined process to assess safety. Consequently, this may be treated as a box-ticking exercise, resulting in a rapid search for the quickest and cheapest TRA.
There are two golden rules:
1. A TRA unsigned by a registered toxicologist is not worth purchasing.
2. Any toxicologist willing to sign a TRA that does not adequately assess the risks is not worth hiring.
A route which some manufacturers take is the automated TRA. The promise is that you input your product and ingredient details online at a relatively small cost and in no time at all, the TRA will be delivered at the other end. Its quick, it’s relatively cheap, and it ticks the box of providing a TRA, but does it? Is this Toxicologist Avatar merely “a wolf in sheep’s clothing”? Here we assess the potential pitfalls of adopting such an approach.
• The manufacturer only inputs the information they have, not all of the ingredients that may cause concern.
• Where there is no Acceptable Daily Exposure (ADE) figure for an ingredient, the avatar has no option but to apply a Toxicology Threshold of Concern (TTC) figure based on the chemicals’ Cramer class. This severely limits the quantity of the ingredient that can be added.
• Where there are ‘emerging’ concerns for carcinogenicity, genotoxicity or reproductive toxicity, the avatar will ignore these unless authoritative sources have previously classified them, rendering users at potential risk where an expert opinion is required.
• Where data is lacking to define the concerns for carcinogenicity, genotoxicity or sensitisation, an avatar cannot perform or apply predictive tools ((Q)SAR) or provide expert opinion, when those predictions are equivocal.
• Where natural products are used, an avatar cannot decide whether to use actual or worse-case data for the presence of undesirable constituents, and the appropriate ADE values to use.
• Where several natural products comprise of directly added ingredients, and/or these individual constituents may be present several times across different flavour complexes, an avatar cannot assess the accumulation of these ‘stacked’ ingredients.
• Where ingredients act on common toxicological pathways or result in similar toxicities e.g. cooling factors, ionones, pyrenes etc, an avatar does not typically assess the group effects of similar-acting ingredients.
• Where an Acceptable Daily Exposure (ADE) value fails to provide a Margin of Safety (MoS), an avatar cannot use expert judgement to calculate a Derived No Effect Level (DNEL) using available data and uncertainty factors, or suggest the use of read-across chemicals, to provide an MoS.
• Where the ADE figure and/or TTC fails to provide an MoS, an avatar cannot assess the known metabolic breakdown products as part of the risk assessment.
These are only some of the pitfalls and these may be known by the owners of the Avatar. If they are, do not be surprised to be given a much steeper quote to re-evaluate those ingredients, or worse still, they are not aware of these pitfalls, and the TRA has not assessed the toxicity at all. The manufacturer is left with two choices:
• Go back to the product design phase and amend the flavour systems.
• Pay for a toxicologist to provide an expert opinion on the gaps the avatar has left.
The reality is that toxicology consultants, like Broughton, utilise a database of ADI values, hazard assessments, a comprehensive array of scientific papers, and most importantly knowledge of clinical use, metabolism and expert-driven rationale. The means we can quickly assess a new formulation/product, provide an early read on any issues, make suggestions on issue mitigation, and then deliver a full fit for purpose TRA in the agreed time and to the agreed cost, and with the confidence it will uphold, regulatory scrutiny, or will pass the red-faced test, e.g knowing the product has a real TRA providing confidence in its safety.