Why EFSA should reject use of thresholds of toxicological concern in risk assessment

Posted by Blogactiv Team on 28/02/12

Guest Post by Paul Whaley, Editor, Health & Environment

Last week, EFSA delayed publication of its opinion on the use of thresholds of toxicological concern (TTCs) in risk assessment. And it was right to do so: TTCs are not only unlikely to be sufficiently protective of human health, their deployment would fly in the face of much of what society and the EU is trying to achieve by modernising chemicals policy and risk assessment.

TTCs are a proposal reduce the amount of data which needs to be generated in order to perform chemical risk assessments by requiring toxicological testing of a substance of unknown toxicity (such as a food contaminant or pesticide metabolite) only in the event that humans are exposed to it above a certain threshold.

Even though this means a risk assessment decision is made in the absence of specific toxicological data, proponents of TTCs argue the exposures are low enough to ensure no threat to health is posed by the unknown substances.

Interest in TTCs is driven by a need for risk management decisions on chemicals in spite of an overwhelming lack of toxicity data on the multitude of chemicals and their breakdown products present in the environment, a desire to reduce the amount of animal-based toxicity testing, and support from industry itself, which although it emphasises the animal welfare benefits of the proposal, must also see substantial financial benefits in facing reduced toxicological test requirements before bringing their products to market.

The European Food Safety Authority has a draft opinion on the application of TTCs to food contaminants (EFSA 2011) while the EU non-food Scientific Committees have also drafted a recommendation on TTCs for cosmetics (SCHER/SCCP/SCENIHR 2008).

A search of the published literature indicates they are being considered for use in a range of risk assessment and regulatory forums, including: prenatal developmental toxicity (van Ravenzwaay et al. 2011), substances regulated under REACH (Rowbotham & Gibson 2011,Marquart et al. 2011), tobacco smoke (Talhout et al. 2011), pesticide metabolites (Dekant et al. 2010), hormonally-active substances (Gross et al.2010), aerosol ingredients (Carthew et al. 2010), household and personal care products (Blackburn et al. 2005) and food additives (Pratt et al. 2009).

TTCs are calculated by creating a database of existing chronic toxicity data for a representative subset of a structural class of chemicals; ranking them from lowest to highest no observed adverse effect levels (NOAEL) in the database; and identifying the 5th percentile NOAEL for the sub-set (see here for a more detailed explanation of the rationale and method behind TTCs).

In theory this means there is only a 1 in 20 chance that a random chemical in the class is toxic at a dose equal to or less than this level. TTCs are then set by dividing this dose by an uncertainty factor of 100.

As a probabilistic method, it is always possible that a chemical is toxic at the TTC. The contention is that there are so few chemicals which are toxic at this dose, there likelihood of harm is insignificant.

Proponents of TTCs are therefore effectively offering policy-makers a trade-off: society foregoes the lesser advantages accrued from generating specific toxicological data on substances to reap the greater rewards of reduced cost and use of fewer animals in toxicological testing.

The acceptability of this trade-off turns on two questions. Firstly, can risk assessors be confident that the health risk posed by a substance below the TTC exposure thresholds really is negligible? And secondly, are the benefits of detailed toxicological testing really so marginal that they are outweighed by the benefits of waiving specific data requirements for risk assessment?

Fully examining the issues is too much for one (or even three) posts, so here we will consider only one objection, by imagining that risk assessors would lose confidence in TTCs if there was a compelling evidence that the threshold doses are too high to reliably prevent harm to health.

Are the thresholds low enough?

The effectiveness of the TTC methodology depends entirely upon how few substances are toxic at the threshold doses. The more conservative the 5th percentile is, the fewer substances will be toxic below the threshold; the more consistently the TTC database over-estimates the NOAELs for a given class of substances, the more substances there will be which are toxic at the threshold dose.

Standard critiques of risk assessment give plenty of reason to hypothesise that the NOAELs on which TTCs are based may well be overestimated. We have covered some of these shortcomings in Health & Environment (see e.g. #42#34) and there are detailed critiques in the peer-reviewed literature (e.g. Myers at al. 2009) describing concerns with insensitive assays, failures to account for sensitive windows of development and sacrifice of animals before disease manifests, to name but three.

Suffice to say, the age of many of the studies used in the Munro databases on which TTCs are based, some of which date from the 1960s, (Munro et al. 1996) makes them all the more likely to be methodologically limited when it comes to determining a substance’s NOAEL (it has been claimed that TTCs derived from this data have been validated against newer studies and for a greater range of substances [Barlow 2005], although how this has been done is unclear).

Additionally, there are doubts that thresholds of effect truly even exist, with the US National Research Council recommending a move away from risk assessments based on no-effect levels (National Research Council 2009). If there are no thresholds of effect, TTCs are necessarily over-estimated.

Direct evidence for the hypothesis that NOAELs are overestimated would come from studies showing effects at doses lower than the 5th percentile NOAELs in the TTC databases. And such studies are straightforward enough to find.

For example, PFOA, deltamethrin and BPA would have TTCs based on a 5th percentile NOAEL of 0.15mg/kgbw/day, yet there is evidence that PFOA has effects at 0.01mg/kgbw/day (Macon et al. 2011), deltamethrin at 0.003mg/kgbw/day (Issam at al. 2009), and BPA from less than 0.05mg/kgbw/day to lower than 0.025mg/kgbw/day (Richter et al. 2007). The TTC for DEHP would be based on a 5th percentile NOAEL of 3mg/kgbw/day, yet effects have been observed at doses as low as 0.045mg/kgbw/day (Andrade et al. 2006).

A few counterexamples do not, of course, prove broken a system which only claims to be right in most cases. However, the more counterexamples there are, the more it should undermine confidence in the accuracy of TTCs, as each example is evidence that the databases of NOAELs set the TTC at too high a dose.

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