The cliff-edge of toxicological concern: highlighting the potential issues of an over-reliance on "less-than-lifetime" thresholds.

Abstract

The Threshold of Toxicological Concern (TTC) is a very well-established concept in applied toxicology, and has become a key tool for the pragmatic human health risk assessment of data-poor chemicals. Within the pharmaceutical sector, regulatory guidance on genotoxins defaults to a TTC of 1.5 μg/day equating to a maximum lifetime cancer risk of 1 in 100,000. Higher doses for drug products where exposures are intermittent or otherwise "less-than-lifetime" (LTL) are also considered tolerable. This also allows substance-specific lifetime Acceptable Intakes (AIs) for known genotoxic carcinogens to be scaled up for shorter durations. The default TTCs for assessing LTL exposures build in conservatism such that there is deviation from strict linearity. However, close to the boundaries between LTL categories there can be such a difference in the default tolerable intakes that a health risk assessment can yield conflicting results. We have presented a theoretical case study based on our recent work that illustrates this apparent "cliff-edge." The total acceptable cumulative dose over a 56-day treatment is - in absolute terms - one third of that allowed over 28 days, despite the maximum cancer risk of the longer exposure being an order of magnitude higher. Our analysis suggests the need for careful consideration of what might represent tolerable exposures in the region of the category limits, rather than simply adopting the hardline default. Where a potential patient exposure is found to be above a default value, there is real value in refining the cancer risk estimates using the Lifetime Cumulative Dose approach.