One of the most critical tools employed by toxicologists when assessing the safety of drug substances (DS) or drug products (DP) they are working on, is the Permitted Daily Exposure (PDE). This concept is mainly applied for the assessment of impurities or contaminants that can be unintentionally present in both DS and DP, as these substances don’t offer therapeutic benefit to patients.
The PDE represents the maximum amount of a potentially harmful substance that an individual can be exposed to daily, for a lifetime, without developing any adverse health effects.
This definition is rather general: in fact, the PDE approach can be applied to pharmaceuticals, food additives, cosmetics, and chemicals used in consumer goods; and not only to impurities, residual solvents and leachables. This allows for its application in different fields, ensuring safety across industries.
But how is a PDE determined?
Generally, the following formula is used:
As we can appreciate, the PDE formula typically consists of key elements such as a selected Point of Departure (PoD), mass adjustments, various uncertainty factors and, eventually, conversion factors. These components work in concert to ensure a safety margin and account for variability among individuals.
Let’s analyze the component of such formula one by one:
One of the most important factors in the formula is the PoD. It is in the expertise of the toxicologist to choose the correct value, taking into consideration an array of factors: route of administration in which the substance for which we are deriving a PDE enters in contact with the body, overall quality of the toxicological study, appropriateness of the selected study and so on. Usually, the PoD relates to either the No Observed Adverse Effect Level (NOAEL) or Lowest Observed Adverse Effect Level (LOAEL), as well as the Benchmark Dose Level (BMD), depending on toxicological data available for tested substance. It is always better to choose a NOAEL/BMD value! The expertise of a toxicologist plays a crucial role in this selection process. It is essential to ensure that the chosen data is not only reliable but also highly relevant. Assessing the quality of a study is a critical step, and one method to achieve this is by utilizing scoring systems like the Klimish score.
The Mass adjustment is set at 50 to cover the whole population, including the pediatric one, who might have a higher risk of overexposure.
The uncertainty factors (UF), also called modifying factors, are several. Their value usually spans from 1 to 10, but in certain cases a value of 100 could also be applied and are related to the toxicity study from which the PoD was derived. In particular:
- F1 is a factor to account for variability between individuals (such as genetics) and has, by default, always a value of 10;
- F2 represents the extrapolation between species, and is directly related to the animal species used in the selected toxicological study;
- F3 takes into account the length of such toxicity study: the shorter, the higher the number;
- F4 takes into account the severity, or lack thereof, of adverse effects noted during the toxicity study;
- F5 takes into account the selected PoD value, whether it is a NOEL, NOAEL, LOAEL or BMD;
- F6 is an optional UF, to account for additional uncertainties present in the selected toxicity study, at discretion of the toxicologist.
Last but not least, we have the PK, also called pharmacokinetic correction. This factor is applied, in a measure of 1 to 10, when an important difference in bioavailability is observed between animal and human data or between different routes of administration. This factor has to be applied on case-by-case basis, having a default value of 1 when no significant differences are highlighted in the literature.
And what about data-poor substances?
When dealing with data-poor substances, the application of a read-across approach may be considered, with the specifics varying on a case-by-case basis.
To conclude, undoubtedly the most demanding aspects of a PDE determination process are the selection of the PoD, as mentioned earlier, and the determination of the appropriate UF4 value. This task necessitates the expertise of a toxicologist, to effectively assess the severity of adverse effects observed during a toxicological study.
As we have elucidated, the determination of a PDE value necessitates a comprehensive assessment of toxicological data, including animal and human studies, if any are available. Throughout this process, the expertise of toxicologists is indispensable in obtaining a PDE value that reflects a thorough evaluation of the complete dataset of information gathered from online literature or provided by the manufacturer.
Article issued by Chiara Gazerro