• December 10, 2023

Unpacking the Pouch

 Unpacking the Pouch
Photo courtesy of Broughton

How we can better understand the toxicological risk of nicotine in modern oral and other nicotine products

By Libby Clarke

Nicotine may be acutely toxic via all routes of exposure if the dose is high enough, but determining the true extent of its toxicity is challenging because of the variation in data. In 2014, Bernd Mayer highlighted the discrepancy between the generally accepted lethal dose of nicotine and documented cases of nicotine intoxication. Examining these accidental oral ingestion case studies gives us another data point for consideration when determining nicotine toxicity.

In this article, Libby Clarke, managing consultant for toxicology at contract research organization (CRO) and scientific consultancy Broughton, explains how manufacturers can understand the true impact of oral pouches and other nicotine-based products.

The U.S. Centers for Disease Control and Prevention and the National Institute for Occupational Safety and Health, along with other sources, report an estimated lethal dose of around 60 mg when nicotine is ingested orally. While broadly accepted by the Food and Drug Administration and other regulatory bodies, this value is derived from a series of self-experiments conducted by two individuals in the 19th century, where non-fatal adverse effects were reported.

Mayer estimated that a dose of 60 mg of nicotine would give rise to a plasma concentration of approximately 0.18 mg per liter based on 20 percent oral bioavailability and assuming linear kinetics. Cases of fatal nicotine intoxication cited by Mayer suggest a much higher lethal nicotine blood concentration of approximately 2 mg per liter, corresponding to 4 mg per liter in plasma. Many existing case studies include data on accidental ingestion in children and infants, where the lethal dose is likely lower, as with nicotine naive adults.

There is a significant disparity in the levels of nicotine that individuals can tolerate and a broad range in the upper level of nicotine that nonsmokers can consume without experiencing adverse effects. Research indicates that tolerance increases with repeated use of nicotine products, but the speed at which tolerance grows depends on the frequency of nicotine use, the amount absorbed systemically and individual genetics.

Research Challenges

Understanding nicotine toxicity is essential for determining the likelihood of adverse effects associated with certain products and concentrations, but research is limited. It is unethical to test nicotine toxicity in nonsmokers, and light or nondaily nicotine users are likely to have a lower tolerance, putting them at a higher risk of experiencing adverse effects such as dizziness, nausea and vomiting. On the other hand, established smokers have upregulated receptors in the brain, meaning many more nicotine receptors are available to bind nicotine than in nonsmokers. Therefore, the higher levels of nicotine that produce adverse reactions in nonsmokers are often required to satisfy the cravings of regular smokers.

The wide range in tolerance among adult nicotine users makes it challenging for manufacturers to define a threshold for nicotine toxicity in their products. Meanwhile, attempting to extrapolate findings from children to adults is not recommended due to differences in metabolic capacity, which increases as people grow. There is also a vast difference in metabolic efficiency, even among adults, which limits extrapolation.

Understanding the Effects of Nicotine

One option is for manufacturers to review case studies, conduct postmarket surveillance (PMS) on the incidence of reported adverse effects and use surveys to understand consumer use and the subjective effectiveness of nicotine delivery. For example, Massen et al. (2020) evaluated case studies reporting the clinical symptoms and outcomes associated with accidental or intentional ingestion of nicotine-containing e-liquids, which are limited to 20 mg per milliliter in the EU. Gerdinique C. Maessen et al. reported that the highest nicotine plasma concentration in the surviving group was 0.8 mg per liter. In comparison, the lowest plasma concentration in the patients who did not survive was 1.6 mg per liter.

Another approach is working with a CRO that can conduct dissolution, aerosol characterization for inhaled products and pharmacokinetic studies to inform on the nicotine levels being delivered to users. CROs can also conduct behavioral studies under controlled conditions to understand the use patterns for certain products and what products and strengths are used across population samples.

When developing oral pouches, manufacturers must adhere to the regulatory guidelines that are starting to be brought in by some markets. The rate at which nicotine transfers from the pouch across the buccal membrane is one of the main factors associated with users experiencing adverse effects, so manufacturers should consider a range of nicotine strengths. Dissolution studies and clinical studies may provide useful data to inform nicotine exposure from pouches, and case studies and PMS may also provide valuable insights. Working with a CRO that can conduct such studies is an effective way of understanding a product’s safety profile and form part of a manufacturer’s product stewardship and duty of care responsibilities.