Evaluating the lifetime cumulative dose as a basis for carcinogenic potency of nitrosamines – a key tenet underpinning less-than-lifetime approaches for establishing acceptable intake limits

HESI Global Nitrosamines Research Program published a paper on evaluating lifetime cumulative dose as a basis of carcinogenic potency specifically for nitrosamines (NAs).

The Issue
Nitrosamines (NAs) are a class of compounds that have garnered significant concern in recent years due to their presence as impurities in pharmaceutical products and their classification as potent carcinogens. While regulatory agencies have set conservative intake limits based on lifetime exposure to mitigate cancer risk, a gap remains in how to appropriately assess risk for drug products intended for short-term or intermittent use.

Why It Matters
Applying a one-size-fits-all risk threshold may unnecessarily limit the availability of certain life-saving medications, particularly when the exposure is temporary. The current default assumption does not consider whether the total cumulative exposure, not just daily dose, drives carcinogenic potency.

The Problem
Existing regulatory guidance lacks clarity on whether less-than-lifetime (LTL) exposure scenarios should warrant adjusted Acceptable Intake (AI) limits for NAs, despite the scientific foundation laid by ICH M7(R2) for other mutagenic impurities. This ambiguity has impeded harmonized global decision-making and risk assessments, particularly for LTL-use medicines.

The Solution
Led by a multi-sector team including HESI Global experts, this review of the literature analyzed rodent carcinogenicity data across eight NAs and one comparator compound, aflatoxin B1. The findings demonstrated that carcinogenic potency correlates strongly with lifetime cumulative dose, not just dose rate or duration, validating the scientific foundation for applying LTL exposure adjustments to nitrosamines.

The Benefit
This study provides critical scientific justification for tailoring AI limits based on realistic exposure durations. Such an approach better aligns with modern principles of cancer risk assessment and supports regulatory flexibility without compromising public health.

This paper marks an important step forward in risk science and policy. Stay tuned for future publications that will further address remaining challenges in applying the LTL approach to nitrosamines.

Read the full paper here:

Evaluating the lifetime cumulative dose as a basis for carcinogenic potency of nitrosamines – a key tenet underpinning less-than-lifetime approaches for establishing acceptable intake limits. Felter et al. 2025. Regulatory Toxicology and Pharmacology. https://doi.org/10.1016/j.yrtph.2025.105903

Learn more about the HESI Global Nitrosamines Research Program