Is current risk assessment of non-genotoxic carcinogens protective?

Abstract

Non-genotoxic carcinogens (NGTXCs) do not cause direct DNA damage but induce cancer via other mechanisms. In risk assessment of chemicals and pharmaceuticals, carcinogenic risks are determined using carcinogenicity studies in rodents. With the aim to reduce animal testing, REACH legislation states that carcinogenicity studies are only allowed when specific concerns are present; risk assessment of compounds that are potentially carcinogenic by a non-genotoxic mode of action is usually based on subchronic toxicity studies. Health-based guidance values (HBGVs) of NGTXCs may therefore be based on data from carcinogenicity or subchronic toxicity studies depending on the legal framework that applies. HBGVs are usually derived from No-Observed-Adverse-Effect-Levels (NOAELs). Here, we investigate whether current risk assessment of NGTXCs based on NOAELs is protective against cancer. To answer this question, we estimated Benchmark doses (BMDs) for carcinogenicity data of 44 known NGTXCs. These BMDs were compared to the NOAELs derived from the same carcinogenicity studies, as well as to the NOAELs derived from the associated subchronic studies. The results lead to two main conclusions. First, a NOAEL derived from a subchronic study is similar to a NOAEL based on cancer effects from a carcinogenicity study, supporting the current practice in REACH. Second, both the subchronic and cancer NOAELs are, on average, associated with a cancer risk of around 1% in rodents. This implies that for those chemicals that are potentially carcinogenic in humans, current risk assessment of NGTXCs may not be completely protective against cancer. Our results call for a broader discussion within the scientific community, followed by discussions among risk assessors, policy makers, and other stakeholders as to whether or not the potential cancer risk levels that appear to be associated with currently derived HBGVs of NGXTCs are acceptable.

Keywords:

• Non-genotoxic carcinogens
• chemicals
• risk assessment
• subchronic toxicity
• repeated dose toxicity
• carcinogenicity
• No-Observed-Adverse-Effect-Level
• benchmark dose approach

Acknowledgements

The authors note with appreciation the value of four sets of comments provided by reviewers selected by the Editor and anonymous to the authors.

Declaration of interest

The employment affiliation of the authors is as shown on the cover page. This work was funded by the Dutch Ministry of Health, Welfare and Sport. All authors participated in preparation of the paper as part of their normal employment and did not receive any special compensation from any source for preparation of the paper. The authors have sole responsibility for the writing and content of the paper. The authors declare that they have no competing interests. None of the authors during the past 5 years have participated in any legal or regulatory proceedings related to the contents of this review.

Supplementary material

Supplemental data for this article can be accessed here.