Title
Is current risk assessment of non-genotoxic carcinogens protective?
Author
Braakhuis, H.M.
Slob, W.
Olthof, E.D.
Wolterink, G.
Zwart, E.P.
Gremmer, E.R.
Rorije, E.
van Benthem, J.
Woutersen, R.
van der Laan, J.W.
Luijten, M.
Publication year
2018
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. © 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group.
Subject
Health
Benchmark dose approach
Carcinogenicity
Chemicals
No-Observed-Adverse-Effect-Level
Non-genotoxic carcinogens
Repeated dose toxicity
Risk assessment
Subchronic toxicity
To reference this document use:
http://resolver.tudelft.nl/uuid:6bfc1dbd-bfa2-47b0-a5e7-48fc7fe1792b
DOI
https://doi.org/10.1080/10408444.2018.1458818
TNO identifier
810181
ISSN
1040-8444
Source
Critical Reviews in Toxicology, 48 (6), 500-511
Document type
article