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dc.contributor.authorBraakhuis, Hedwig M
dc.contributor.authorSlob, Wout
dc.contributor.authorOlthof, Evelyn D
dc.contributor.authorWolterink, Gerrit
dc.contributor.authorZwart, Edwin P
dc.contributor.authorGremmer, Eric R
dc.contributor.authorRorije, Emiel
dc.contributor.authorvan Benthem, Jan
dc.contributor.authorWoutersen, Ruud
dc.contributor.authorvan der Laan, Jan Willem
dc.contributor.authorLuijten, Mirjam
dc.date.accessioned2018-05-15T09:20:07Z
dc.date.available2018-05-15T09:20:07Z
dc.date.issued2018-05-10
dc.identifier.citationIs current risk assessment of non-genotoxic carcinogens protective? 2018:1-12 Crit. Rev. Toxicol.en
dc.identifier.issn1547-6898
dc.identifier.pmid29745287
dc.identifier.doi10.1080/10408444.2018.1458818
dc.identifier.urihttp://hdl.handle.net/10029/621943
dc.description.abstractNon-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.
dc.language.isoenen
dc.rightsinfo:eu-repo/semantics/closedAccessen
dc.titleIs current risk assessment of non-genotoxic carcinogens protective?en
dc.typeArticleen
dc.identifier.journalCrit Rev Toxicol 2018; 10:1-12en
html.description.abstractNon-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.


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