An integrative test strategy for cancer hazard identification

Luijten, Mirjam; Olthof, E.D.; Hakkert, Betty C.; Rorije, Emiel; Laan, Jan van der; Woutersen, Ruud; Benthem, Jan van

doi:10.3109/10408444.2016.1171294

Cited by 35 publications

(31 citation statements)

References 202 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…52 A tiered strategy for cancer hazard identification has been proposed. 53 The authors indicate they are well aware of the fact that, at this time, we do not have a good handle on short-term approaches for detecting nongenotoxic compounds that might be carcinogenic. In addition to genotoxic potential, they rely on histopathology, evidence of hormone perturbation and, as yet to be developed, toxicogenomics approaches to discern nongenotoxic carcinogens.…”

Section: Goodbye Bioassaymentioning

confidence: 99%

“…In addition to genotoxic potential, they rely on histopathology, evidence of hormone perturbation and, as yet to be developed, toxicogenomics approaches to discern nongenotoxic carcinogens. 53 My emphasis on the "as yet to be determined toxicogenomics approaches" is not intended to connote criticism. While surely being a worthy pursuit, the task of developing a human-relevant toxicogenomics approach to discern nongenotoxic chemicals which are potential human carcinogens will be, to put it mildly, very difficult.…”

Section: Goodbye Bioassaymentioning

confidence: 99%

See 1 more Smart Citation

Goodbye to the bioassay

Goodman

2018

Toxicology Research

View full text Add to dashboard Cite

It is time to say goodbye to the standard two-year rodent bioassay. While a few, primarily genotoxic, compounds which are clearly associated with human cancer test positive in the bioassay, there is no science-based, sound foundation for presuming it provides either a valid broad (across different chemicals) capability for discerning potential human carcinogens or a valid starting point for making human risk assessment decisions. The two basic assumptions underlying the bioassay are: (1) rodent carcinogens are human carcinogens; and (2) results obtained at high doses are indicative of results that will occur at lower, environmentally relevant, doses. Both of these assumptions are not correct. Furthermore, a reevaluation of National Toxicology Program bioassay data has revealed that if the dose group size were increased from 50 to 200 rodents per group the number of bioassays deemed to be positive would increase from approximately 50% to very close to 100%. Thus, under the extreme conditions of the bioassay (, high doses, lifetime exposure and, at times, a non-physiological route of administration) virtually all chemicals tested could be made into rodent carcinogens. In recent years there have been a number of proposals to move away from the standard bioassay. In particular, a recently formulated decision tree (Cohen, 2017), which places an emphasis on dose-response relationships and invites the use of MOA information, provides a sound basis for moving on from the bioassay and towards a rational approach to both identify chemicals which appear to have the potential to cause cancer in humans and take dose-response relationships into consideration in order to place the extent, if any, of the risk they might pose into proper perspective.

show abstract

Section: Goodbye Bioassaymentioning

confidence: 99%

Section: Goodbye Bioassaymentioning

confidence: 99%

Goodbye to the bioassay

Goodman

2018

Toxicology Research

View full text Add to dashboard Cite

show abstract

“…At this time, we are not aware of any curated databases of clearly non-genotoxic chemicals, and therefore identifying a priority list of humanrelevant (and potentially relevant) non-genotoxic carcinogens for re-assessment of TTC values will probably need to be carried out on a case-by-case basis. Despite the challenges in forming a priority list of human-relevant (and potentially relevant) non-genotoxic carcinogens, there are several welldocumented processes that can lead to tumor formation via a non-genotoxic MOA (see Hernandez et al 2009;BAuA 2014;Jacobs et al 2016;Luijten et al 2016), for example:…”

Section: In Vitro Mammalian Cell Mutationmentioning

confidence: 99%

Origin of the TTC values for compounds that are genotoxic and/or carcinogenic and an approach for their re-evaluation

Boobis

Brown

Cronin

et al. 2017

Critical Reviews in Toxicology

Self Cite

View full text Add to dashboard Cite

(2017) Origin of the TTC values for compounds that are genotoxic and/or carcinogenic and an approach for their re-evaluation, Critical Reviews in Toxicology, 47:8, 710-732, DOI: 10.1080/10408444.2017 The threshold of toxicological concern (TTC) approach is a resource-effective de minimis method for the safety assessment of chemicals, based on distributional analysis of the results of a large number of toxicological studies. It is being increasingly used to screen and prioritize substances with low exposure for which there is little or no toxicological information. The first step in the approach is the identification of substances that may be DNA-reactive mutagens, to which the lowest TTC value is applied. This TTC value was based on the analysis of the cancer potency database and involved a number of assumptions that no longer reflect the state-of-the-science and some of which were not as transparent as they could have been. Hence, review and updating of the database is proposed, using inclusion and exclusion criteria reflecting current knowledge. A strategy for the selection of appropriate substances for TTC determination, based on consideration of weight of evidence for genotoxicity and carcinogenicity is outlined. Identification of substances that are carcinogenic by a DNA-reactive mutagenic mode of action and those that clearly act by a non-genotoxic mode of action will enable the protectiveness to be determined of both the TTC for DNA-reactive mutagenicity and that applied by default to substances that may be carcinogenic but are unlikely to be DNA-reactive mutagens (i.e. for Cramer class I-III compounds). Critical to the application of the TTC approach to substances that are likely to be DNA-reactive mutagens is the reliability of the software tools used to identify such compounds. Current methods for this task are reviewed and recommendations made for their application.

show abstract

“…Although QSAR models have proven useful in predicting mutagens, the method is more challenging for non-genotoxic carcinogens (Silva Lima and Van der Laan, 2000; Benigni et al, 2013; Luijten et al, 2016). There are several explanations for this difference, e.g., a better mechanistic understanding of how mutagenic compounds cause cancer, compared to non-genotoxic carcinogens.…”

Section: Discussionmentioning

confidence: 99%

Combining QSAR Modeling and Text-Mining Techniques to Link Chemical Structures and Carcinogenic Modes of Action

Papamokos

Silins

2016

Front. Pharmacol.

View full text Add to dashboard Cite

There is an increasing need for new reliable non-animal based methods to predict and test toxicity of chemicals. Quantitative structure-activity relationship (QSAR), a computer-based method linking chemical structures with biological activities, is used in predictive toxicology. In this study, we tested the approach to combine QSAR data with literature profiles of carcinogenic modes of action automatically generated by a text-mining tool. The aim was to generate data patterns to identify associations between chemical structures and biological mechanisms related to carcinogenesis. Using these two methods, individually and combined, we evaluated 96 rat carcinogens of the hematopoietic system, liver, lung, and skin. We found that skin and lung rat carcinogens were mainly mutagenic, while the group of carcinogens affecting the hematopoietic system and the liver also included a large proportion of non-mutagens. The automatic literature analysis showed that mutagenicity was a frequently reported endpoint in the literature of these carcinogens, however, less common endpoints such as immunosuppression and hormonal receptor-mediated effects were also found in connection with some of the carcinogens, results of potential importance for certain target organs. The combined approach, using QSAR and text-mining techniques, could be useful for identifying more detailed information on biological mechanisms and the relation with chemical structures. The method can be particularly useful in increasing the understanding of structure and activity relationships for non-mutagens.

show abstract

An integrative test strategy for cancer hazard identification

Cited by 35 publications

References 202 publications

Goodbye to the bioassay

Goodbye to the bioassay

Origin of the TTC values for compounds that are genotoxic and/or carcinogenic and an approach for their re-evaluation

Combining QSAR Modeling and Text-Mining Techniques to Link Chemical Structures and Carcinogenic Modes of Action

Contact Info

Product

Resources

About