EUROTOX 2018 ControlCenter

Online Program Overview Session: Session 22

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Mode of action as a key in risk assessment of chemical carcinogens

Session chair: Dieter Schrenk Germany; Jan Vondracek Czech Republic
Shortcut: Session 22
Date: Tuesday, 4 September, 2018, 16:30
Room: Gold Hall
Session type: Session



Reassessment the Two Year Rodent Carcinogenicity Bioassay (#769)

A. W. Hayes1

1 University of South Florida, College of Public Health, TEMPLE TERRACE, Florida, United States of America

The two-year rodent carcinogenicity bioassay has long been the subject of controversy. Numerous articles have identified issues surrounding the bioassay, and many have questioned the predictability, utility, and even the necessity of this assay when other more appropriate means of achieving information to determine the cancer potential in humans and inform risk management decisions are available today. 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 assumptions are probably incorrect. Furthermore, the extreme conditions of the bioassay (e.g., high doses, lifetime exposure and, at times, a non-physiological route of administration) leads to the outcome that virtually all chemicals tested could be rodent carcinogens. While there remain strongly held opinions on the bioassay, the 21st century trend in toxicology is to promote hypothesis, tier-based testing that draws on a broad array of information from several sources including predictions from computational and molecular methods.

Keywords: cancer bioassay, reassessment, 21st Century

Current approaches to risk assessment of carcinogens (#119)

D. Schrenk1

1 University of Kaiserslautern, Food Chemistry and Toxicology, Kaiserslautern, Rhineland-Palatinate, Germany

Chemical carcinogens are compounds which can cause cancer in humans and experimental animals. This property is attributed to many chemicals of public concern, resulting in a widespread perception of danger and threat. In contrast, a scientific analysis of the wide and non-critical use of the term ‚carcinogenic’ is warranted.

First, it has to be clarified if the compound acts in a genotoxic or non-genotoxic manner. In the latter case, an ineffective (safe) threshold dose without cancer risk can be assumed. In addition, it needs to be investigated if the mode-of-action causing tumors in laboratory animals is relevant at all for humans.

In case the compound is clearly directly genotoxic, an ineffective threshold dose cannot be assumed. However, also in this case it is evident that high doses of the compound are associated with a high cancer risk, low doses with a lower one. Previously, it appeared useful to define a practically achievable (lowest) dose level by management measures (ALARA principle) while in recent years, a science-based approach seems to be preferred. Based on dose-response data from animal experiments, quantification of the cancer risk is ideally carried out by mathematical modeling. A dose with a pre-defined cancer risk (e.g. 10% tumor-bearing animals) is frequently used as Point of Departure (POD). If the Margin of Exposure (MoE) between the POD and the current human exposure exceeds 10,000, the degree of possible concern is classified as low, while below 10,000 it is considered as of possible concern. Alternatively, an ‘acceptable’ dose with a pre-defined hypothetical risk (e.g. one in a million expected additional cancer cases) can be derived from a linear extrapolation of the dose-response data. Finally, the Threshold of Toxicological Concern (TTC) approach was designed to allow risk assessment of compounds bearing structural alerts for genotoxicity and carcinogenicity without relevant toxicological data. In contrast, the existence of a threshold dose without concern is widely accepted for carcinogens with indirect genotoxic effects mediated e.g. via oxidative stress.

Keywords: Chemical carcinogens, Margin of Exposure, Risk assessment

Mode of action and human relevance of rodent liver tumours produced by nongenotoxic CAR and PPARα activators (#191)

B. G. Lake1

1 University of Surrey, Guildford, United Kingdom

Many nongenotoxic chemicals have been shown to produce liver tumours in rats and mice. Such chemicals include activators of the constitutive androstane receptor (CAR) and of the peroxisome proliferator-activated receptor alpha (PPARα), which induce cytochrome P450 (CYP) enzymes in the CYP2B and CYP4A subfamilies, respectively. Robust modes of action (MOAs) for rodent liver tumour formation have been established for both CAR activators (e.g. phenobarbital/sodium phenobarbital and the natural pyrethrins) and for PPARα activators (e.g. di-(2-ethylhexyl)phthalate, gemfibrozil and other hypolipidaemic agents). Key events for the MOAs for both CAR and PPARα activators include receptor activation, increased hepatocyte replicative DNA synthesis (RDS), clonal expansion leading to altered foci and formation of liver adenomas/carcinomas; with associate events including liver hypertrophy and induction of CYP enzymes. The key species difference between the hepatic effects of CAR and PPARα activators in the rat and mouse compared to humans, is that human hepatocytes are refractory to the mitogenic effects of these compounds. In this respect humans are similar to other species including the Syrian hamster and guinea pig. Studies performed in a number of laboratories have demonstrated that while CAR and PPARα activators can induce RDS in cultured rat and mouse hepatocytes, such effects are not observed in human hepatocytes. However, as a measure of functional viability, treatment with epidermal growth factor (EGF) or hepatocyte growth factor was shown to induce RDS in hepatocytes from all species. In addition, in in vivo studies performed in chimeric mice with humanised livers, a number of CAR and PPARα activators have been shown not to induce RDS in human hepatocytes, whereas significant increases in RDS were observed after treatment of the chimeric mice with human EGF. Overall, the MOAs for rat and mouse liver tumour formation by both CAR and PPARα activators can be considered to be qualitatively not plausible for humans. This conclusion is supported by data from human epidemiological studies with phenobarbital and hypolipidaemic drugs.

Keywords: Mode of action, Rodent liver tumours, Constitutive androstane receptor, Peroxisome proliferator-actiavted receptor alpha, Human relevance

Multiple modes of action converge in carcinogenicity of polycyclic aromatic hydrocarbons (#96)

J. Vondracek1, M. Machala2

1 Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic
2 Veterinary Research Institute, Brno, Czech Republic

Polycyclic aromatic hydrocarbons (PAHs) are an important class of environmental pollutants with carcinogenic properties. Both individual PAHs, such as benzo[a]pyrene (BaP), and their complex mixtures, have been associated with adverse human health effects, including cancer. Their carcinogenicity is primarily attributed to their genotoxic effects, linked with formation of covalent DNA adducts. Nevertheless, PAHs represent a highly diverse group of compounds, and our recent studies have suggested that PAHs may elicit a number of non-genotoxic effects, which might play a role in their carcinogenicity or co-carcinogenicity. In a variety of cellular models representing lung and/or liver tissues, PAHs have been found to disrupt cell proliferation control, to alter cell-to-cell communication (in particular gap junctional intercellular communication), or to interact with a number of intracellular signaling pathways, including those deregulated during tumor development. Importantly, activation of the aryl hydrocarbon receptor (AhR) has been found to play major roles not only in bioactivation of PAHs to their genotoxic metabolites, but also in their other effects (including disruption of signaling pathways linked with tumor promotion and/or further steps of chemical carcinogenesis). These studies indicate that more attention should be paid to the non-genotoxic modes of action (MOA) of PAHs and their complex environmental mixtures. In particular, future work should address the relevance of identified in vitro non-genotoxic MOAs for human risk assessment. Our work is currently supported by the Czech Science Foundation (project no.18-00145S). 

Keywords: non-genotoxic, aryl hydrocarbon receptor, DNA damage, cell proliferation, cell-to-cell communication, genotoxic, PAHs