Human relevance of follicular thyroid tumors in rodents caused by non-genotoxic substances

Bartsch, Ruediger; Brinkmann, Britta; Jahnke, Gunnar; Laube, Britta; Lohmann, R; Michaelsen, S.; Neumann, Ingrid; Greim, Helmut

doi:10.1016/j.yrtph.2018.07.025

Cited by 35 publications

(25 citation statements)

References 110 publications

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“…This MOA is considered not likely relevant to women where prolactin is not luteotrophic. Likewise, a role for hormonal dysregulation affecting the pituitary-thyroid axis and the rat specific thyroid homoeostasis is generally supposed as likely cause for follicular cell neoplasia in rat carcinogenicity studies and is considered a rat-specific response (Alison et al 1994;Bartsch et al 2018;Capen 1997;Capen and Martin 1989;Khan et al 1999;Maronpot et al 2015;Neumann 1991). In summary, these target tissue-specific neoplastic responses are accepted to represent rat-specific MOAs, not likely predictive for human cancer risk (Maronpot et al 2015).…”

Section: Acrylamidementioning

confidence: 99%

Mode of action-based risk assessment of genotoxic carcinogens

et al. 2020

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The risk assessment of chemical carcinogens is one major task in toxicology. Even though exposure has been mitigated effectively during the last decades, low levels of carcinogenic substances in food and at the workplace are still present and often not completely avoidable. The distinction between genotoxic and non-genotoxic carcinogens has traditionally been regarded as particularly relevant for risk assessment, with the assumption of the existence of no-effect concentrations (threshold levels) in case of the latter group. In contrast, genotoxic carcinogens, their metabolic precursors and DNA reactive metabolites are considered to represent risk factors at all concentrations since even one or a few DNA lesions may in principle result in mutations and, thus, increase tumour risk. Within the current document, an updated risk evaluation for genotoxic carcinogens is proposed, based on mechanistic knowledge regarding the substance (group) under investigation, and taking into account recent improvements in analytical techniques used to quantify DNA lesions and mutations as well as “omics” approaches. Furthermore, wherever possible and appropriate, special attention is given to the integration of background levels of the same or comparable DNA lesions. Within part A, fundamental considerations highlight the terms hazard and risk with respect to DNA reactivity of genotoxic agents, as compared to non-genotoxic agents. Also, current methodologies used in genetic toxicology as well as in dosimetry of exposure are described. Special focus is given on the elucidation of modes of action (MOA) and on the relation between DNA damage and cancer risk. Part B addresses specific examples of genotoxic carcinogens, including those humans are exposed to exogenously and endogenously, such as formaldehyde, acetaldehyde and the corresponding alcohols as well as some alkylating agents, ethylene oxide, and acrylamide, but also examples resulting from exogenous sources like aflatoxin B1, allylalkoxybenzenes, 2-amino-3,8-dimethylimidazo[4,5-f] quinoxaline (MeIQx), benzo[a]pyrene and pyrrolizidine alkaloids. Additionally, special attention is given to some carcinogenic metal compounds, which are considered indirect genotoxins, by accelerating mutagenicity via interactions with the cellular response to DNA damage even at low exposure conditions. Part C finally encompasses conclusions and perspectives, suggesting a refined strategy for the assessment of the carcinogenic risk associated with an exposure to genotoxic compounds and addressing research needs.

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Section: Acrylamidementioning

confidence: 99%

Mode of action-based risk assessment of genotoxic carcinogens

et al. 2020

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“…No adenomas or carcinomas have been detected in the low-dose group. The statistical analysis led to the conclusion that the incidence is not statistically significant nevertheless does the occurrence of thyroid tumors need to be carefully considered [2,81,82].…”

Section: In Vivo Toxicity Of E171mentioning

confidence: 99%

Possible Adverse Effects of Food Additive E171 (Titanium Dioxide) Related to Particle Specific Human Toxicity, Including the Immune System

Bischoff

Kok

Sijm

et al. 2020

IJMS

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Titanium dioxide (TiO2) is used as a food additive (E171) and can be found in sauces, icings, and chewing gums, as well as in personal care products such as toothpaste and pharmaceutical tablets. Along with the ubiquitous presence of TiO2 and recent insights into its potentially hazardous properties, there are concerns about its application in commercially available products. Especially the nano-sized particle fraction (<100 nm) of TiO2 warrants a more detailed evaluation of potential adverse health effects after ingestion. A workshop organized by the Dutch Office for Risk Assessment and Research (BuRO) identified uncertainties and knowledge gaps regarding the gastrointestinal absorption of TiO2, its distribution, the potential for accumulation, and induction of adverse health effects such as inflammation, DNA damage, and tumor promotion. This review aims to identify and evaluate recent toxicological studies on food-grade TiO2 and nano-sized TiO2 in ex-vivo, in-vitro, and in-vivo experiments along the gastrointestinal route, and to postulate an Adverse Outcome Pathway (AOP) following ingestion. Additionally, this review summarizes recommendations and outcomes of the expert meeting held by the BuRO in 2018, in order to contribute to the hazard identification and risk assessment process of ingested TiO2.

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“…A role for hormonal dysregulation affecting the pituitary–thyroid axis and the rat specific thyroid hormonal milieu is generally accepted as an explanation for follicular cell neoplasia in rat carcinogenicity studies and is considered a rat-specific response (Alison et al 1994 ; Bartsch et al 2018 ; Capen 1997 ; Capen and Martin 1989 ; Khan et al 1999 ; Maronpot et al 2009 , 2015 ; Neumann 1991 ). As genotoxic damage to the thyroid at the dosages applied is likely improbable, (as discussed below) such rodent thyroid tumors are conceived to result from continuous interference with the pituitary-thyroid hormonal homeostasis of rats and considered not likely relevant to humans.…”

Section: Introductionmentioning

confidence: 99%

Revisiting the evidence for genotoxicity of acrylamide (AA), key to risk assessment of dietary AA exposure

Eisenbrand

2020

Arch Toxicol

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The weight of evidence pro/contra classifying the process-related food contaminant (PRC) acrylamide (AA) as a genotoxic carcinogen is reviewed. Current dietary AA exposure estimates reflect margins of exposure (MOEs) < 500. Several arguments support the view that AA may not act as a genotoxic carcinogen, especially not at consumer-relevant exposure levels: Biotransformation of AA into genotoxic glycidamide (GA) in primary rat hepatocytes is markedly slower than detoxifying coupling to glutathione (GS). Repeated feeding of rats with AA containing foods, bringing about uptake of 100 µg/kg/day of AA, resulted in dose x time-related buildup of AA-hemoglobin (Hb) adducts, whereas GA-Hb adducts remained within the background. Since hepatic oxidative biotransformation of AA into GA was proven by simultaneous urinary mercapturic acid monitoring it can be concluded that at this nutritional intake level any GA formed in the liver from AA is quantitatively coupled to GS to be excreted as mercapturic acid in urine. In an oral single dose–response study in rats, AA induced DNA N7-GA-Gua adducts dose-dependently in the high dose range (> 100 µg/kg b w). At variance, in the dose range below 100 µg/kg b.w. down to levels of average consumers exposure, DNA N7 -Gua lesions were found only sporadically, without dose dependence, and at levels close to the lower bound of similar human background DNA N7-Gua lesions. No DNA damage was detected by the comet assay within this low dose range. GA is a very weak mutagen, known to predominantly induce DNA N7-GA-Gua adducts, especially in the lower dose range. There is consensus that DNA N7-GA-Gua adducts exhibit rather low mutagenic potency. The low mutagenic potential of GA has further been evidenced by comparison to preactivated forms of other process-related contaminants, such as N-Nitroso compounds or polycyclic aromatic hydrocarbons, potent food borne mutagens/carcinogens. Toxicogenomic studies provide no evidence supporting a genotoxic mode of action (MOA), rather indicate effects on calcium signalling and cytoskeletal functions in rodent target organs. Rodent carcinogenicity studies show induction of strain- and species-specific neoplasms, with MOAs not considered likely predictive for human cancer risk. In summary, the overall evidence clearly argues for a nongenotoxic/nonmutagenic MOA underlying the neoplastic effects of AA in rodents. In consequence, a tolerable intake level (TDI) may be defined, guided by mechanistic elucidation of key adverse effects and supported by biomarker-based dosimetry in experimental systems and humans.

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Human relevance of follicular thyroid tumors in rodents caused by non-genotoxic substances

Cited by 35 publications

References 110 publications

Mode of action-based risk assessment of genotoxic carcinogens

Mode of action-based risk assessment of genotoxic carcinogens

Possible Adverse Effects of Food Additive E171 (Titanium Dioxide) Related to Particle Specific Human Toxicity, Including the Immune System

Revisiting the evidence for genotoxicity of acrylamide (AA), key to risk assessment of dietary AA exposure

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