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R Kroes

Publications and source records attributed to R Kroes.

At least 19 recordsLinked to original sources
PubMed2006

Risk assessment of substances that are both genotoxic and carcinogenic report of an International Conference organized by EFSA and WHO with support of ILSI Europe.

The European Food Safety Authority (EFSA) and the World Health Organization (WHO), with the support of the International Life Sciences Institute, European Branch (ILSI Europe), organized an international conference on 16-18 November 2005 to discuss how regulatory and advisory bodies evaluate the potential risks of the presence in food of substances that are both genotoxic and carcinogenic. The objectives of the conference were to discuss the possible approaches for risk assessment of such substances, how the approaches may be interpreted and whether they meet the needs of risk managers. ALARA (as low as reasonably achievable) provides advice based solely on hazard identification and does not take into account either potency or human exposure. The use of quantitative low-dose extrapolation of dose-response data from an animal bioassay raises numerous scientific uncertainties related to the selection of mathematical models and extrapolation down to levels of human exposure. There was consensus that the margin of exposure (MOE) was the preferred approach because it is based on the available animal dose-response data, without extrapolation, and on human exposures. The MOE can be used for prioritisation of risk management actions but the conference recognised that it is difficult to interpret it in terms of health risk.

Animals↗
PubMed2005

Tooth whitening products and the risk of oral cancer.

Tooth whitening products (TWP) containing hydrogen peroxide (HPO) or carbamide peroxide (CPO) were evaluated in relation to potential oral cancer risk from their use. HPO is genotoxic in vitro, but such activity is not expressed in vivo. The genotoxic risk of HPO exposure of the oral mucosa encountered from TWP use is likely therefore to be vanishingly small. Available animal data on the carcinogenicity of HPO are of limited relevance to risk assessment of oral hazard of HPO exposure from TWP, and where relevant, do not indicate that there is an increased oral cancer risk for people using TWP. Clinical data on HPO-containing TWP only show evidence of mild, transient gingival irritation and tooth sensitivity, with no evidence for the development of preneoplastic or neoplastic oral lesions. Exposures to HPO received by the oral cavity, including areas commonly associated with oral cancer, are exceedingly low and do not plausibly pose a risk for the promotion of initiated cells or for induction of co-carcinogenic effects in conjunction with cigarette smoke or alcohol. The use of TWP was concluded not to pose an increased risk for oral cancer in alcohol abusers and/or heavy cigarette smokers. Furthermore, TWP were concluded to be safe for use by all members of the population, including potential accidental use by children.

Animals↗
PubMed2005

The threshold of toxicological concern concept in risk assessment.

The concept that "safe levels of exposure" for humans can be identified for individual chemicals is central to the risk assessment of compounds with known toxicological profiles. The Threshold of Toxicological Concern (TTC) is a concept that refers to the establishment of a level of exposure for all chemicals, whether or not there are chemical-specific toxicity data, below which there would be no appreciable risk to human health. The concept proposes that a low level of exposure with a negligible risk can be identified for many chemicals, including those of unknown toxicity, based on knowledge of their chemical structures. The present paper aims to describe the history of the TTC principle, its use to date, its potential future applications and the incorporation of the TTC principle in the Risk Assessment paradigm.

Animals↗
PubMed2004

Safety issues of botanicals and botanical preparations in functional foods.

Although botanicals have played a role in the marketing of health products for ages, there is an increased interest today due to their perceived health benefits. Not only do consumers increasingly take charge of their health, but the scientific information and understanding of the beneficial health effects of bioactive substances in food, functional foods and food supplements have improved. Increasing use of these products has also led to concerns about their actual safety. Recorded cases of intoxications have triggered such concerns. The safety assessment of these substances is complicated by, amongst others, the variability of composition. Furthermore, consumption of such functional products is expected to produce physiological effects, which may lead to low margins of safety as the margin between exposure of such products and the safe level of intake are likely to be small. The safety assessment of botanicals and botanical preparations in food and food supplement should at least involve: the characterisation and quality of the material, its quality control; the intended use and consequent exposure; history of use and exposure; product comparison(s); toxicological information gathering; Risk characterisation/safety assessment. As a guidance tool, a decision tree approach is proposed to assist in determining the extent of data requirements based on the nature of the such product. This guidance tool in safety assessment was developed by an expert group of the International Life Sciences Institute (ILSI), European Branch, and is currently in press. In this paper a summarised version of this tool is presented.

Decision Trees↗
PubMed2004

Structure-based thresholds of toxicological concern (TTC): guidance for application to substances present at low levels in the diet.

The threshold of toxicological concern (TTC) is a pragmatic risk assessment tool that is based on the principle of establishing a human exposure threshold value for all chemicals, below which there is a very low probability of an appreciable risk to human health. The concept that there are levels of exposure that do not cause adverse effects is inherent in setting acceptable daily intakes (ADIs) for chemicals with known toxicological profiles. The TTC principle extends this concept by proposing that a de minimis value can be identified for many chemicals, in the absence of a full toxicity database, based on their chemical structures and the known toxicity of chemicals which share similar structural characteristics. The establishment and application of widely accepted TTC values would benefit consumers, industry and regulators. By avoiding unnecessary toxicity testing and safety evaluations when human intakes are below such a threshold, application of the TTC approach would focus limited resources of time, cost, animal use and expertise on the testing and evaluation of substances with the greatest potential to pose risks to human health and thereby contribute to a reduction in the use of animals. An Expert Group of the European branch of the International Life Sciences Institute-ILSI Europe-has examined the TTC principle for its wider applicability in food safety evaluation. The Expert Group examined metabolism and accumulation, structural alerts, endocrine disrupting chemicals and specific endpoints, such as neurotoxicity, teratogenicity, developmental toxicity, allergenicity and immunotoxicity, and determined whether such properties or endpoints had to be taken into consideration specifically in a step-wise approach. The Expert Group concluded that the TTC principle can be applied for low concentrations in food of chemicals that lack toxicity data, provided that there is a sound intake estimate. The use of a decision tree to apply the TTC principle is proposed, and this paper describes the step-wise process in detail. Proteins, heavy metals and polyhalogenated-dibenzodioxins and related compounds were excluded from this approach. When assessing a chemical, a review of prior knowledge and context of use should always precede the use of the TTC decision tree. The initial step is the identification and evaluation of possible genotoxic and/or high potency carcinogens. Following this step, non-genotoxic substances are evaluated in a sequence of steps related to the concerns that would be associated with increasing intakes. For organophosphates a TTC of 18microg per person per day (0.3 microg/kg bw/day) is proposed, and when the compound is not an OP, the TTC values for the Cramer structural classes III, II and I, with their respective TTC levels (e.g. 1800, 540 and 90 microg per person per day; or 30, 9 and 1.5 microg/kg bw /day), would be applied sequentially. All other endpoints or properties were shown to have a distribution of no observed effect levels (NOELs) similar to the distribution of NOELs for general toxicity endpoints in Cramer classes I, II and III. The document was discussed with a wider audience during a workshop held in March 2003 (see list of workshop participants).

Animals↗
PubMed2000

Pan-European research challenges in toxicology and epidemiology: twinning for the better.

At the Third Ministerial Conference on Environment and Health held in London in June 1999, a document on environment and health research for Europe was discussed and endorsed. This initiative - developed by the European Science Foundation, the European Commission and the WHO European Region - will be one of the largest of its kind in Europe. The programme described in particular an analysis of the more than 80 research recommendations which served as the basis for the high priority research questions presented in London. The need for an integrated multi-disciplinary approach is emphasised. The ultimate aim is to provide risk managers with tools to implement remediation and prevention effectively and efficiently in a prioritised fashion. Related research challenges in toxicology for the new millennium are described.

Congresses as Topic↗
PubMed2000

Safety evaluation and risk assessment of the herbicide Roundup and its active ingredient, glyphosate, for humans.

Reviews on the safety of glyphosate and Roundup herbicide that have been conducted by several regulatory agencies and scientific institutions worldwide have concluded that there is no indication of any human health concern. Nevertheless, questions regarding their safety are periodically raised. This review was undertaken to produce a current and comprehensive safety evaluation and risk assessment for humans. It includes assessments of glyphosate, its major breakdown product [aminomethylphosphonic acid (AMPA)], its Roundup formulations, and the predominant surfactant [polyethoxylated tallow amine (POEA)] used in Roundup formulations worldwide. The studies evaluated in this review included those performed for regulatory purposes as well as published research reports. The oral absorption of glyphosate and AMPA is low, and both materials are eliminated essentially unmetabolized. Dermal penetration studies with Roundup showed very low absorption. Experimental evidence has shown that neither glyphosate nor AMPA bioaccumulates in any animal tissue. No significant toxicity occurred in acute, subchronic, and chronic studies. Direct ocular exposure to the concentrated Roundup formulation can result in transient irritation, while normal spray dilutions cause, at most, only minimal effects. The genotoxicity data for glyphosate and Roundup were assessed using a weight-of-evidence approach and standard evaluation criteria. There was no convincing evidence for direct DNA damage in vitro or in vivo, and it was concluded that Roundup and its components do not pose a risk for the production of heritable/somatic mutations in humans. Multiple lifetime feeding studies have failed to demonstrate any tumorigenic potential for glyphosate. Accordingly, it was concluded that glyphosate is noncarcinogenic. Glyphosate, AMPA, and POEA were not teratogenic or developmentally toxic. There were no effects on fertility or reproductive parameters in two multigeneration reproduction studies with glyphosate. Likewise there were no adverse effects in reproductive tissues from animals treated with glyphosate, AMPA, or POEA in chronic and/or subchronic studies. Results from standard studies with these materials also failed to show any effects indicative of endocrine modulation. Therefore, it is concluded that the use of Roundup herbicide does not result in adverse effects on development, reproduction, or endocrine systems in humans and other mammals. For purposes of risk assessment, no-observed-adverse-effect levels (NOAELs) were identified for all subchronic, chronic, developmental, and reproduction studies with glyphosate, AMPA, and POEA. Margins-of-exposure for chronic risk were calculated for each compound by dividing the lowest applicable NOAEL by worst-case estimates of chronic exposure. Acute risks were assessed by comparison of oral LD50 values to estimated maximum acute human exposure. It was concluded that, under present and expected conditions of use, Roundup herbicide does not pose a health risk to humans.

Abnormalities, Drug-Induced↗
PubMed1999

Sialidase gene transfection enhances epidermal growth factor receptor activity in an epidermoid carcinoma cell line, A431.

Glycosphingolipids expressed in cancer cells have been implicated in the modulation of tumor cell growth through their interaction with transmembrane signaling molecules such as growth factor receptors. For glycosphingolipids to interact with growth factor receptors, the presence of sialic acid seems to be essential. Stable transfection of a gene encoding a soluble Mr 42,000 sialidase into a human epidermoid carcinoma cell line (A431) provided an approach by which the level of terminal lipid-bound sialic acid on the cell surface could be altered. In the sialidase-positive clones, the level of ganglioside GM3 was diminished, and little change was observed in protein sialylation. Sialidase-transfected cells grew faster than control cells. Sialidase expression did not modify the binding of epidermal growth factor (EGF) to its receptor but enhanced EGF receptor (EGFR) tyrosine autophosphorylation as compared to that of parental cells or cells transfected with the vector (pcDNA3) alone. Moreover, the phosphorylation of the EGFR, as well as other protein substrates, was observed at low EGF concentrations, suggesting an increase in the receptor kinase sensitivity. These data provided evidence that changes in ganglioside expression in cancer cells by appropriate gene transfection can dramatically affect EGFR kinase activity. Hence, the modulation of ganglioside expression may represent an approach to alter tumor cell growth.

Carcinoma, Squamous Cell↗
PubMed1995

European School of Oncology Advisory report to the European Commission for the "Europe Against Cancer Programme" European Code Against Cancer.

A European School of Oncology Advisory Group has reviewed the European Code Against Cancer after its initial use over a 6-year period. With minor modifications, the original ten recommendations were found to be adequate, although it was agreed that an Annex was necessary to explain the scientific evidence supporting each point, and is presented herewith. Tobacco smoking clearly remains the most important cause of cancer, and now it can be quantified better than ever before. It is also clear that it is never too late to stop smoking: stopping even in middle age, prior to the onset of serious illness has a beneficial effect on life expectancy. Alcohol drinking is an important cause of cancer, and yet modest consumption levels protect against cardiovascular disease mortality. The optimal strategy seems to be a consumption not exceeding 2-3 drinks per day, although this limit may be lower for women. Increased consumption of fruits and vegetables, reduction in consumption of fatty foods, reduction of obesity and increased physical activity can all be recommended to reduce cancer risk. Exposure to excessive sunlight remains a problem which should be limited. Control of occupational cancer is a three-way partnership: legislation identifies and limits exposure to known carcinogens, employers enact the legislation and workers should respect the measures introduced. There are a number of signs and symptoms which may lead to cancer being diagnosed earlier, and patients with these should be referred to a doctor. For women, participation in organised programmes of cervical cancer and breast cancer (after 50 years of age) should lead to a reduction in mortality from these forms of cancer. The key element is organised programmes, where quality control and quality assurance are in force. These revised recommendations are the result of an agreement following advice, review and dialogue with cancer experts throughout Europe. They were approved by the European Community Cancer Experts at their meeting in Bonn on 28-29 November 1994. Their implementation by the European population should greatly reduce cancer incidence and mortality.

Alcohol Drinking↗
PubMed1994

The intake of chemicals related to age in long-term toxicity studies--considerations for risk assessment.

The estimation of acceptable daily intake (ADI) is generally based on results from long-term toxicity studies. Long-term exposure of rodent and nonrodent species is extrapolated to lifetime exposure in humans, using uncertainty factors to compensate inter- and intraspecies differences. Special consideration can be given to groups of humans at increased risk, such as children, due to higher susceptibility or higher predicted intake. A retrospective study of long-term carcinogenesis studies was performed at the National Toxicology Program of the National Institute of Environmental Health Sciences to gain insight into the relationship between age and intake of test compounds. In these long-term studies, average intake of feed and drinking water, and consequently chemicals dosed in these, was approximately two times higher on a body weight basis in young animals (postweaning) than in adults. Thus, estimating an ADI from the NOEL of this type of studies already includes a higher dose for the young. When maximum levels for food additives are being set using the already established ADI, it may not be necessary to add an additional uncertainty factor for different ages, unless there are other specific reasons to do so, such as unduly high exposure and toxicity at a certain age. Compared to intake per kilogram of body weight at the end of the study, the ADI already includes an extra uncertainty factor of approximately 2 for young individuals.

Aging↗