Rob Kroes

Threshold of toxicological concern for chemical substances present in the diet: A practical tool for assessing the need for toxicity testing

The de minimis concept acknowledges a human exposure threshold value for chemicals below which there is no significant risk to human health. It is the underlying principle for the US Food and Drug Administration (FDA) regulation on substances used in food-contact articles. Further to this, the principle of Threshold of Toxicological Concern (TTC) has been developed and is now used by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) in their evaluations. Establishing an accepted TTC would benefit consumers, industry and regulators, since it would preclude extensive toxicity evaluations when human intakes are below such threshold, and direct considerable time and cost resources towards testing substances with the highest potential risk to human health. It was questioned, however, whether specific endpoints that may potentially give rise to low-dose effects would be covered by such threshold. In this review, the possibility of defining a TTC for chemical substances present in the diet was examined for general toxicity endpoints (including carcinogenicity), as well as for specific endpoints, namely neurotoxicity and developmental neurotoxicity, immunotoxicity and developmental toxicity. For each of these endpoints, a database of specific no-observed-effect levels (NOELs) was compiled by screening oral toxicity studies. The substances recorded in each specific database were selected on the basis of their demonstrated adverse effects. For the neurotoxicity and developmental neurotoxicity databases, it was intended to cover all classes of compounds reported to have either a demonstrated neurotoxic or developmentally neurotoxic effect, or at least, on a biochemical or pharmacological basis were considered to have a potential for displaying such effects. For the immunotoxicity endpoint, it was ensured that only immunotoxicants were included in the database by selecting most of the substances from the Luster et al. database, provided that they satisfied the criteria for immunotoxicity defined by Luster. For the developmental toxicity database, substances were selected from the Munro et al. database that contained the lowest NOELs retrieved from the literature for more than 600 compounds. After screening these, substances showing any effect which could point to developmental toxicity as broadly defined by the US were recorded in the database. Additionally, endocrine toxicity and allergenicity were addressed as two separate cases, using different approaches and methodology. The distributions of NOELs for the neurotoxicity, developmental neurotoxicity and developmental toxicity endpoints were compared with the distribution of NOELs for non-specific carcinogenic endpoints. As the immunotoxicity database was too limited to draw such a distribution of immune NOELs, the immunotoxicity endpoint was evaluated by comparing immune NOELs (or LOELs-lowest-observed-effect levels-when NOELs were not available) with non-immune NOELs (or LOELs), in order to compare the sensitivity of this endpoint with non-specific endpoints. A different methodology was adopted for the evaluation of the endocrine toxicity endpoint since data currently available do not permit the establishment of a clear causal link between endocrine active chemicals and adverse effects in humans. Therefore, this endpoint was analysed by estimating the human exposure to oestrogenic environmental chemicals and evaluating their potential impact on human health, based on their contribution to the overall exposure, and their estrogenic potency relative to endogenous hormones. The allergenicity endpoint was not analysed as such. It was addressed in a separate section because this issue is not relevant to the overall population but rather to subsets of susceptible individuals, and allergic risks are usually controlled by other means (i.e. labelling) than the Threshold of Toxicological Concern approach. (ABSTRACT TRUNCATED)

Risk characterisation of chemicals in food and diet

This report presents a review of risk characterisation, the final step in risk assessment of exposures to food chemicals. The report is the second publication of the project Food Safety in Europe: Risk Assessment of Chemicals in the Food and Diet (FOSIE). The science underpinning the hazard identification, hazard characterisation and exposure assessment steps has been published in a previous report (Food Safety in Europe, 2002). Risk characterisation is the stage of risk assessment that integrates information from exposure assessment and hazard characterisation into advice suitable for use in decision-making. The focus of this review is primarily on risk characterisation of low molecular weight chemicals, but consideration is also given to micronutrients and nutritional supplements, macronutrients and whole foods. Problem formulation, as discussed here, is a preliminary step in risk assessment that considers whether an assessment is needed, who should be involved in the process and the further risk management, and how the information will provide the necessary support for risk management. In this step an evaluation is made of whether data are available and what level of resources are needed, as well as the timeline for completing the assessment. The report describes good evaluation practice as an organisational process and the necessary condition under which risk assessment of chemicals should be planned, performed, scrutinised and reported. The outcome of risk characterisation may be quantitative estimates of risks, if any, associated with different levels of exposure, or advice on particular levels of exposure that would be without appreciable risk to health, e.g. a guidance value such as an acceptable daily intake (ADI). It should be recognised that risk characterisation often is an iterative and evolving process. Historically, different approaches have been adopted for the risk characterisation of threshold and non-threshold effects. The hazard characterisation for threshold effects involves the derivation of a level of exposure at or below which there would be no appreciable risk to health if the chemical were to be consumed daily throughout life. A guidance value such as the ADI, is derived from the no-observed-adverse-effect-level (NOAEL) or other starting point, such as the benchmark dose (BMD), by the use of an uncertainty or adjustment factor. In contrast, for non-threshold effects a quantitative hazard estimate can be calculated by extrapolation, usually in a linear fashion, from an observed incidence within the experimental dose-response range to a given low incidence at a low dose. This traditional approach is based on the assumption that there may not be a threshold dose for effects involving genotoxicity. Alternatively, for compounds that are genotoxic, advice may be given that the exposure should be reduced to as low as reasonably achievable (ALARA) or practicable (ALARP). When a NOAEL can be derived from a study in humans, this would be utilised in the derivation of guidance values or advice. However, there may be uncertainties related to the possible role of confounders and the precision of both the incidence and exposure data. Individuals may be at an increased risk because of their greater exposure or their greater sensitivity. Risk characterisation should include information not only on the general population, but also on any subpopulation considered to be potentially susceptible.

A review of the safety of DHA45-oil

Polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA), are natural constituents of the human diet; however, dietary intakes of these fatty acids are below recommended values. The main dietary source of DHA is fatty fish, with lesser amounts provided by shellfish, marine mammals, and organ meats. The addition to traditional food products of refined oils produced by marine microalgae represents potential sources of supplemental dietary DHA. DHA45-oil is manufactured through a multi-step fermentation and refining process using a non-toxigenic and non-pathogenic marine protist. Comprising approximately 45% DHA, and lesser concentrations of palmitic acid and docosapentaenoic acid, DHA45-oil is intended for use in foods as a dietary source of DHA. The safety of DHA45-oil was evaluated in various genotoxicity and acute, subchronic, and reproductive toxicity studies. DHA45-oil produced negative results in genotoxicity assays and demonstrated a low acute oral toxicity in mice and rats. Dietary administration of DHA45-oil to rats in subchronic and one-generation reproductive studies produced results consistent with those observed in oral studies using high concentrations of omega-3 PUFAs from fish or other microalgal-derived oils. The results of these studies, as well as those of various published metabolic, toxicological, and clinical studies with DHA-containing oils, support the safety of DHA45-oil as a potential dietary source of DHA.

Forestomach Carcinogens: Pathology and Relevance to Man

Squamous cell carcinomas of the forestomach have been observed in many carcinogenicity studies in rodents, especially after oral or gavage exposure. The histopathological diagnosis of forestomach lesions and the relevance of the data for human risk estimation can be controversial. The pathological classification may be troublesome because of the low-grade malignancy and the pseudoepitheliomatous hyperplasia that may develop after ulceration and inflammation. For human risk estimation it is important to understand the mechanism of action; this is illustrated by examples using butylated hydroxyanisole, methyl bromide, and epichlorohydrin. Another feature that complicates risk estimation is the absence of a homologue for the forestomach in man. The potential risk from non-genotoxic forestomach carcinogens in man involves exposure of the mouth, pharynx, and esophagus at dose levels that exert irritating action. It is assumed that exposure to non-genotoxic chemicals at concentrations far below those having irritating potential is not hazardous to humans.

Approaches for Integrated Risk Assessment

Recognizing the need to enhance the effectiveness and efficiency of risk assessments globally, the World Health Organizations International Programme on Chemical Safety, the U.S. Environmental Protection Agency, the European Commission, and the Organization for Economic Cooperation and Development developed a collaborative partnership to foster integration of assessment approaches used to evaluate human health and ecological risks. The objectives of this effort included: improving understanding of the benefits of integration, identifying obstacles to the integration process, and engaging key agencies, organizations, and scientific societies to promote integration. A framework with supporting documentation was developed to describe an approach for integration. Four case studies were constructed to illustrate how integrated risk assessments might be conducted for chemical and nonchemical stressors. The concepts and approaches developed in the project were evaluated in an international workshop. The goal of this effort was international acceptance of guidance for integrated risk assessment.

Integrated Risk Assessment - Results from an International Workshop.

The World Health Organizations International Programme on Chemical Safety and international partners have developed a framework for integrated assessment of human health and ecological risks and four case studies. An international workshop was convened to consider how ecological and health risk assessments might be integrated, the benefits of and obstacles to integration, and the research and mechanisms needed to facilitate implementation of integrated risk assessment. Using the case studies, workshop participants identified a number of opportunities to integrate the assessment process. Improved assessment quality, efficiency, and predictive capability were considered to be principal benefits of integration. Obstacles to acceptance and implementation of integrated risk assessment included the disciplinary and organizational barriers between ecological and health disciplines. A variety of mechanisms were offered to overcome these obstacles. Research recommendations included harmonization of exposure characterization and surveillance methods and models, development of common risk endpoints across taxa, improved understanding of mechanisms of effect at multiple scales of biological organization, and development of methods to facilitate comparison of risks among endpoints.

Original Paper: Gastro-oesophageal reflux disease in primary care Comparison and evaluation of existing national guidelines and development of uniform European guidelines

Objectives: Symptoms of gastro-oesophageal reflux and gastro(o)esophageal reflux disease (GERD) are common and are managed mainly in primary care. Evidence-based medicine and development of guidelines offer a means of ensuring a cost-effective approach to this disease. We have evaluated several existing national guidelines for GERD in primary care for their agreement and evidence base, to develop a basis for European guidelines and to detect issues that need further research in this area.Methods: National guidelines were sought in the United Kingdom, Sweden, Norway, Denmark, Germany, the Netherlands and Italy. A Medline and cross-reference literature search was carried out, based on several decision points in the guidelines.Results: Five national guidelines were available; in two countries no national guidelines existed. A good degree of agreement in the national guidelines was generally found on the diagnosis of GERD but guidance on the treatment of GERD varied more, especially with respect to the class ...

Them and Us: Questions of Citizenship in a Globalizing World

At the dawn of the twenty-first century, all of us consider ourselves to be citizens of something--but of what? Nation-states? Regions? Ethnic groups? Corporations? An accomplished set of meditations by one of Europes leading Americanists, Them and Us is a rich comparative study of European and American cultural traditions and their influence on conceptions of community. In contrast with the ethnic and nationalist allegiances that historically have splintered Europe, Rob Kroes identifies a complex of cultural practices that have mitigated against ethnically rooted divisions in the United States. He argues that the American approach--articulated by a national rhetoric emphasizing openness rather than closure, diversity rather than uniformity--has much to offer a Europe where the nationalist and ethnic conflicts that spawned two world wars continue to sow terror and destruction. Kroes discusses European and American attitudes toward the welfare state, the human rights tradition in the United States, and the role of regionalism in shaping conceptions of national identity. He also considers new, transnational forms of cultural membership that are emerging to take the place of nation-based citizenship. He contends that the frame of reference Europeans now use to make sense of their collective situation draws on ingredients provided by the worldwide dissemination of American mass culture. He investigates the way this emerging world culture, under American auspices, affects the way people in their local and national settings structure their sense of the past and conceive of their citizenship. Imagining a new set of cultural relationships that could serve as the basis for global citizenship, Them and Us is an insightful consideration of the types of solidarity that might weave humankind together into a meaningful community.

The Ascent of the Falling Man: Establishing a Picture's Iconicity

Why is it that some photographs have a power of epic concentration, condensing larger moments in history into one iconic image? This piece about the photography of 9/11 addresses this question. Its focus is on one photograph in particular, Richard Drews image of the Falling Man. Central to the argument is the awareness of a paradox: to explore something quintessentially photographic – the force of images that give them iconic power – using a medium for reflection and communication that is inherently non-photographic: i.e. language. The author aims at accounting for the fascination of Drews image, in a struggle to find words to describe its impact. To that end he looks at how others – the photographer himself, and other creative minds, in essay form, fiction or graphic novels – have translated their fascination into language that may help us account for the way this image continues to haunt us.

“Deficits Don’t Matter”: Abundance, Indebtedness and American Culture

If deficits, nor defaults, don’t really matter anymore, what sign of our times is it? What has changed from the days that Franklin Delano Roosevelt risked the fragile economic recovery from the great depression by returning, in 1937, to the standard of his economic orthodoxy, a belief in fiscal rectitude and anaversion to debts and deficits? If that was a sign of a certain American character, what has happened to it? A massive shift in public culture must have occurred, affecting people’s views on public probity and political rectitude. The following is an attempt to trace some of the main shifts on the way to our present quandary.