Authors E. Dybing, J. Doe, J. Groten, J. Kleiner, J. O'Brien, A.G. Renwick, J. Schlatter, P. Steinberg, A. Tritscher, R. Walker, M. Younes
Abstract
Hazard characterisation of low molecular weight chemicals in food and diet generally use a no-observed-adverse-effect level (NOAEL) or a benchmark dose as the starting point. For hazards that are considered not to have thresholds for their mode of action, low-dose extrapolation and other modelling approaches may be applied. The default position is that rodents are good models for humans. However, some chemicals cause species-specific toxicity syndromes. Information on quantitative species differences is used to modify the default uncertainty factors applied to extrapolate from experimental animals to humans. A central theme for extrapolation is unravelling the mode of action for the critical effects observed. Food can be considered as an extremely complex and variable chemical mixture. Interactions among low molecular weight chemicals are expected to be rare given that the exposure levels generally are far below their NOAELs. Hazard characterisation of micronutrients must consider that adverse effects may arise from intakes that are too low (deficiency) as well as too high (toxicity). Interactions between different nutrients may complicate such hazard characterisations.
The principle of substantial equivalence can be applied to guide the hazard identification and hazard characterisation of macronutrients and whole foods. Macronutrients and whole foods must be evaluated on a case-by-case basis and cannot follow a routine assessment protocol. Research needs Low-molecular weight chemicals Central to the interpretation and extrapolation of dose-response toxicity data is the understanding of the underlying modes of action. Thus, for a number of low-molecular weight chemicals where the mode of action is not presently understood, there is an obvious need for mechanistic-type studies. This would especially be needed in situations where the range of human exposures are close the the ADI/TDI derived from default assumptions. Also, clarification is necessary of the relevance of the endpoint for humans where there are obvious species differences in response. Mechanistic-type studies should address whether the modes of action for the observed effects may be extrapolated downwards to realistic human exposure levels as well as whether they are relevant for humans. Further developments in application of non-radiolabelled technology such as nuclear magnetic resonance (NMR) spectroscopy, will presumably increase the understanding of toxicokinetics and thus improve the process of hazard characterisation. However, further validation and experience is necessary and an increaseing database will allow for better interpretation of results. Future application of novel molecular biological methods including those in genomics and proteomics, will generate a vast amount of data.
It will therefore be a major challenge to interpret such data and incorporate them in a hazard identification and characterisation context. This will call for studies in integrated, whole organism models in order to sort out the insignificant responses from critical events. Also, application of the molecular biological methods in conjunction with conventional toxicological studies is warranted in order to develop experience on how data from such methods can be interpreted. Chemical mixtures Hazard characterisation of chemicals in food are usually performed on single entities, although food exposures always represent complex mixtures. It is therefore an obvious need for more data on potential interactions of chemicals in food. Despite the potential use of available methods, mixture design studies need further extensive testing and cross validation. The hazard characterisation process of chemical mixtures requires a multidisciplinary approach by toxicologists, epidemiologists, mathematicians, model developers and health assessors to justify the selection of those compounds of particular interest for the hazard characterisation of a mixture. For new food chemicals which show target organ toxicity at doses above the NOAEL, studies are warranted in order to identify any interactions with food chemicals in use, based on the possibility of a common mechanism of toxicity. Micronutrients and nutritional supplements There is an obvious need for updating the scientific basis for establishment of lower and upper safe intake levels of micronutrients in food. Particular attention should be given to micronutrients with a narrow safe range of intake. There is also a need to generate more human data on the kinetics and potential adverse health effects of micronutrients and nutritional supplements at different levels of intake, and the variability of these parameters in the population. Increased research on the variability of the kinetics of micronutrients and nutritional supplements related to age, gender, physiological conditions (pregnancy and lactation) and nutritional status (e.g. high fat intake) is warranted.
The bioavailability of the industrially produced micronutrient may be different from its natural counterpart. Furthermore, synthetic micronutrients may contain isomers which differ from those present in the natural material and thus be metabolised differently, which may result in a different health effect. Many interactions are described for minerals and trace elements, although mostly in a qualitative way. Both deficient and excessive intakes of minerals and trace elements can cause interactions that have an adverse effect on the absorption and metabolism of other constituents of the diets. Some of the vitamins also have the potential of interacting with other nutrients. Thus, there is a need for research addressing the quantitative interactions between micronutrients, nutritional supplements and other food constituents. It is important that research studies are designed in close collaboration between nutritionists and toxicologists. Novel foods, macronutrients and whole foods In the area of safety assessment of novel foods, macronutrients and whole foods, the steps of hazard identification and hazard characterisation are not as separate and sequential as those for low-molecular weight chemicals. Safety evaluation, is based on a comparison with traditional foods and has to be performed on a case-by-case basis, following a strategy devided in following phases: collection and evaluation of background information, comparison with traditional foods, targeted toxicity testing. For valid comparison, adequate characterisation and description of the test material is important and guidelines for (minimal) data requirements would greatly improve the application of the concept of substantial equivalence. Hazard characterisation of macronutrients and whole foods is complex in that, in addition to identifying potential toxic effects, the nutritional impact of the test material has to be assessed. This implies a need for improved knowledge of nutrient requirements, nutrient interactions and influence on bioavailability of other nutrients in both the test species and in humans.
Further research is necessary to establish guidelines on nutritional boundaries for rodent studies. Increased collaboration between nutritionists and toxicologists will greatly improve knowledge on study design and interspecies extrapolations. The traditional approach for safety assessment based on animal feeding studies is limited in the area of macronutrients and whole foods, and the doses applied cannot encompass an uncertainty factor of at least 100. The need for acceptance of lower uncertainty factors has been acknowledged, however guidance is needed on what is acceptable. In this context a concept should be developed combining aspects of uncertainty factors and nutritional homeostasis. There is clearly an increased need for human data to be included early on in the safety evaluation of macronutrients and whole foods. The development of suitable biological indicators for nutritional changes in animal studies can help to design human studies and so greatly improve their value. Validation for such indicators is required. Several approaches for guidelines or decision trees on the evaluation of macronutrients and whole foods, as well as foods with a specific nutritional purpose ('functional foods') have been proposed. An overall review of published proposals can serve as a basis to develop overall guidance on improved testing strategies and to develop a common proposal on a process-based/decision tree approach.
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