These developments both individually, and overall, demonstrated a need for an appropriate focus of developments in nutritional research, and in particular, the expected introduction of health claims was anticipated by what could be seen as a renaissance of food science. The European Union and International Life Sciences Institute—Europe (ILSI-Europe) coordinated Concerted Action, “Functional food science in Europe” (FUFOSE), re-emphasized the importance in nutritional science of understanding the sequential relationship between initial exposure to dietary component, usually a nutrient, in its dietary matrix, the intestine uptake and transfer of the nutrient and/or its metabolites to the body, the subsequent intermediate metabolism of fate of the component itself, and their ultimate effect on organ or tissue architecture and function including, with particular relevance to health claims to improved physiological, or behavioural function, or a reduced risk of disease . FUFOSE illustrated how this mechanistic schema could be explored to demonstrate evidence of causality based on the use of good quality-assured science and validated markers that demonstrated the strength of causal inference in the individual steps of the chain, and the chain overall.
An important uncertainty in this chain is the efficiency with which the dietary component is utilized systemically, that is, the component’s bioavailability. Evidently, there is a need to relate the systemic outcome to the initial exposure and internal body burden if one is going to use that information to develop reference values, or to develop a case justifying a health claim, or a safe upper limit of intake. Bioavailability is therefore not just an important concept in nutritional science, but also, an important value. However, to say the least, it is difficult to measure, although many approaches have been used in an attempt to do so. Most of these do not measure bioavailability according to the above definition–probably the incorporation of iron into haemoglobin is the best example of the few outcomes that actually measure “bioavailability.” Otherwise, the various and diverse methods which have been used to measure bioavailability measure different variants of true or net intestinal or mucosal uptake and transfer of a nutrient and do not consider the further systemic metabolism, excretion and utilization of the dietary component. Furthermore, what is often measured and called bioavailability focuses on the characteristics of the component and of the dietary matrix as they affect the intestinal uptake and transfer of the component to the neglect of host factors which set the intestinal mucosa for the absorption of the component in question. As such, the term “bioavailability” has more often than not been applied to some aspect of absorption in such a way as to suit the experimental design rather than to address a pivotal generic phenomenon of nutritional science. This uncritical use of “bioavailability” has no value in objective nutritional risk assessment and cannot be expected to withstand forensic examination. In fact, to accommodate the complete concept of bioavailability, it is arguable that the term has become devalued and an impediment to transparent and objective assessment of dietary nutritional and risk assessment. A potentially more rewarding approach would be to adopt from nutrition’s sister disciplines of pharmacology and toxicology the analysis of systemic metabolism of a component with the Absorption, Distribution, Metabolism, Excretion (ADME) model. This would provide the basic dose–response data relevant to intake and metabolism of a dietary component and its subsequent effects on the host; should the appropriate data not exist, then it would enable a clear exposition of the relevant uncertainties in the nutritional and risk assessment of a dietary component.
The components of an ADME schema fit well with the mechanistic schema envisaged by FUFOSE as a means of addressing the functionality of foods or food components and assessing the evidence available which could be appraised against the FUFOSE construct. “Health claims” relate to what a food or food constituent does in relation to nutritional or physiological beneficial effects such as contributions to health maintenance, health improvements and disease risk reduction. Consumers should be able to make informed choices based on clear and accurate information and to have confidence in the scientific and regulatory processes used to support claims. Many of the recent and ongoing developments on the scientific substantiation of health claims with particular reference to approaches come from activities of Codex, the European food safety authority (EFSA) and the US Food and Drug Administration (US FDA). These authorities have developed and adopted methodologies for the assessment of the totality of the available data and for a suitable framework for weighing the evidence to reflect state-of-the-art nutrition science, to promote future research and to determine the extent to which a causal relationship can be demonstrated. In these approaches, scientific assessments need to be proportionate to meet the legitimate expectations of researchers and applicants for the authorization of a health claim, and there is a need to link the totality of the available data and the strength, consistency and biological plausibility of evidence to claims that are truthful and meaningful to consumers. In the European context, another ILSI-Europe hosted Concerted Action the Process for the Assessment of Scientific Support for Claims on Foods (PASSCLAIM)  addressed the strategic presentation and integration of all the evidence relevant to, including that which might limit a claim, supporting causality. It placed no particular emphasis or hierarchical precedence of the types of evidence used but rather emphasized the expectation that the integrity and coherence of the evidence should be assessed on a case-by-case basis by appropriately competent assessors and that these assessments would be accompanied by an exposition of any uncertainties which might limit confidence in any claimed causal inference.
The expectations and analyses of evidence relevant to claims have become conditioned by the expectations of evidence-based approaches. The underpinning assumption being that evidence-based medicine (EBM) represents the use of current best evidence in making decisions about clinical care and that randomized controlled trials (RCTs), systematic reviews and meta-analyses of such trials are best practice, and there is little need, therefore, to heed other forms of evidence such as cohort studies or expert opinion. Somewhat paradoxically, therefore, clinical recommendations and guidelines are most frequently made by expert committees who themselves evaluate the evidence. Interestingly, evaluation of RCTs versus observational studies shows they produce very similar findings overall . The gold-standard RCT is difficult to apply to nutrition for several reasons. It is practically impossible to create a “study nutrient free” placebo group. While drugs often have a single target, nutrition most often has multiple targets. Effect size for nutrition may be small, but across multiple systems. However, small effects can be very important at the population level. Dose–response relationships between nutrient intake and outcome are often nonlinear and may be different for different outcomes. There may be interactions (additive, synergistic, antagonistic) with other nutrients or with drugs. Failure to recognize these features may explain the failure of some nutrition RCTs and wrong conclusions and judgements can be made as a result. Systematic reviews and meta-analyses are increasingly being applied to nutrition and, being based mainly upon RCT evidence, can suffer from the same confounding features. The earliest detailed descriptions of EBM recognized that observational data and expert judgment are essential parts of the EBM decision-making process  and appreciated that RCTs were developed to compensate the lack of information and quality assurance about underpinning mechanisms and the difficulty to muster sufficient information to enable an adequate appraisal by the Hill principles . The crucial element in this context is the competency and appropriate knowledge of those who review and assess evidence. It is important that systematic reviews be conducted by persons with expertise in the subject being reviewed. The setting of dietary and nutrient guidelines and recommendations has typically (and rightly) valued expert opinion, and often cohort studies have been considered as providing evidence of at least equal import to that of RCTs. It is clear that, although the philosophy to use the best quality evidence is shared between “medicine” and “nutrition,” the approach used to evaluating the totality of the relevant evidence needs to be different. As used to support policy and to satisfy regulatory requirements, evidence-based nutrition (EBN) and EBM are different. However, the improving mechanistic insights available through modern cell biology and its integration into systemic physiology has opened up opportunities for the more extensive use of mechanistic and metabolic markers relevant to assessing in an exposure-related fashion the functional and toxic effects of food components; this is congruent with the FUFOSE mechanistic schema and with a more integrated analysis of the available data as a process of evidence-based mechanistic reasoning [7, 8].