Working Procedures

B. SCIENTIFIC REVIEW AND EVALUATION

4. Mechanistic and other relevant data

In evaluating an intervention, effects other than cancer are described and weighed. Furthermore, information that facilitates an understanding of the applicability of findings to different species, or to different human populations is particularly important: this includes metabolic, kinetic, and genetic data. Whenever possible, quantitative data, including information on dose, duration, and potency, are considered.

The focus on this section is on studies in humans, including intervention trials and epidemiological studies with cancer-relevant molecular biomarkers or intermediate end-points as an outcome. Studies in experimental systems can strengthen the evidence for the potential cancer-preventive effect of an intervention observed in humans, and can elucidate the mechanism(s) of cancer prevention. A brief summary of important findings in experimental systems is therefore included.

Evaluation of the results of intervention studies in humans includes consideration of quality, as described above. Study quality factors generally consider the adequacy of the methods and the reporting of results, addressing: (1) the description of the methods; (2) the appropriateness of control populations; (3) whether toxic effects were considered in the outcome; (4) whether the data were appropriately compiled and analysed; (5) whether appropriate quality controls were used; (6) whether appropriate concentration ranges were used; (7) whether adequate numbers of independent measurements were made per group; and (8) the relevance of the end-points.

The observation of effects on the occurrence of lesions presumed to be preneoplastic, or the emergence of benign or malignant tumours, may aid in assessing the mode of action of the intervention being considered. Particular attention is given to assessing the reversibility of these lesions and their predictive value in relation to cancer development.

(a) Toxicokinetics

Information is given on absorption, distribution (including placental transfer), metabolism and excretion in humans. If human data are sparse, evidence from experimental animals may be summarized. Studies in humans that indicate the metabolic pathways and fate of an intervention are summarized. Data indicating long-term accumulation in human tissues are included. Observations are made on inter-individual variations and relevant metabolic polymorphisms. Physiologically based pharmacokinetic models and their parameter values are relevant and are included whenever they are available.

Information from experimental systems, including on the fate of the compound within tissues and cells (transport, role of cellular receptors, compartmentalization, binding to macromolecules) may be briefly summarized.

The metabolic consequences of interventions are described.

(b) Mechanisms of cancer prevention

For a rational implementation of cancer-preventive measures, it is essential not only to assess protective end-points, but also to understand the mechanisms by which the intervention exert its anticarcinogenic action. Data on mechanisms will be primarily from studies in humans. Data from relevant experimental models can also be summarized, including studies of the inhibition of tumorigenesis in vivo, studies of intermediate biomarkers in vivo, analyses of interactions between agents and specific molecular targets, and studies of specific end-points in vitro. Information on the mechanisms of cancer-preventive activity inferred from relationships between chemical structure and biological activity can also be included.

Cancer-preventive interventions may act at different levels: (1) extracellular, for example, inhibiting the uptake or endogenous formation of carcinogens, or forming complexes with, diluting and/or deactivating carcinogens; (2) intracellular, for example, trapping carcinogens in non-target cells, modifying transmembrane transport, modulating metabolism, blocking reactive molecules, inhibiting cell replication or modulating gene expression or DNA metabolism; or (3) at the level of the cell, tissue or organism, for example, affecting cell differentiation, intercellular communication, proteases, signal transduction, growth factors, cell adhesion molecules, angiogenesis, interactions with the extracellular matrix, hormonal status and the immune system.

Many cancer-preventive interventions are known or suspected to act by several mechanisms, which may operate in a coordinated manner and allow them a broader spectrum of anticarcinogenic activity. Therefore, a range of possible mechanisms of action are taken into account in the evaluation of cancer prevention. These can be conceptually organized to encompass impacts on one or more related key characteristics of carcinogens (Smith et al., 2015), particularly, interference with: (1) metabolic activation of carcinogens; (2) mutagenesis; (3) DNA repair or genomic instability; (4) epigenetic effects; (5) oxidative stress; (6) inflammation; (7) immune function; (8) receptor-mediated effects; (9) immortalization; or (10) cell proliferation, cell death, or nutrient supply.

(c) Susceptible populations

This section summarizes studies of cancer in humans that have addressed differential susceptibility due to toxicokinetics, mechanisms of cancer prevention, and other factors. Such studies may identify individuals, populations, and life-stages with greater or lesser susceptibility. Examples of host and genetic factors that affect individual susceptibility include sex, genetic polymorphisms of genes involved in the metabolism of the intervention, differences in metabolic capacity due to life-stage or the presence of disease, differences in DNA repair capacity, competition for alteration of metabolic capacity by medications or other chemical exposures, a pre-existing hormonal imbalance that is exacerbated by a chemical exposure, a suppressed immune system, periods of higher-than-usual tissue growth or regeneration, and genetic polymorphisms that lead to differences in behaviour (e.g. addiction). Genotyping is being used increasingly, not only to identify subpopulations at increased or decreased risk for cancers but also to characterize variation in the biotransformation of and response to cancer-preventive interventions. Such data can substantially increase the strength of the evidence from epidemiological data and enhance the linkage of in-vivo and in-vitro laboratory studies to humans.

(d) Adverse effects

Relevant clinical or other evidence that would impact any recommendations may be summarized as appropriate.

Posted 5 July 2016