The Key Events Dose-Response Framework: Its Potential for Application to Foodborne Pathogenic Microorganisms

Abstract

The Key Events Dose-Response Framework (KEDRF) is an analytical approach that facilitates the use of currently available data to gain insight regarding dose-response relationships. The use of the KEDRF also helps identify critical knowledge gaps that once filled, will reduce reliance on assumptions. The present study considers how the KEDRF might be applied to pathogenic microorganisms, using fetal listeriosis resulting from maternal ingestion of food contaminated with L. monocytogenes as an initial example. Major biological events along the pathway between food ingestion and the endpoint of concern are systematically considered with regard to dose (i.e., number of organisms), pathogen factors (e.g., virulence), and protective host mechanisms (e.g., immune response or other homeostatic mechanisms). It is concluded that the KEDRF provides a useful structure for systematically evaluating the complex array of host and pathogen factors that influence the dose-response relationship. In particular, the KEDRF supports efforts to specify and quantify the sources of variability, a prerequisite to strengthening the scientific basis for food safety decision making.

Modeling of Pathogen Survival during Simulated Gastric Digestion

“…A 3-ml aliquot of each diluted bacterial suspension (ϳ10 7 CFU/ml), prepared as described above, was added to 27 ml SGF maintained at 37°C to obtain an initial concentration of 6 CFU/ml in SGF. The mixture was incubated at 37°C in a water bath for 240 min, and sampling (1 ml) was carried out after 10,20,30,45,60,90,120,150,180, and 240 min. Samples serially diluted in 0.1% peptone water (0.1 ml) were plated in duplicates onto Trypticase soy agar (TSA; Merck).…”

“…To solve differential equation 1, the r max was transformed to the specific inactivation rate (k max ) using a natural logarithm. The relationship between them is as follows: k max ϭ r max ϫ ln (10), where ln is the natural logarithm. The effect of the SGF pH on the absolute value of k max can be described by using the following simple square-root-type model as follows (36) …”

“…The currently available dose-response models of microbial risk assessment are derived from the following different source data: human-feeding volunteer tests (14), extrapolation of the results of animal experiments to humans (44,51), and estimations from epidemiological studies of outbreaks of food-borne illness (8). However, these approaches to dose-response modeling of low-dose exposures to pathogens rely on multiple assumptions and extrapolations, which reflect the current lack of knowledge regarding the fundamental mechanisms underlying the responses to a dose (10).…”

“…Recently, a new concept, called the key-events dose-response framework (KEDRF), has been introduced as an alternative approach for the development of dose-response models (10). In the KEDRF approach, the following five major and necessary steps, termed key events, are proposed: (i) survival of pathogens in the upper gastrointestinal tract, (ii) establishment in the intestine and attachment to and uptake into epithelial cells, (iii) survival and escape from phagosomes in enterocytes and transfer of pathogen to phagocytes, (iv) transfer of pathogens across placenta, and (v) pathogen growth leading to fetal morbidity and mortality.…”

Listeria monocytogenes Dose Response Revisited—Incorporating Adjustments for Variability in Strain Virulence and Host Susceptibility

“…Short-term strategies identified during this workshop included updating the doseresponse model developed by FDA/FSIS (4) by incorporating new data and insights about differences in strain virulence and L. monocytogenes pathophysiology. A key-events approach to dose-response modeling (29) was identified as a promising though extremely challenging, data-intensive, and potentially unachievable framework for future microbial doseresponse models. (2) Current dose-response models linked to epidemiological data tend to agree that a low dose of L. monocytogenes leads to an average low probability of invasive listeriosis in the general population as well as in broadly defined populations with heightened susceptibility.…”