CFSAN Regulatory Codes: X.A.
CFSAN Program Priority Codes: 1.3B.1
Start Date: 10/1/1998    Completion Date: 9/30/2002

Statement of Research Problem:
We know that bacteria contaminating our food can cause sickness and even death. Many gaps in our knowledge remain, including:

• The relationship between dose and the probability and severity of illness.
• The direct and indirect monetary costs associated with different pathogens and associated illnesses.
• How to relate animal or in vitro studies to human dose response.

Statement of Project Objective(s):
The research will provide models of what happens when we are exposed to different levels of microbial hazards from the food supply. The models deal with dose response in the broadest sense. The components include laboratory studies on dose response at the level of target issues, exploration and use of appropriate mathematical models, and the translation of response data into values that can be used for policy analysis.

1. The project will help support FDA regulation of microbial hazards by providing a better projections of the numbers of organisms required to present specific health hazards.

Project Priority Changes During FY2000: None

Collaborators: Members of Economics Team, OSAS/DMS

The technique involves searching among statistical models or equations to determine if they are suitable for use in a microbial risk assessment. Models are judged according to how well they fit data, their level of simplicity, and their consistency with accepted theories.

1. Create two-dimensional dose-frequency function.
2. Create curve-fitting program for two-dimensional function.

1. Model for Listeria monocytogenes risk assessment.

1. Extensive work on CFSAN Listeria risk assessment.

1. Incorporation of feedback from risk assessment into modeling program.

1. Enhancement of functions in the dose response program to incorporate new data and feedback from earlier versions.

The output of dose response models and risk assessments is not immediately applicable to regulatory impact analysis, which requires measures of costs and benefits. The monetary values of illnesses from different hazards are necessary to link the outputs of dose response models to regulatory policy. This component of the project aims to create better (more flexible and more complete) monetary measures of the health effects of illnesses caused by microbial pathogens.

1. New measures of quality-adjusted life days
2. New estimates of the monetary costs of morbidity from food-borne pathogens.
3. New estimates of the monetary costs of mortality from food-borne pathogens.

1. Papers, presentations, and analyses of regulations.
2. New models for estimating the monetary valuing of preventing food borne illnesses.

1. Helped to plan and organize conference on valuing the health benefits of food safety.
2. Began interagency project on valuing the long-term health effects associated with chronic sequelae associated with Salmonella and other pathogens

1. Conference proceedings on valuation of illness.
2. Abstract on conference results.

1. Draft paper on arthritis project.

Validation studies of physiologically based pharmacokinetic (PBPK) modeling for endotoxins will provide pharmacokinetic data that are needed to validate an exposure model for risk assessment of bacterial endotoxin.

Component 3 Objectives:
The physiological approach allows FDA to extrapolate from low to high doses, between routes of exposure and in various species tested to quantitate the human exposure and risks. The model is a predictive tool that helps identify data gaps, and may help the Center set research priorities.
Component 3 FY 2000 Deliverables:
The PBPK model has been developed with the mathematical description of the relationship between bacterial endotoxin, LPS, and target tissue exposure over time. The model needs to be validated with experimental data.
Component 3 FY 2000 Progress:
The first phase of validation experiments to synthesize the radiolabelled LPS from Salmonella typhimurium is completed. The second phase of in vivo pharmacokinetic experiments by using radiolabelled LPS is in progress.
Technical Barriers to Meeting Component 3 Objectives or Deliverables: none listed
Component 3 FY 2001 Deliverables:
Initiate the validation of the PBPK model with experimental data obtained from animal experiments in vivo.
Component 3 FY 2002 Deliverables:
Final refinement of the model and preparation of manuscripts.