Predicting human dose-response relationships from multiple biological models: Dr. Stephen Schaub
September 28, 2000
USDA Center at Riverside
Riverdale, Maryland
Introduction | Agenda | Speaker list and presentations | Meeting handout PDF
Dr. Stephen Schaub's presentation transcript (slides not included):
During this session we're going to have three speakers who will talk about the essential components of the doses-response cycle which take place during human infection by pathogens such as Cryptosporidium.
I'm just going to give a brief background of the doses response cycle although probably everyone here is knowledgeable about the microbiology and dose response factors, but just to give a little refresher about these considerations. The major factors that we have to be concerned about are the pathogen factors, human susceptibility factors, and the exposure matrix (or how is the pathogen encountered - in water or food). Some of these are things to think about during this morning's technical presentations which may be considerations this afternoon when we discuss animals or in vitro models or other models that may be applicable.
First of all the pathogen factors we need to consider. The pathogen characteristics which influence infection and its outcome are obviously the invasive ness, infectivity, virulence, and potential toxic factors for the organism when it enters the body. What are the strains, the various mutations that might have occurred such as antibiotic resistance, or various types of changes which may influence the susceptibility of the pathogen to humeral or cellular immunity factors within the body and the expression of pathogen characteristics once inside the host. Even though a characteristic that contributes to establishment of an infection may be present in the genome, it has to be expressed during the infection process to attain the virulence or invasive ness or toxicity characteristics necessary to be successful in establishing that infection.
Environmental factors (both the natural environment and the environment once in contact with the host) are also important to the success of a pathogen. In other words what factors allow the pathogen to manage to get into and through the stomach and allow their survival or even their growth in the gastrointestinal tract. Therefore, if a pathogen is present in the food or water that is consumed, it is necessary for the pathogen to have a reasonable chance of survival until such time as it is able to make the appropriate contact with the susceptible cells of the host to achieve a successful infective process.
There are critical life cycle factors unique to each pathogen, which includes the historical ecology of the pathogen, its host preferences, and even influences of the previous type of host upon its subsequent host ranges which also affect the chances of successfully causing new infections.
With respect to host susceptibility considerations, the host factors
are also going to significantly influence the exposure outcome to the
pathogen.
Most probable outcomes are: no infection; infection with no obvious disease;
disease which is expressible and determinable; the development of sequella
or long-term effects (examples - diabetes, reactive arthritis); and
of
course, mortality. There are a number of factors which are either intrinsic,
such as the age, sex, genetic make-up or ethnic characteristics of
the
individuals or population. Also there is the general individual or population
immunity profile against the pathogen as well as the general health
of
the population, presence of underlying disease, or nutritional and physical
stresses on members of the population. Special concerns are individuals
who's immune systems have been compromised through other infections
(e.g., AIDS), or through medical procedures (e.g., transplantation
immunity suppression).
Finally there are differences in the types of exposure settings peculiar
to lifestyles and consumption habits which impact on the probability
of
exposure.
It is important to take a holistic approach to determining the exposure and pathogen load from multiple sources. The total burden may not be a single food or water consumption event but may be the accumulation of several events and possibly even from different sources.
An exciting area of research related to the overall dose response equation is the examination of the food or water matrix and the impacts these matrices have on successful infection. The types and quantities of food or liquid consumed can have a major impact on the rate and duration of passage of these materials through the stomach to the intestines (generally considered the point at which infection begins) and also the gastrointestinal tract survival, growth, and viability/infectivity state of the pathogens which were present in the ingested materials. Several scenarios come to mind: 1) the nature of the foodstuff in the stomach itself can have a negative impact on the lethal effects of the stomach digestive enzymes and may raise stomach pH to a level which is not effective for pathogen degradation, e.g., some food types may protect the pathogens from destruction; 2) the amount of food or water taken in at a given time may affect the kinetics of passage of the pathogens to the intestines. More rapid passage will reduce the period for stomach enzymes and low pH to successfully reduce the infective pathogen load. Certain types of pathogens such as Cryptosporidium, the focus of today's discussions, actually require digestive mechanisms to take place in order to release the infectious sporozoites within the protective oocyst so that they can attack the intestinal epithelial cells.
Another consideration is the physical distribution of the pathogens and this may also play an important role in the infection process. Pathogen clumping, aggregation, and intimate association (e.g., coating, absorption) with food particles may increase the success for surviving in the environment and in passing through the stomach intact to the intestinal epithelium as these physical factors decrease the capabilities of the environment as well as the stomach mechanisms to fully destroy all of the microbes during their travels from one host to the next.
Some important features to keep in mind for today's discussions regarding surrogate animals or in vitro models and their applicability in predicting human dose response against various pathogens are that we need to make sure that the results seen with these surrogates are consistent with and provide equivalent interpretations for the exposure route related to the human population of concern. It is also important that the particular pathogen - dose response relationships are related to the same health endpoints (infection, disease, mortality, etc.)
Dr. Long mentioned earlier why we chose Cyryptosporidium
for today's forum. The Dose Response working group actually agonized
about choices over a number of steering committee meetings to determine
what
pathogen would be a good representative for determining the efficacy
of various types of dose response models, and for human exposure scenarios
for this meeting. We finally chose Cryptosporidium because it
was a pathogen of concern for both food and water and had been associated
with a number of waterborne and food borne outbreaks from which we have
epidemiological outbreak data.
While there are still some information gaps about this organism I think
that for an enteric pathogen we probably have more data on it regarding
many facets of the infectious disease triangle than we have for most
other
pathogens of the enteric group. We have information on its life cycle
and genetics, phenotypic expression and strain differences in virulence
and host range characteristics, human exposure routes, dose response
data
from human feeding trials, cryptosporidiosis health effects data for
general and sensitive populations, plus animal and in-vitro models of
infection.
Additionally, there have already been some attempts to fit the mathematical
models for dose-response with this particular organism. We will hear
about
this data in great detail today and I think everyone will find
it very interesting and informative.
I would next like to introduce our first speaker of this session.
