PredictBT Workshop 2 Summary

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Development of Pathway Prioritization System (PPSII)

May 6-7, 2005, University of Minnesota, St Paul, MN USA

Goals

The goal of the workshop was to extend the utility of the Pathway Prediction System (PPS) found on the UM-BBD. The PPS currently returns all known reactions, based on its rule system, that a particular compound might undergo in the environment. The PPS predicted reactions derive from more than 250 biotransformation rules that are based on the information from approximately 1000 biochemical reactions contained in the UM-BBD. One limitation of the PPS, for some users, is that it returns too many predicted metabolic pathways, some of which will likely not occur in certain environments. In this context, our new goal is to expand the PPS to rank the predicted reactions for their relative likelihood of occurrence under given conditions. This additional feature will help the user make a more informed decision about the fate of chemicals in the environment.

Users

Anticipated users of the expanded PPS are government regulators, environmental agencies, industrial scientists, and academicians. Newly synthesized chemical compound must be assessed for ease of biodegradation and their potential to produce toxic intermediates during degradation. It is not possible to test all new chemicals for their effects on the environment. Only 10% of the compounds that entered the market before 1980 have safety data. And government regulatory agencies currently demand more information on the biodegradability of any new chemical produced industrially. Therefore, industries are also under increasing pressure to know the environmental fate of their products. Research scientists will also find this system useful to discern amongst different pathways for a compound. Even some consumer groups now demand safety data.

The proposed system will provide a better understanding of the environmental fate of synthetic chemicals for which experimental data is unavailable. Unfortunately, such compounds form a large percentage of the total chemicals synthesized. The experts agreed that the science of toxicology should be moved from observed to deductive knowledge.

Uniqueness of the system

Commercial software packages designed to guide industry about biodegradability are opaque, not publicly accessible, and often expensive. PPSII will be freely available on the World Wide Web for everybody to use. The scientific logic behind the system will be open and clearly explained. Everybody agreed to make the system as transparent as possible. However the development area will be password protected with the authority to make changes given to a selected group of individuals. One of the suggestions was to have an editorial board comprised of experts with the final authority. Since it is proposed to be an internet based system, the international scientific community will be free to make comments and point out the shortcomings.

Some systems that are available today place emphasis on analyzing a compound's structure and thermodynamic data to predict their biodegradability. However, knowing if a compound is biodegradable, or not biodegradable, is not enough. It is also important to know the possible intermediates in the biodegradation pathways. This is where the proposed system is useful.

Approach

The current PPS works on the 250 biotransformation (bt) rules based on reaction contained within the UM-BBD. The bt rules will be ranked for relative likelihood. Everybody agreed on the importance of environmental conditions on biodegradation prediction. It was decided that assuming standard conditions described below would be a good way to start.

Standard conditions

Aerobic, moderate moisture
In soil or water with diverse bacterial population
no toxic materials, for example, heavy metals
pH - neutral
Temperature - 25°C

Should the scale for ranking be 1-3 or 1-5? Everybody agreed on a scale of 1-5 with '1'= most likely and '5'= least likely would be best to differentiate between the possible reactions. The 5 levels of rankings were defined prior to the workshop. Accordingly experts were asked to assign rankings to all the bt rules. In most cases, all 2 or 3 experts who ranked a rule agreed on the relative likelihood of the rule. However, there were rules where expert opinion differed by 2 or more scores. Those rules were discussed. For most rules, consensus was reached. However, certain rules need some refinement.
There was discussion on the manner of presenting ranking information on the web; for example, using different colors for different rankings.

Exceptions

It is expected that the ranking for a rule, although applicable in most cases, will fail to be valid for certain classes of compounds or mixture of substituents. These will be termed as "exceptions" for a particular rule. The rankings for these groups of exceptions would be different than the general rank for the rule.

Immediate work

Work on rules that need refinement
Investigate the literature to reach to consensus on ranking for the few disputed rules and any exceptions
Compilation of information on bt rules with respective rankings
Refine bt-rule pages similar to UM-BBD reaction pages providing additional information to justify the rule ranking and also include rule exceptions
Develop color scheme to represent the relative rule ranking

Limits of the system

It was agreed that at this stage there are other systems doing a better job at commenting on the biodegradability of chemicals. Hence it was decided to set limits to PPS II. Little or no information will be provided on following topics related to biodegradability:

Rate of biodegradation or the half-life of the chemicals
Partitioning between phases
Bioavailability, extent of Bioaccumulation
Photochemical stability

Experts will largely rank a rule based on their experience and literature published on that topic. One of the approaches discussed would be to give a rule a smaller value if that type of reaction is known to occur in large number of bacteria and many examples of that are published. However a shortcoming of this approach would be that a certain very common reaction could be only recently discovered. As a result there would be little information available on it. Hence the rule ranking assignment should largely rely on expert opinion and their knowledge of biochemical reactions. Therefore it is very important that the system does not over-predict. The system should be as unsure about certain rules as the human experts who made it.

Some Final Expert Comments

There should be a molecular weight cut-off for R-groups while generalizing PPS rules.
In the real world there is always a mixture of conditions. Even under aerobic conditions there are certain anaerobes present. The environment is also susceptible to sudden changes.
Perhaps many new industrial compounds, when they first enter the environment, are not readily biodegraded. Over time however, microorganisms evolve to metabolize these compounds more efficiently. Hence it would be useful to incorporate a knowledge of metabolic evolution into biodegradation prediction.

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