Predicting Chemical Effects Based on Known Responses
Structure-Activity Relationship (SAR) is a means by which the effect of a drug or toxic chemical on an animal, plant, or the environment can be related to its molecular structure. This type of relationship may be assessed by considering a series of molecules, each with a slightly different structure, then noting the difference in biological activity associated with each structural variation. Alternatively, it may be possible to assess a large body of toxicity data using intelligent tools such as neural networks to try to establish relationships between structures and activity.
Ideally, such relationships can be characterized mathematically as Quantitative Structure Activity Relationships (QSAR), in which some degree of predictive capability is present. QSAR can be applied in the context of software tools.
The Value of SAR
Environmental managers are faced with the task of understanding the effects of a large number of assorted chemicals in diverse media, and for an increasing number of toxicity endpoints. Because animal testing is often impractical or expensive, alternative methods relating chemical structure to biological activity and biological potency have become increasingly valued for many diverse problem settings. By accelerating improved understanding of chemical mechanisms of toxicological endpoints, and by consolidating toxicological data, managers can be better prepared to address potential human health issues, and to plan or respond in cost-optimum ways.
Case Studies
Intertox has performed SAR analyses for clients in the past, including the DOE Hanford facility (Richland, WA) where Intertox developed toxicity guidelines for over 1000 storage tank chemicals, and for airborne vapors, to support evaluation of potential short-term toxicological consequences of accidental human exposures. SAR was employed where chemical toxicity data were lacking. In addition, software was developed to facilitate rapid identification of compounds likely to pose the greatest hazard.
In another example, Intertox assessed potential toxicity of fire suppression substitutes. The goal was to predict the short- and long-term toxicity of a series of theoretical halogenated chemical molecules being considered for development as substitutes for the ozone-depleting fire suppression agent Halon.
In still another project, Intertox used SAR methods to evaluate the potential toxicity of a series of chemical isomers potentially present in a hydraulic fluid mixture used in commercial aircraft.
SAR & Chemical Risk Management
Related to SAR/QSAR, risk management brings together risk assessment, exposure control and risk monitoring. It attempts to identify and develop suitable responses to potential hazards, taking into account relevant regulatory, political, environmental, engineering, and social factors.
Intertox has frequently applied risk management tools and techniques on behalf of clients. Site-specific risk assessments at corporate facilities and properties have been undertaken to assess the possibility of occupational and/or residential exposures, including assessment of normal as well as catastrophic risk occurrences. For example, Intertox supported an evaluation of occupational hazards associated with sluicing tank vapors. Services included deriving toxicity guideline values, and correlating past exposure conditions with current worker signs and symptoms.
Such assessments lead to well founded risk management plans that minimize human, environmental, and corporate risk in a common unit of effort.
Chemical Synergistic Effects
It is not uncommon for the effect of two chemicals on an organism to be greater than either the effect of each chemical individually, or the sum of the individual effects. The presence of one chemical affects the toxicity of the second. For example, this can occur when both chemicals compete for the same cellular endpoint. When the effect is greater than the sum of the individual effects, this is called synergism. This subject area is currently the focus of extensive investigation in toxicology and pharmacology.
Intertox’s scientists are well-versed in the state-of-the-science regarding chemical synergistic effects, and have applied such knowledge to predicting how exposures to chemical mixtures, in the context of risk management plans as well as SAR/QSAR modeling, can affect human health.