Predictive toxicology, principles

Whatever methods are employed to link assessment end points with measures of effect, it is important to apply the methods in a manner consistent with sound ecological and toxicological principles. For example, it is inappropriate to use structure-activity relationships to predict toxicity from chemical structure unless the chemical under consideration has a similar mode of toxic action to the reference chemicals. Similarly extrapolations from upland avian species to waterfowl may be more credible if factors such as differences in food preferences, physiology, and seasonal behavior (e.g., mating and migration habits) are considered. 

This approach in predictive toxicology has manifest itself by the incorporation of certain key principles. These include ... 

Vracko, M., Bandelj, V, Barbieri, R, Benfenati, E., Chaudhry, Q., Cronin, M. T. D., Devillers, J., Gallegos, A., Gini, G., Gramatica, R, etal. (2006). Vahdation of counter propagation neural network models for predictive toxicology according to the OECD principles A case study. SAR QSAR Environ. Res. 17,265-284. 

Aptula, A.O. and Roberts, D.W. (2006) Mechanistic applicability domains for nonanimal-based prediction of toxicological end points general principles and application to reactive toxicity. Chemical Research in Toxicology, 19, 1097-1105. 

Robertson D, Beuhausen S, Pennie W. Toxicopanomics applications of genomics, proteomics and metabonomics in predictive and mechanistic toxicology. In Hayes AW, ed. Principles and Methods of Toxicology. 5th ed. Florida CR Press, 2007. 

In this chapter, we outline the issues and principles that are relevant to toxicity assessments of combined exposures. The scope of this overview is limited to combinations of chemicals, but excludes the topic of nonchemical stressors acting in concert with chemicals. Because the issues are of a generic nature, we draw on examples from human, environmental, and ecological toxicology. Section 3.2 briefly outlines approaches to mixture effects assessment (Chapter 4 elaborates these approaches in more detail), Section 3.3 discusses mixture effects in relation to modes and mechanisms of action, and Section 3.4 addresses the problems and possibilities of predicting mixture effects. In Sections 3.5 and 3.6, emphasis is on the predictability of synergism and on effects at low concentration or dose levels of chemicals in mixtures. Section 3.7 provides an overview of scarcely available data on mixture effects in real-world exposure scenarios. This chapter ends with an outlook to the future. 

Biomarkers in clinical pathology can be established on evidence that supports the performance characteristics of the test—analytical accuracy and reproducibility—and in which the use of the test is supported by toxicological, pharmacological, or physiological in vivo evidence. Some biomarkers are designed to confirm either the theoretical principle or the mechanism of action of a drug. Ideally, a biomarker should apply to all laboratory animal species, have similar diagnostic value, and be predictive for human safety the biomarker should be specific, sensitive, and minimally invasive. Unfortunately, many biochemical markers in current use are not ideal in these respects. 

Finally, the oral toxicity and risks to human health posed by macrocyclic imine toxins has not yet been resolved. There have been no long-term trials on the affects of chronic sublethal exposure to cyclic imines in any animal model or even any concerted attempt to predict such consequences based upon pharmacological first principles reported in the literature. Development of a rational and precautionary strategy for human health protection will require more comprehensive knowledge on the toxicology and pharmacological implications of these compounds than is currently accessible. 

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