Citation:

KOSTICH, M., J. M. LAZORCHAK, AND G. P. TOTH. AN INFORMATIC APPROACH TO ESTIMATING ECOLOGICAL RISKS POSED BY PHARMACEUTICAL USE. Presented at SETAC, Baltimore, MD, November 13 - 17, 2005.

Impact/Purpose:

The indeterminate condition of exposure indicator research stands to change markedly with the ability to connect molecular biological technologies with cellular or tissue effects and outcomes. Three focal areas of ecological research aim to develop a sequence of approaches where "the earliest recognizable signatures of exposure" (i.e., unique patterns of up- and down-regulated genes and proteins) are identified for numerous stressors, demonstrable in case studies and incorporated into Agency, State and Regional studies supported by EMAP and other programs.

Area 1, Computational Toxicology Research: Exposure assessment has historically been based on use of chemical analysis data to generate exposure models. While biological activity of chemicals has been recognized to be important for exposure risk assessments, measurement of such activity has been limited to whole organism toxicity tests. Use of molecular approaches will improve extrapolation between components of source-to-outcome continuum (source , exposure, dose, effect, outcome)

Using a systems modeling approach, gene and protein expression data, in small fish models (fathead minnow and zebrafish), will be integrated with metabolomic and histopathological data. This will assist in prediction of environmental transformation and chemical effects based on structural characteristics, and enhance quantitative risk assessments, including areas of uncertainty such as a basis for extrapolation of effects of endocrine disrupting chemicals, interspecies extrapolation, complex chemical mixtures and dose-response assessment.

Area 2, Ecological Research-Environmental Diagnostics: Development of molecular diagnostic indicators contributes to several of the GPRA Diagnostic Research Goals. Methods will employ DNA microarray technology and expression proteomics, focusing on species of relevance to aquatic ecosystem risk assessment. Significantly, these diagnostic indicators will open the door to understanding subcellular interactions resulting from exposure to complex chemical mixtures.

define relationship between genetic disposition of populations and degree/specificity of stressor-specific gene transcriptional response in aquatic organisms (fish and invertebrates)

identify of chemical mixture induced transcriptional "patterns" using microarrays and hyperspectral scanning - via collaboration with DOE Sandia National Labs

apply molecular indicators to watershed level stressor study, including pilot studies with targeted pesticides and toxins indicators

develop molecular indicators of exposure for invertebrates (Daphnia, Lumbriculus, Chironomus)

Area 3, Exposure Research in Endocrine Disruptors:

Subobjective 1: Develop exposure methods, measurement protocols, and models for assessment of risk management practices of endocrine disrupting compounds. As risk management approaches are identified and developed, there will be a need to identify, adapt and develop bioassay screening tools and other analytical methods to assess their efficacy. Measurements research will be performed to define management needs. This effort will entail cross-lab participation from NRMRL, NERL and NHEERL.

Subobjective 2: Determine extent of environmental and human exposures to EDCs, characterize sources and factors influencing these exposures, develop and evaluate risk management strategies to reduce exposures. In order to develop effective risk management strategies, it is important to understand the extent of exposures to endocrine disrupting compounds and factors influencing source-to-exposure-to-dose relationships.

apply molecular indicators of exposure to estrogenic compounds in selected wastewater treatment plants located in ten USEPA Regions

identify differential gene expression following exposure of fathead minnows to environmental androgens and androgen-like compounds

apply molecular indicators of exposure to estro

Description:

Pharmaceuticals administered to humans and other animals are often excreted from treated organisms as intact drug or as active metabolites. Some of these active materials have been shown to make their way into the environment. However, the environmental concentrations of the vast majority of pharmaceuticals and their metabolites are not known. The sensitivity of native organisms to chronic exposure to the doses of active material likely to be found in the environment is also not known. Direct determination of these important parameters is too expensive to perform on the entire pharmacopoeia, and a rational way of prioritizing individual drugs for more detailed study is needed. For many drugs sufficient information is available in the scientific literature and within regulatory filings to estimate the upper bound of environmental concentrations and most probable mechanisms of environmental toxicity. Although these estimates involve large confidence intervals, they are quickly and cheaply produced, and are probably the best available criteria for prioritizing drugs for more expensive direct tests of environmental impact. Here we describe a new method similar to that employed by the EU and by the US FDA for estimating risks of human prescription pharmaceuticals based on information found in regulatory filings as well as scientific and trade literature. Available data on usage patterns, metabolic transformation, and physical/chemical properties are fed into models of dilution, degradation, partition between matrices, and bioavailability in order to estimate effective environmental concentrations. Available data on mechanisms of action and modes of toxicity are considered together with cursory phylogenetic analysis to estimate the sensitivity of select native organisms to the estimated highest likely environmental concentrations of each drug. Scores produced by this procedure will be used to prioritize pharmaceuticals for more detailed analytical and toxicological follow-up. The applicability of modified versions of this method to over-the-counter pharmaceuticals and veterinary pharmaceuticals is also described.

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