Science Inventory

NON-TRADITIONAL RESPONSES TO PHARMACEUTICALS IN AQUATIC ECOSYSTEMS

Citation:

BROOKS, B., R. BRAIN, D. HUGGETT, J. M. LAZORCHAK, H. SANDERSON, J. STANLEYS, AND J. SUMPTER. NON-TRADITIONAL RESPONSES TO PHARMACEUTICALS IN AQUATIC ECOSYSTEMS. Presented at SETAC North America, Milwaukee, WI, November 11 - 15, 2007.

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 exposu

Description:

Quantitation of human and veterinary pharmaceuticals in environmental matrices has resulted in pharmaceuticals in the environment receiving unprecedented attention from the scientific community. Aquatic hazard assessments often use quantitative structure activity relationships and standardized toxicity tests, which assess mortality, growth or reproduction responses following short term exposures. Although these traditional approaches are appropriate for many substances, their application to pharmaceuticals has been questioned. For example, if an aquatic criterion were developed for ethinylestradiol, an estrogen receptor agonist, or trenbolone, a synthetic androgen, following traditional approaches, the criterion for each compound could be estimated at levels several orders of magnitude higher than previously reported effect levels for fish reproduction. We examined recent reports of pharmaceutical effects to aquatic plants, invertebrates and vertebrates with a particular focus on non-standardized response variables. Several examples of these nontraditional responses include molecular and biochemical biomarkers, physiological and behavioral studies, and fish partial or full life cycle responses. If a pharmaceutical exhibits high acute-to-chronic ratio (ACR), it may chronically elicit responses through a specific mechanism of action (MOA), potentially similar to its activity in mammals. In the case of biomarkers and other non-traditional endpoints, the type of chronic response used to generate an ACR can influence whether a biomarker may be useful in the exposure and effect analysis phases of ecological risk assessment; for example, biomarkers have been historically distinguished as either indicators of exposure or effect in retrospective risk assessments. It appears that aquatic responses to pharmaceuticals that are MOA-specific and sensitive can provide indicators of exposure or effect at concentrations below those eliciting adverse responses in standardized bioassays. However, for a biomarker of effect to be useful in ecological risk assessment, its response should be directly linked to a physiologically and ecologically relevant endpoint.

Record Details:

Record Type:DOCUMENT( PRESENTATION/ ABSTRACT)
Product Published Date:11/13/2007
Record Last Revised:10/17/2007
Record ID: 174788