"Weight of Evidence" (WoE) approaches are often used to critically examine, prioritize, and integrate results from different types of studies to reach general conclusions. For assessing hormonally active agents, WoE evaluations are necessary to assess screening assays that identify potential interactions with components of the endocrine system, long-term reproductive and developmental toxicity tests that define adverse effects, mode of action studies aimed at identifying toxicological pathways underlying adverse effects, and toxicity, exposure and pharmacokinetic data to characterize potential risks. We describe a hypothesis-driven WoE approach for hormonally active agents and illustrate the approach by constructing hypotheses for testing the premise that a substance interacts as an agonist or antagonist with components of estrogen, androgen, or thyroid pathways or with components of the aromatase or steroidogenic enzyme systems for evaluating data within the US EPA's Endocrine Disruptor Screening Program. Published recommendations are used to evaluate data validity for testing each hypothesis and quantitative weightings are proposed to reflect two data parameters. Relevance weightings should be derived for each endpoint to reflect the degree to which it probes each specific hypothesis. Response weightings should be derived based on assay results from the test substance compared to the range of responses produced in the assay by the appropriate prototype hormone and positive and negative controls. Overall WoE scores should be derived based on response and relevance weightings and a WoE narrative developed to clearly describe the final determinations.

Weight of evidence (WoE) approaches are recommended for interpreting various toxicological data, but few systematic and transparent procedures exist. A hypothesis-based WoE framework was recently published focusing on the U.S. EPA's Tier 1 Endocrine Screening Battery (ESB) as an example. The framework recommends weighting each experimental endpoint according to its relevance for deciding eight hypotheses addressed by the ESB. Here we present detailed rationale for weighting the ESB endpoints according to three rank ordered categories and an interpretive process for using the rankings to reach WoE determinations. Rank 1 was assigned to in vivo endpoints that characterize the fundamental physiological actions for androgen, estrogen, and thyroid activities. Rank 1 endpoints are specific and sensitive for the hypothesis, interpretable without ancillary data, and rarely confounded by artifacts or nonspecific activity. Rank 2 endpoints are specific and interpretable for the hypothesis but less informative than Rank 1, often due to oversensitivity, inclusion of narrowly context-dependent components of the hormonal system (e.g., in vitro endpoints), or confounding by nonspecific activity. Rank 3 endpoints are relevant for the hypothesis but only corroborative of Ranks 1 and 2 endpoints. Rank 3 includes many apical in vivo endpoints that can be affected by systemic toxicity and nonhormonal activity. Although these relevance weight rankings (W REL ) necessarily involve professional judgment, their a priori derivation enhances transparency and renders WoE determinations amenable to methodological scrutiny according to basic scientific premises, characteristics that cannot be assured by processes in which the rationale for decisions is provided post hoc.

Abstract-An outdoor freshwater microcosm study was conducted in which pyridaben, an insecticide-miticide, was directly applied to water to determine its fate and biological effects on an aquatic community. The following paper describes the design, specific techniques, and fate of pyridaben in microcosms including model prediction of the estimated environmental concentration, whereas the subsequent paper describes the responses of biota. An analysis of variance design was used with four treatments in which pyridaben was applied as an aqueous suspension (75% wettable powder) at three concentrations (0.34, 3.4, 34.0 g/L) plus an untreated control to 24 microcosm tanks (23 m 3 ). Each treatment was replicated six times. Pyridaben was applied to each microcosm once in April and once in May 1993 to simulate actual crop application. The Exposure Analysis Modeling System predicted that as a result of a drift (5.0%) exposure scenario, the half-life of pyridaben in water was 30 to 34 h. The model also predicted negligible concentrations of pyridaben in sediment after drift. Surface runoff was not considered an important source of pyridaben to aquatic systems, because the Pesticide Root Zone Model predicted a maximum runoff concentration of 0.1 g/L. The half-life in microcosm water for the low, middle, and high treatment concentrations for both applications ranged from 11.8 to 28.5 h. After both applications at 3.4 g/L, pyridaben was not detected in sediment within 24 h, whereas at 34.0 g/L the half-life of pyridaben in sediment was 9.8 d.

The effects of pyridaben, an insecticide‐miticide on zooplankton, macroinvertebrates, and fish were studied in outdoor freshwater microcosms using an analysis of variance design with three chemical concentrations (0.34, 3.4, 34.0 μg/L) and one untreated control randomized among 24 tanks. Each treatment was replicated six times. Monitoring was conducted during an 11‐month baseline phase followed by a total of three months for treatment and posttreatment phases. Two applications of a wettable powder formulation were sprayed directly below the water surface with a 30‐d interval between treatments. Copepoda adult abundance was significantly reduced at 34.0 μg/L but recovery occurred within 6 weeks after application. Abundance of copepoda nauplii was significantly reduced at 3.4 and 34.0 μg/L, after applications one and two; effects were more severe at 34.0 μg/L and recovery was more rapid at 3.4 μg/L. Abundance of Rotifera was reduced at 34.0 μg/L, after applications one and two, and recovery occurred within 8 weeks for all groups except Polyarthra and Keratella. Of the most abundant Cladocera, abundance of Alona was not significantly affected and abundance of Latonopsis was significantly reduced at 34.0 μg/L, after applications one and two, but recovery occurred within 6 weeks. Abundance of Latonopsis also was significantly reduced at 3.4 μg/L, after applications one and two, but recovery occurred within 2 weeks. A significant decrease occurred in the abundances of Cnidaria, Insecta, and Hydracarina at 34.0 μg/L, only after application one. Pyridaben was toxic to bluegill at 34.0 μg/L, but was not acutely toxic at the laboratory 96‐h LC50 concentration (∼3.4 μg/L).

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