Evaluation of in silico model predictions for mammalian acute oral toxicity and regulatory application in pesticide hazard and risk assessment.

The United States Environmental Protection Agency (USEPA) uses the lethal dose 50% (LD50) value from in vivo rat acute oral toxicity studies for pesticide product label precautionary statements and environmental risk assessment (RA). The Collaborative Acute Toxicity Modeling Suite (CATMoS) is a quantitative structure-activity relationship (QSAR)-based in silico approach to predict rat acute oral toxicity that has the potential to reduce animal use when registering a new pesticide technical grade active ingredient (TGAI). This analysis compared LD50 values predicted by CATMoS to empirical values from in vivo studies for the TGAIs of 177 conventional pesticides. The accuracy and reliability of the model predictions were assessed relative to the empirical data in terms of USEPA acute oral toxicity categories and discrete LD50 values for each chemical. CATMoS was most reliable at placing pesticide TGAIs in acute toxicity categories III (>500-5000 mg/kg) and IV (>5000 mg/kg), with 88% categorical concordance for 165 chemicals with empirical in vivo LD50 values ≥ 500 mg/kg. When considering an LD50 for RA, CATMoS predictions of 2000 mg/kg and higher were found to agree with empirical values from limit tests (i.e., single, high-dose tests) or definitive results over 2000 mg/kg with few exceptions.

Application of an integrated testing strategy to the U.S. EPA endocrine disruptor screening program.

New approaches to generating and evaluating toxicity data for chemicals are needed to cope with the ever-increasing demands of new programs. One such approach involves the use of an integrated testing and evaluation strategy based on the specific properties and activities of a chemical. Such an integrated strategy, whether applied to existing or future programs, can promote efficient use of resources and save animals. We demonstrate the utility of such a strategy by applying it to the current U.S. Environmental Protection Agency Endocrine Disruptor Screening Program (EDSP). Launched in October 2009, the EDSP utilizes a two-tiered approach, whereby each tier requires a battery of animal-intensive and expensive tests. Tier 1 consists of five in vitro and six in vivo assays that are intended to determine a chemical's potential to interact with the estrogen (E), androgen (A), or thyroid (T) hormone pathways. Tier 2 is proposed to consist of multigenerational reproductive and developmental toxicity tests in several species and is intended to determine whether a chemical can cause adverse effects resulting from E, A, or T modulation. In contrast to the existing EDSP structure, we show, using the pesticide atrazine as an example, that a multilevel testing framework combined with an integrated evaluation process would significantly increase efficiency by minimizing testing.