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.

Use of the RISK21 roadmap and matrix: human health risk assessment of the use of a pyrethroid in bed netting.

The HESI-coordinated RISK21 roadmap and matrix are tools that provide a transparent method to compare exposure and toxicity information and assess whether additional refinement is required to obtain the necessary precision level for a decision regarding safety. A case study of the use of a pyrethroid, "pseudomethrin," in bed netting to control malaria is presented to demonstrate the application of the roadmap and matrix. The evaluation began with a problem formulation step. The first assessment utilized existing information pertaining to the use and the class of chemistry. At each stage of the step-wise approach, the precision of the toxicity and exposure estimates were refined as necessary by obtaining key data which enabled a decision on safety to be made efficiently and with confidence. The evaluation demonstrated the concept of using existing information within the RISK21 matrix to drive the generation of additional data using a value-of-information approach. The use of the matrix highlighted whether exposure or toxicity required further investigation and emphasized the need to address the default uncertainty factor of 100 at the highest tier of the evaluation. It also showed how new methodology such as the use of in vitro studies and assays could be used to answer the specific questions which arise through the use of the matrix. The matrix also serves as a useful means to communicate progress to stakeholders during an assessment of chemical use.