Implementing a framework for integrating toxicokinetics into human health risk assessment for agrochemicals.

A strategic and comprehensive program in which toxicokinetic (TK) measurements are made for all agrochemicals undergoing toxicity testing (both new compounds and compounds already registered for use) is described. This approach provides the data to more accurately assess the toxicokinetics of agrochemicals and their metabolites in laboratory animals and humans. Having this knowledge provides the ability to conduct more insightful toxicity studies, refine and interpret exposure assessments and reduce uncertainty in risk assessments.

Analysis of EPA's endocrine screening battery and recommendations for further review.

EPA's Endocrine Disruptor Screening Program Tier 1 battery consists of eleven assays intended to identify the potential of a chemical to interact with the estrogen, androgen, thyroid, or steroidogenesis systems. We have collected control data from a subset of test order recipients from the first round of screening. The analysis undertaken herein demonstrates that the EPA should review all testing methods prior to issuing further test orders.

Gender differences in the incidence of background and chemically induced primary pulmonary neoplasms in B6C3F1 mice: a retrospective analysis of the National Toxicology Program (NTP) carcinogenicity bioassays.

The National Toxicology Program (NTP) database of technical reports on carcinogenicity bioassays has been interrogated for the incidence of primary pulmonary neoplasms in B6C3F1 mice. A total of 170 study reports were selected, from studies that completed the in-life phase during 1983-2007, which included neoplasm incidence data for 180 control groups comprising both male and female mice. The incidence (median and inter-quartile range) of males with alveolar/bronchiolar adenoma was 16% (12-20%), and for females it was 5% (2-8%); the incidence of males with alveolar/bronchiolar carcinoma was 8% (4-12%), and for females it was 2% (0-4%); and the incidence of males with combined alveolar/bronchiolar adenoma or carcinoma was 24% (18-30%), and for females it was 8% (6-12%).

Statistical methodology to determine kinetically derived maximum tolerated dose in repeat dose toxicity studies.

Several statistical approaches were evaluated to identify an optimum method for determining a point of nonlinearity (PONL) in toxicokinetic data. (1) A second-order least squares regression model was fit iteratively starting with data from all doses. If the second order term was significant (α<0.

Dose-response and operational thresholds/NOAELs for in vitro mutagenic effects from DNA-reactive mutagens, MMS and MNU.

The dose-response relationships for in vitro mutagenicity induced by methylmethanesulfonate (MMS) or methylnitrosourea (MNU) in L5178Y mouse lymphoma (ML) cells were examined. DNA adducts (N7-methylguanine, N7MeG and O(6)-methylguanine, O(6)MeG) were quantified as biomarkers of exposure. Both endpoints were assessed using 5replicates/dose (4-h treatment) with MMS or MNU (0.