Repeated-measure analyses: Which one? A survey of statistical models and recommendations for reporting.

Repeated-measure analysis of variance is a general term that can imply a number of different statistical models used to analyze data from studies in which measurements are taken from each subject on more than one occasion. Repeated-measure analyses encompass univariate models (with or without sphericity adjustment), multivariate models, mixed models, analysis of covariance, multilevel models, latent growth models, and hybrids of these models. These models are based on different assumptions, especially regarding correlations (sphericity) between within-subject factors, which comprise the variance-covariance matrix.

Oral gavage subchronic neurotoxicity and inhalation subchronic immunotoxicity studies of ethylbenzene in the rat.

The potential for neurotoxicological and immunotoxicological effects of ethylbenzene was studied in young adult Crl:CD(SD) rats following 90-day oral (neurotoxicity) or 28-day inhalation (immunotoxicity) exposures. In the neurotoxicity study, ethylbenzene was administered orally via gavage twice daily at 0, 25, 125, or 250 mg/kg per dose (total daily dosages of 0, 50, 250, or 500 mg/kg bwt/day [mg/kg bwt/day]) for 13 weeks and the functional observational battery (FOB), automated tests for motor activity and neuropathological examination were conducted. In the immunotoxicity study, animals were exposed by inhalation to 0, 25, 100, or 500 ppm ethylbenzene (approximately 26, 90, or 342 mg/kg bwt/day as calculated from physiologically based pharmacokinetic modeling).

Practical considerations on the design, execution and analysis of developmental neurotoxicity studies to be published in Neurotoxicology and Teratology.

The present article is an attempt to use the "ILSI Research Foundation/Risk Science Institute Reports from the Expert Working Group on Neurodevelopmental Endpoints" (2008) to help improve the quality of the manuscripts submitted to Neurotoxicology and Teratology, as well as the quality of their review. The points discussed in the present paper have been encountered during the peer-review process. A number of recommendations are proposed on the basis of general principles (clarity, full disclosure, and evidence-based interpretation) to help authors and reviewers.

Statistical issues and techniques appropriate for developmental neurotoxicity testing: a report from the ILSI Research Foundation/Risk Science Institute expert working group on neurodevelopmental endpoints.

The data from developmental neurotoxicity (DNT) guideline studies present a number of challenges for statistical design and analysis. The importance of specifying the planned statistical analyses a priori cannot be overestimated. A review of datasets submitted to the US Environmental Protection Agency revealed several inadequate approaches, including issues of Type I error control, power considerations, and ignoring gender, time, and litter allocation as factors in the analyses.

Effects of intensity and type of prepulse stimulus on prepulse inhibition in scopolamine treated rats.

Prepulse inhibition (PPI) of the auditory startle response (ASR) is a behavioral test that has been used to measure auditory thresholds, to assess sensory-motor integration functions, and its use has been recommended in the United States Environmental Protection Agency Developmental Neurotoxicity Guideline (OPPTS 870.6300). The purpose of the present study was to determine to what extent the intensity and/or type of prepulse stimuli modulate PPI in scopolamine-treated rats.

Differential sensitivity of blood, peripheral, and central cholinesterases in beagle dogs following dietary exposure to chlorpyrifos.

Two studies were performed to find out whether exposure limits that protect brain acetylcholinesterase (AChE) will protect peripheral tissue AChE after exposure to chlorpyrifos (CPF), an organophosphate insecticide. In a methods-development study, male dogs (3/dose) were exposed to 0.0, 0.

Neurotoxicity test validation, positive controls and proficiency: are chemicals necessary?

The USEPA neurotoxicity guidelines require the use of positive control data in support of toxicology studies submitted to the Agency and emphasize the use of chemicals to accomplish this requirement. These guidelines, though, propose a number of different rationales for the use of chemicals as positive control agents. We re-evaluated the potential roles of positive control data in addressing three questions: 1) what does the test measure? 2) is the performing laboratory proficient in the use of the test? 3) do the complementary data submitted in support of neurotoxicity studies conducted with the test material provide enough context for the interpretation of the biological significance of an effect? While, for most types of guideline neurotoxicity tests, the use of test chemicals has been emphasized for positive control testing, the use of non-chemical procedures (i.

Workshop proceedings: managing conflict of interest in science. A little consensus and a lot of controversy.

There is no doubt that participants in the Conflict of Interest (COI) Workshop at the Society of Toxicology (SOT) 2005 Annual Meeting (New Orleans, 6-10 March 2005) engaged in a vigorous and useful exchange of diverse ideas and viewpoints. While there was consensus on the value and interest of this Workshop, there was less consensus and more controversy over many of the issues discussed during the Workshop, which included the distinction between bias and conflict, the success or failure of policies of disclosure, whether waivers should or should not be granted to conflicted individuals in order to seat a "balanced" committee with appropriate expertise, whether conflicted individuals retain the ability to recognize their own conflict, and more. The discussion left no doubt, however, that conflict of interest will remain an important and controversial issue in the scientific community for some time to come.

Developmental neurotoxicity study of styrene by inhalation in Crl-CD rats.

This study was conducted to assess potential adverse functional and/or morphological effects of styrene on the neurological system in the F2 offspring following F0 and F1 generation whole-body inhalation exposures. Four groups of male and female Crl:CD (SD)IGS BR rats (25/sex/group) were exposed to 0, 50, 150, and 500 ppm styrene for 6 hr daily for at least 70 consecutive days prior to mating for the F0 and F1 generations. Inhalation exposure continued for the F0 and F1 females throughout mating and through gestation day 20.

Validation of an auditory startle response system using chemicals or parametric modulation as positive controls.

Neurotoxicity regulatory guidelines mandate that automated test systems be validated using chemicals. However, in some cases, chemicals may not necessarily be needed to prove test system validity. To examine this issue, two independent experiments were conducted to validate an automated auditory startle response (ASR) system.

Factors affecting grip strength testing.

The rodent grip strength test was developed decades ago and is a putative measure of muscular strength. This test has been included in the functional observational battery (FOB) to screen for neurobehavioral toxicity, and changes in grip strength have been interpreted as evidence of motor neurotoxicity. Despite its widespread use, questions remain about what the grip strength test actually measures.