title: A qualitative retrospective analysis of positive control data in developmental neurotoxicity studies.
abstract: Testing for neurodevelopmental effects commonly involves both functional and neuropathological assessments in offspring during and following maternal exposure. The use of positive controls in neurotoxicity screening has been advocated by numerous expert groups. Evaluation of positive control data allows evaluation of laboratory proficiency in detecting changes in the structure and function of the developing nervous system and comparison of the sensitivity of assessments in different studies and laboratories. This project surveyed approaches taken in contract and industrial laboratories in generating and providing these data. Positive control data submitted in support of 34 developmental neurotoxicity (DNT) studies from 16 different laboratories were summarized by test method for information on the following: age relevance of test subjects, the presence of a dose-response relationship, gender, group size, statistics, report quality, quality assurance, and the year the study was conducted. Endpoints included the following: developmental landmarks, clinical observations (CO), motor activity, startle response, learning and memory, qualitative neuropathology, and quantitative brain morphometry (linear measurements of selected brain regions). Results ranged from no positive control data for three laboratories, to one laboratory that submitted 17 separate positive control reports. The qualitative range was similarly broad, from excellent to poor. Various problems were identified, including the following: inappropriate report structure (e.g., copies of poster presentations), lack of individual data, inadequate methodological details, submission of very old data (>10 years) or data from completely different laboratories, use of inappropriate positive control chemicals or doses that were without effect, lack of statistical analysis, use of only one sex, and use of incompatibly aged animals. Analyses revealed that there were only 3 out of 16 laboratories that had submitted positive control data adequate for proficiency purposes for all of the major endpoints in the DNT study. Adequate positive control data are very useful in a weight-of-evidence approach to help determine the biological significance of results, and also to increase the confidence in negative results from DNT studies.
authors.affiliation: Neurotoxicology Division, National Health and Environmental Effects Research Laboratory, ORD, MD-B105-04, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA. crofton.kevin@epa.gov
authors.forename: K M
authors.initials: KM
authors.lastname: Crofton
authors.forename: S L
authors.initials: SL
authors.lastname: Makris
authors.forename: W F
authors.initials: WF
authors.lastname: Sette
authors.forename: E
authors.initials: E
authors.lastname: Mendez
authors.forename: K C
authors.initials: KC
authors.lastname: Raffaele
mesh_terms: D000818:Animals; D023381:Endpoint Determination; D005069:Evaluation Studies as Topic; D005260:Female; D006801:Humans; D008297:Male; D009422:Nervous System Diseases / Q000139:chemically induced / Q000196:embryology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011786:Quality Control; D012015:Reference Standards; D012106:Research; D012189:Retrospective Studies; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D018675:Toxicity Tests / Q000379:methods; D014116:Toxicology / Q000379:methods* / Q000592:standards