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A QUALITATIVE RETROSPECTIVE ANALYSIS OF POSITIVE CONTROL DATA IN DEVELOPMENTAL NEUROTOXICITY STUDIES.
Citation:
Crofton, K M., S. L. Makris, W. F. Sette, E. Mendez, AND K. C. Raffaele. A QUALITATIVE RETROSPECTIVE ANALYSIS OF POSITIVE CONTROL DATA IN DEVELOPMENTAL NEUROTOXICITY STUDIES. NEUROTOXICOLOGY AND TERATOLOGY 26:345-352, (2004).
Description:
A manuscript reviews positive control data submitted by registrants in support of Developmental Neurotoxicity (DNT) guideline studies. Adequate positive control data are needed to evaluate laboratory proficiency in detecting changes in the structure and function of the developing nervous system. The data is needed in a weight-of-evidence approach to help determine the biological significance of results and to increase the confidence in negative results from DNT studies. This survey identified three problem categories: faulty design, inadequate results and problems with the manner in which the data were reported. Analyses reveal that only 3 of 16 laboratories were judged to have submitted positive control data adequate for proficiency purposes. Publication of this manuscript will be useful to registrants and contract laboratories by enhancing understanding of Agency expectations regarding the type of positive control data that should be submitted in support of DNT studies. Enhanced understanding of Agency expectations should led to improved design and reporting of positive control studies.
Background:
Submission of positive control (PC) data is recommended by several toxicity study guidelines, including the Developmental Neurotoxicity (DNT) study. Adequate positive control data are needed to evaluate laboratory proficiency in detecting changes in the structure and function of the developing nervous system. The data is needed in a weight-of-evidence approach to help determine the biological significance of results and to increase the confidence in negative results from DNT studies.
Study Description:
NHEERL and HED/OPP staff have assembled and reviewed (qualitatively) the positive control data submitted in support of all available guideline DNT studies. This project was part of an ongoing effort to evaluate and improve the quality of these data submissions. The objective was to gain a better overall understanding of how best to incorporate these data into weight-of-evidence evaluations for pesticide chemicals.
A paper has been prepared by HED and NHEERL scientists that summarizes the results of a review of the positive control data for DNT studies.
The paper addresses:
- the availability of positive control data from submitting laboratories
- the quality of the submitted data reports
- the adequacy of submitted reports to support the reliability of the procedures used in submitted guideline DNT studies
- No attempt was made to evaluate acceptability of data generated for test pesticides
Results:
- Inadequacies were identified in the positive control data that EPA has received. Positive control reports submitted to support DNT guideline studies had three problem categories, faulty design, inadequate results, and problems with the manner in which the data were reported.
- Study design issues generally involved: lack of dose-response data, testing of only one sex, use of small group sizes, or lack of use of positive control compounds.
- The major problem with study results was that lack of effect of the positive control agent (e.g., results did not demonstrate reliability of procedures)
- Reporting of results was the major problem with a large percentage of the reports. Many reports lacked summary statistics (e.g., group means). Some reports consisted of nothing other than copies of poster presentations from scientific meetings.
Conclusions:
Only 3 of 16 laboratories were judged to have submitted positive control data adequate for proficiency purposes.
Deficiencies in the positive control data do not negate the value of the DNT study treatment results, although the level of confidence in negative results may be reduced.
A large number of the problems with the positive control reports, and subsequent proficiency ratings can be easily addressed by better report structure.