Workshop on the qualitative and quantitative comparability of human and animal developmental neurotoxicity, work group IV report: Triggers for developmental neurotoxicity testing

Levine, Tina E.; Butcher, Richard E.

doi:10.1016/0892-0362(90)90100-q

Cited by 20 publications

(6 citation statements)

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“…A large body of research has provided an immense database on the ability of the functional observational battery to detect and characterize the effects of drugs and environmental chemicals in adult and developing animal models (Gad 1982; Irwin 1968; Moser et al 1988). This early work was followed by wide-ranging efforts to characterize the specificity of these test methods and the impact of both organismal and experimental factors (e.g., noise, species, strain, gender, test history) (Gerber and O’Shaughnessy 1986; Levine and Butcher 1990; MacPhail et al 1989; Spencer et al 1993). Ultimately, the result of more than 30 years of work in this area is a consensus opinion of neuro toxicologists that proper use and interpretation of the data derived from these test methods provide unique insight into the impact of xenobiotics on the developing and adult nervous system [Cory-Slechta et al 2001; International Programme on Chemical Safety (IPCS) 2001; Tyl et al 2008].…”

Section: Scientific Basis Of Dnt Guidelinementioning

confidence: 99%

A Retrospective Performance Assessment of the Developmental Neurotoxicity Study in Support of OECD Test Guideline 426

Makris

Raffaele

Allen

et al. 2009

Environ Health Perspect

161

130

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ObjectiveWe conducted a review of the history and performance of developmental neurotoxicity (DNT) testing in support of the finalization and implementation of Organisation of Economic Co-operation and Development (OECD) DNT test guideline 426 (TG 426).Information sources and analysisIn this review we summarize extensive scientific efforts that form the foundation for this testing paradigm, including basic neurotoxicology research, interlaboratory collaborative studies, expert workshops, and validation studies, and we address the relevance, applicability, and use of the DNT study in risk assessment.ConclusionsThe OECD DNT guideline represents the best available science for assessing the potential for DNT in human health risk assessment, and data generated with this protocol are relevant and reliable for the assessment of these end points. The test methods used have been subjected to an extensive history of international validation, peer review, and evaluation, which is contained in the public record. The reproducibility, reliability, and sensitivity of these methods have been demonstrated, using a wide variety of test substances, in accordance with OECD guidance on the validation and international acceptance of new or updated test methods for hazard characterization. Multiple independent, expert scientific peer reviews affirm these conclusions.

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Section: Scientific Basis Of Dnt Guidelinementioning

confidence: 99%

A Retrospective Performance Assessment of the Developmental Neurotoxicity Study in Support of OECD Test Guideline 426

Makris

Raffaele

Allen

et al. 2009

Environ Health Perspect

161

130

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“…Furthermore, because assessment via structure-activity relationships (SAR) constitutes an important component of preliminary screening for toxicity, it is important to note that chemicals affecting the nervous system generally do not conform to the SAR paradigm for toxicity prediction (Levine and Butcher 1990). Several examples exist in the literature, including acrylamide, diethylbenzene, and acetylpyridine.…”

Section: Supporting Rationalementioning

confidence: 99%

Histopathological Evaluation of the Nervous System in National Toxicology Program Rodent Studies

et al. 2011

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This article outlines the changes and underlying rationale for modifications to the histopathological evaluation of the nervous system during toxicology and carcinogenesis studies conducted by the National Toxicology Program (NTP). In the past, routine evaluation of the nervous system was mostly limited to three sections of brain, and occasionally the spinal cord and peripheral nerves. Factors such as the increasing occurrence of human neurological diseases and associated economical cost burden, the role of unidentified environmental stressors in neurodegenerative disorders, multiple therapeutic drug-induced neuropathies noted in human clinical trials, and the exponential use of environmental chemicals with unknown neurotoxic potential necessitate a more extensive evaluation of the nervous system. The NTP has modified its protocol to include examination of key anatomic subsites related to neurodegenerative diseases such as Parkinson's disease. Modifications include four additional sections of the brain. Increasing the number of brain sections permits examination of a greater number of specific anatomic subsites with unique vulnerability. In addition, the spinal cord, peripheral nerves, trigeminal ganglion, and intestinal autonomic ganglia will be evaluated as needed. It is expected that this modified approach will increase the sensitivity of detecting neurotoxicants and neurocarcinogens important in human neurologic and neurodegenerative disorders.Keywords: neuropathology; histopathology; brain; nervous system; NTP; nervous system; screening.Since its inception in 1978, one of the major goals of the National Toxicology Program (NTP) has been to identify carcinogens (based on carcinogenicity for laboratory animals under conditions of study as adopted by NTP since 1983) based on 2-year rodent bioassays. The standard three sections of the brain examined in such routine studies were taken at the levels of (1) the basal ganglia, including the cerebrum at the frontal cortical level; (2) the thalamus at the mid-infundibular level; and (3) a mid-cerebellar section that included the cerebellum and medulla. For studies in which clinical neurological signs were noted, or studies in which agents were suspected to be neurotoxic, sections of the spinal cord and the sciatic nerve were also examined. In addition to the identification of carcinogens, the NTP has recently started a number of initiatives to assess adverse, nonneoplastic toxicological effects. Since environmental factors that affect nonneoplastic conditions such as immune-mediated diseases (Virgolini et al. 2005) and reproductive disorders (Davey et al. 2008) are increasingly common, initiatives within the NTP have included enhanced immunopathology as well as revised criteria for histopathological evaluation in reproductive and developmental toxicity studies. Similarly, increasing attention to the role of environmental factors in neurological disorders such as Parkinson's disease ) and autism (Cavagnaro 2007) also emphasizes the need for improved toxicity e...

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“…Accordingly, animal testing for potential DNT is an important element of the registration package presented to regulatory agencies for new chemical entities. The push for evidence-based DNT regulation is decades old (Buelke-Sam and Mactutus 1990;Francis, Kimmel, and Rees 1990;Levine and Butcher 1990;Rees, Francis, and Kimmel 1990;Stanton and Spear 1990;Tyl and Sette 1990), but only recently has the degree of communal experience expanded to the point where intelligent adjustments to regulatory guidelines may be considered (Crofton et al 2004;de Groot, Bos-Kuijpers, et al 2005;Crofton et al 2008;Tyl et al 2008;Makris et al 2009;Raffaele et al 2010;Tsuji and Crofton 2012).…”

Section: Introductionmentioning

confidence: 99%

Recommended Methods for Brain Processing and Quantitative Analysis in Rodent Developmental Neurotoxicity Studies

Garman¹,

Kaufmann

et al. 2015

Toxicol Pathol

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Neuropathology methods in rodent developmental neurotoxicity (DNT) studies have evolved with experience and changing regulatory guidance. This article emphasizes principles and methods to promote more standardized DNT neuropathology evaluation, particularly procurement of highly homologous brain sections and collection of the most reproducible morphometric measurements. To minimize bias, brains from all animals at all dose levels should be processed from brain weighing through paraffin embedding at one time using a counterbalanced design. Morphometric measurements should be anchored by distinct neuroanatomic landmarks that can be identified reliably on the faced block or in unstained sections and which address the region-specific circuitry of the measured area. Common test article-related qualitative changes in the developing brain include abnormal cell numbers (yielding altered regional size), displaced cells (ectopia and heterotopia), and/or aberrant differentiation (indicated by defective myelination or synaptogenesis), but rarely glial or inflammatory reactions. Inclusion of digital images in the DNT pathology raw data provides confidence that the quantitative analysis was done on anatomically matched (i.e., highly homologous) sections. Interpreting DNT neuropathology data and their presumptive correlation with neurobehavioral data requires an integrative weight-of-evidence approach including consideration of maternal toxicity, body weight, brain weight, and the pattern of findings across brain regions, doses, sexes, and ages.

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Workshop on the qualitative and quantitative comparability of human and animal developmental neurotoxicity, work group IV report: Triggers for developmental neurotoxicity testing

Cited by 20 publications

References 9 publications

A Retrospective Performance Assessment of the Developmental Neurotoxicity Study in Support of OECD Test Guideline 426

A Retrospective Performance Assessment of the Developmental Neurotoxicity Study in Support of OECD Test Guideline 426

Histopathological Evaluation of the Nervous System in National Toxicology Program Rodent Studies

Recommended Methods for Brain Processing and Quantitative Analysis in Rodent Developmental Neurotoxicity Studies

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