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Developmental Neurotoxicity Study (DNT)

Posted on 27-Sep-2016 by Deepak Ujawane
Developmental Neurotoxicity Study (DNT)

Throughout its process of ontogenesis, the central nervous system (CNS) is extremely sensitive to the exposure to various chemical and physical factors. The brain, in its developmental phase, has unique characteristics and different sensitivity to influencing factors as compared to a developed brain. Exposure to various chemicals (including pharmaceutical drugs, industrial or agro chemicals) during prenatal, peri/postnatal development can cause subtle structural and/or functional alterations at the level of neurotransmitters and their receptors. Any damage at these levels can lead to a permanent change during the critical phases of brain development. Outcome of such changes, are manifested at a later stage of life. It is actually challenging to unequivocally interpret the behavioural deficit in the progeny in young or adults back to a drug taken by their mothers during pregnancy, unless such an experimental data is generated. Hence, this study is carried out to analyse potentially harmful effects of any chemical on brain / neural system development and experimentally establish the relation with the test substance.

Developmental neurotoxicity (DNT) is a study to determine adverse effects of chemical substances and physical agents on the developing nervous system. One of the marked manifestations of CNS activity is behavioral dysfunction due to the functional alterations of the CNS. These studies are designed to generate data on various parameters, mainly dose-response, as well as potential functional and morphological effects, on the developing nervous system of the offspring that may arise due to the exposure in in utero and during early life.

The evaluation consists of observations to detect gross neurological and behavioural abnormalities. This includes the assessment of physical development, behavioural ontogeny, motor activity, motor and sensory function; learning and memory; the evaluation of brain weights and neuropathology during postnatal development and adulthood. 

Performing a DNT study is a very challenging and an uphill task. Only a handful, well-established research organisations, throughout the world, have the required skills and infrastructure to conduct DNT study, on account of extreme complexity involved in it and the skills to manage the diverse phases of this study. DNT requires well-designed study plan, time management skills, and a thorough knowledge to interpret the result. The study requires management of large number of endpoints of several animals on a given day.  Perfect day-to-day calendar driven management is the key to the success of such studies.  DNT study has numerous sets of the neuro-behavioural observations needed to be performed at the designated post-natal days (PND) and every pup has different PND. On a given date/ time, there may be more than one PNDs. 

Availability of trained and professional resources for handling the animals is extremely critical. Availability of well-established and experienced research group, endowed with pertinent scientific expertise and the professionally trained staff, ensure successful conduct and conclusion of such studies.  Calibrated and validated state-of-the-art equipment and the laboratory infrastructure, typically the equipment for FOB, startle response, Morris maze systems are very essential for concluding this complicated study.

 

Pup selection: The pups are selected, randomly using random selection table, to avoid human bias.

Blind Observation: To minimise the bias, the scientists involved in treatment and those involved in the neurobehavioural observations are separate teams. 

It is essential that the technician/scientist who handles a specific observation, continues to do so till the end of the study to minimise “handler” driven effect on the behaviour of the animal.

To conclude, these studies are indeed complex. They can only be managed by the laboratories with experienced scientific staff having expertise in the management of long-term reproductive/developmental toxicity study or neurotoxicity study.

Following are some globally harmonised test guidelines which have been designed to perform these tests.

EPA OCSPP 870.6300

OECD 426

  •  Comments (1)
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