The 5 challenges of neurotoxicity testing
Jessica Legradi
Why neurotoxicity is interesting for me
▪ Increasing cases of neurological disorders ▪ Very hard to cope/relate too ▪ Very limited amounts of treatments
Relevance
▪ A link between human exposure to some chemical substances and neurotoxicity has been firmly established (Anger, 1986; OTA, 1990). ▪ It has been estimated that alone in Europe, exposure to solely endocrine disrupters that lead to neurological disorders, costs society €150 billion per year (Bellanger 2015) ▪ The number of chemicals with neurotoxic potential has been estimated to range from 3% to 28% of all chemicals (OTA, 1990) Majority of the materials in commercial use have not been tested for neurotoxic potential (NRC, 1984) What is neurotoxicity?
Neurotoxicity is toxicity in the nervous system. It occurs when exposure to natural or artificial toxic substances, which are called neurotoxins, alters the normal activity of the nervous system in such a way as to cause damage to nervous tissue
wikipedia What is neurotoxicity?
Neurotoxicity is toxicity in the nervous system. It occurs when exposure to natural or artificial toxic substances, which are called neurotoxins, alters the normal activity of the nervous system in such a way as to cause damage to nervous tissue
wikipedia Challenge 1
What is the nervous system?
Where compounds could be active and how? The nervous system
▪ nerve system = neural system = nervous system
CNS: a) brain b) Spinal cord
PNS: a) Somatic - voluntary movements b) Autonomic - sympathetic and parasympathetic c) Enteric - gastrointestinal system Structural elements
▪ Nerve cells ▪ Glial cells Molecular elements
▪ Neurotransmitter ▪ Enzymes ▪ Calcium, Sodium,..
▪ ATP…. ▪ TNF-α, caspases,… Blood-Brain-Barrier Neurogenesis
to nervous tissue Challenge 2
How to asses neurotoxicty? What is neurotoxicity?
Neurotoxicity is toxicity in the nervous system. It occurs when exposure to natural or artificial toxic substances, which are called neurotoxins, alters the normal activity of the nervous system in such a way as to cause damage to nervous tissue
wikipedia Microelectrode Array
▪ high throughput microelectrode array (MEA) technology to monitor electrophysiological activity ▪ Neurons grown on microelectrode arrays recapitulate many features of neurons in vivo, including spontaneous activity (spiking and bursting), plasticity, organisation Neurite outgrowth assay ECVAM report 1994 Acetylcholinesterase inhibition assay
Kostelnik et al 2016 Behavioral studies
▪ Behavioural effects may be a reflection of changes in nerve cell communication and integration as well as the morphological alterations. The PMR and high-throughput behavioral barcoding The PMR and high-throughput behavioral barcoding What is neurotoxicity?
Neurotoxicity is toxicity in the nervous system. It occurs when exposure to natural or artificial toxic substances, which are called neurotoxins, alters the normal activity of the nervous system in such a way as to cause damage to nervous tissue
Neurotoxicity is an adverse change in the structure or function of the central and/or peripheral nervous system following exposure Challenge 3
What is an adverse neurotoxic effect?
Relevance of bioassays AOP From AOP wiki From AOP wiki EPA Guideline
Adverse effects include alterations from baseline or normal conditions that diminish an organism's ability to survive, reproduce, or adapt to the environment From AOP wiki Challenge 4
The non monotonic dose- response curves.
Dose-response-curve Alcohol
Mac Phail et al 2009 Dose-response-curve Alcohol
http://www.biology.arizona.edu/chh/problem_sets/toxicology/07t.html Point of return
Mac Phail et al 2009 Mixtures ??? Challenge 5
Transferability between assays/species. (especially to humans) Transferability
Spontaneous movement Louis Saint-Amant et al., 1998 Transferability Transferability- Neurite outgrowth assay
Trigger-values for neurotoxicity Human Risk assessment - EPA Guideline
▪ there are different levels of concern based on the magnitude of effect, duration of exposure, and reversibility of some neurotoxic effects
• even reversible neurotoxic changes should be of concern (adaptation) • progressive effects (those that continue to worsen even after the causal agent has been removed) • delayed-onset effects (those that occur at a time distant from the last contact with the causal agent) • residual effects (those that persist beyond a recovery period), • latent effects (those that become evident only after an environmental challenge or aging) have a high level of concern So what to do ???? Thank you
Let’s discuss how to solve this challenges……