Neurotoxicity testing mechanisms

In the summary of the aforementioned report, the authors recommend, as did earlier reviewers of this subject, the development and evaluation of a tiered testing strategy for neurotoxicity. The further development of in vitro models for establishing mechanisms of neurotoxicity should be part of this strategy. Full consideration should also be given to advances in the omics and other technological fields. 

Clinical signs of peripheral neuropathy similar to those seen in human occupational exposures to w-hexane can be produced in rats via the inhalation and oral routes, but not in other test species (Altenkirch et al. 1982 De Martino et al. 1987 Dunnick et al. 1989 Frontali et al. 1981 Huang et al. 1989 IRDC 1981 Krasavage etal. 1980 NTP 1991 Schaumburg and Spencer 1976 Takeuchi etal. 1980). Paranodal axonal swelling in mice (Dunnick et al. 1989 NTP 1991) and leg weakness in chickens (Abou-Donia et al. 1985) can be produced with inhalation exposure to -hexane, but these conditions do not progress to the severe neurotoxicity observed in humans and rats. The molecular mechanism... 

Vinorelbine is a semisynthetic derivative of vinblastine whose mechanism of action is identical to that of vinblastine and vincristine, ie, inhibition of mitosis of cells in the M phase through inhibition of tubulin polymerization. This agent has activity in non-small cell lung cancer, breast cancer, and ovarian cancer. Myelosuppression with neutropenia is the dose-limiting toxicity, but other adverse effects include nausea and vomiting, transient elevations in liver function tests, neurotoxicity, and SIADH. 

More in-depth behavioral tests are required if dose-related toxicant effects are noted in screening tests. These tests may also be required as part of more selective toxicological screening, such as for developmental neurotoxicity. Focused tests of neuromotor function and activity, sensory functions, memory, attention, and motivation help to identify sites of toxicant-mediated lesioning, aid in the classification of neurotoxicants, and may suggest mechanisms of action. Some of these tests, like the schedule-controlled operant behavior tests for cognitive function, require animal training and extensive operator interaction with the animals. 

Dinuclear and trinuclear compounds represent a new class of platinum anticancer complexes and are among the most studied platinum compounds in antitumor chemistry. Many of these complexes circumvent cisplatin-resistance mechanisms. In contrast to cisplatin, the polynuclear complexes predominantly form interstrand cross-links. The dinuclear complex [ tranx-PtCl(NH3)2 2 /u.-(H2N(CH2) NH2) ]2+ (l,l/t,t) (17, Figure 9) is antitumor-active and shows no cross-resistance in cisplatin-resistant cell fines. Binding studies sfiowed tfiat DNA binding for this compound is different from that for cisplatin, as illustrated by the increased interstrand cross-linking. However, clinical testing was abandoned because of severe neurotoxicity. 

However, the complexity of the CNS represents a major challenge to be mimicked in vitro. Currently in vitro tests are mainly used to study the mechanisms of neurotoxicity rather than to predict hazards to human health, and so far they play only a complementary role to in vivo testing. 

With respect to neurotoxins, there are a number of industrial chemicals (acrylamide, n-hexane, methyl n-butyl ketone, cresyl phosphate), pharmaceuticals (nitrofuradantoin, isoniazid), and pesticides (leptophos, Kepone ) which have been associated with neuropathic effects in humans (for reviews, see References 107,123, 124). Subchronic exposure studies in rodents and other animals such as cats have been used to identify and study the mechanism of action of neurotoxic chemicals which produce paralysis and behavioral changes in exposed animals. Studies are currently underway to evaluate the relative sensitivities of behavioral tests and morphological assays of peripheral and central nervous system axon morphology for detecting the earliest signs of chemically induced neuropathies. " ... 

Many of the substituted (hydroxy, dihydroxy) tryptamines are neurotoxic. These molecules have not been tested in human subjects for obvious reasons. In the study of brain biochemistry, neurotoxins are discovered and then molecules are developed to block the actions of the toxins. Drugs which block these neurotoxic effects might be useful in the treatment of mental illness. In many cases drugs which have been effective in the treatment of mental illness have been found to block the neurotoxic effects of various molecules. This allows scientists to gain a better understanding of disease mechanisms and future development of more effective drugs for the mentally ill. 

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