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A structure-activity relationship for the neurotoxicity of triazole fungicides
1Neurotoxicology Division, National Health Effects and Environmental Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.
Abstract:
Previous work has demonstrated that acute exposures to the triazole fungicide triadimefon affects central nervous system (CNS) catecholamines and induces a transient syndrome in rats that consists of hyperactivity and stereotyped behaviors. The present research was designed to determine whether this type of CNS toxicity is characteristic of other triazoles. Dose-effect functions were determined for 14 different triazoles or structurally related pesticides in adult male Long-Evans rats. All chemicals were administered per os in corn oil. Hyperactivity was measured for 2 h in figure-eight mazes. Results indicated that only triadimefon and triadimenol were able to induce hyperactivity; none of the other chemicals produced this effect. These data suggest a very rigid structure-activity relationship (SAR) for the hyperactivity syndrome and indicate that CNS effects may be minimized in the future design of triazoles without impacting fungicidal efficacy.
Insights
Triazole fungicides like triadimefon can affect the central nervous system (CNS), causing hyperactivity in rats. However, this CNS toxicity is not common to all triazoles, suggesting potential for safer fungicide design.
Area of Science:
- Environmental toxicology
- Neuroscience
- Organic chemistry
Background:
- Triazole fungicides are widely used in agriculture.
- Previous studies linked triadimefon exposure to central nervous system (CNS) effects, including hyperactivity in rats.
- The characteristic CNS toxicity of triadimefon needed further investigation across other triazoles.
Purpose of the Study:
- To investigate the central nervous system (CNS) toxicity of various triazole fungicides.
- To determine if the hyperactivity syndrome induced by triadimefon is a common effect among related triazole compounds.
- To explore the structure-activity relationship (SAR) for CNS effects of triazoles.
Main Methods:
- Dose-effect functions were established for 14 triazole pesticides in adult male Long-Evans rats.
- Chemicals were administered orally (per os) in corn oil.
- Hyperactivity was quantified using figure-eight mazes over a 2-hour period.
Main Results:
- Only triadimefon and its metabolite triadimenol induced significant hyperactivity.
- None of the other 12 tested triazole compounds exhibited similar neurotoxic effects.
- A rigid structure-activity relationship (SAR) was observed for the induction of hyperactivity.
Conclusions:
- The capacity to induce hyperactivity is specific to certain triazoles, like triadimefon and triadimenol.
- CNS effects associated with triazole fungicides may be minimized through careful molecular design.
- Future triazole development could potentially reduce neurotoxicity without compromising fungicidal activity.