Developmental neurotoxicity induced by therapeutic and illicit drugs.

Abstract

The developmental neurotoxicity of phenytoin, isotretinoin, and methamphetamine has been reviewed to illustrate effects from both therapeutic and illicit drugs to which people are exposed and which either induce or show the potential for inducing learning disabilities following in utero exposure. In each case both human and experimental animal data are presented and compared where possible. The findings point to several conclusions. First, some drugs in current use induce developmental neurotoxicity, and it cannot safely be assumed that there are not more as yet unidentified. Second, of the types of neurotoxicity induced by drugs, learning disabilities figure prominently. Third, the effects observed are dependent on both the drug's mechanism of action and the period of brain development during which exposure occurs. Fourth, with the exception of CNS teratogens, it is not yet possible to predict which periods of brain development are the most vulnerable for the induction of learning disabilities, as seen by the different patterns of critical periods for phenytoin and isotretinoin compared to methamphetamine. Fifth, as seen with isotretinoin, existing drugs that cause developmental neurotoxicity are not the only problem; new drugs with such effects are still being introduced. Sixth, only a small fraction of the drugs currently in use have ever been examined for developmental neurotoxicity; hence, the full scope of the problem cannot even be accurately estimated based on current information. It is concluded that prevention of new cases caused by drugs such as isotretinoin should be a high priority for future regulatory action. -Environ Health Perspect 102(Suppl 2): 145-153 (1994).

Effects of Neonatal Antiepileptic Drug Exposure on Cognitive, Emotional, and Motor Function in Adult Rats

“…In particular, Vorhees and colleagues observed increased open-field activity as well as deficits in maze learning (in the Morris water maze, among other tasks) in adult mice exposed to phenytoin in utero (Adams et al, 1990;Vorhees, 1994). However, the latter investigation showed increases in auditory startle, an abnormality not observed in our animals, suggesting that certain outcomes are specific to the developmental stage of exposure.…”

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

“…Developmental neurotoxicity (DNT) is a recognized hazard in human infants and juveniles who have been exposed to many different xenobiotics (Vorhees 1994;Andersen, Nielsen, and Grandjean 2000;Bearer 2001). Accordingly, animal testing for potential DNT is an important element of the registration package presented to regulatory agencies for new chemical entities.…”

Neuropathology Evaluation in Juvenile Toxicity Studies in Rodents: Comparison of Developmental Neurotoxicity Studies for Chemicals With Juvenile Animal Studies for Pediatric Pharmaceuticals

“…A juvenile toxicity study is likely warranted if damage is anticipated in one or many developing organs, 9,10,30 of which the nervous system is a principal target. 31 The CNS (and particularly the brain) of developing animals and humans is known to be targeted by certain small molecule classes including ethanol, 32,33 anesthetics (eg, isoflurane, ketamine, and other N-methyl-D-aspartate receptor antagonists), 11,34 antiepileptics (eg, phenytoin, sodium valproate, vigabatrin), 11,[35][36][37] antineoplastic chemotherapies, 38,39 retinoids, 36 and stimulants (eg, caffeine, methamphetamine) 36,40 as well as many environmental contaminants (chemicals and metals) [41][42][43] and various endogenous metabolites. 33 Neurodevelopmental effects of such agents depend on the developmental age of exposure.…”