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FRAME Annual Lecture. International co-operation: an essential requirement for replacing animal toxicity tests.

The Three Rs concept, which was developed by Russell and Burch in 1959, was implemented into the legal framework in the European Union (EU) for the protection of vertebrate animals used for experimental and other scientific purposes, when Directive 86/609/EEC was adopted in 1986. One focus of activity under this Directive is the use of animals and alternative methods in regulatory testing. To reduce or replace animal testing for regulatory purposes, non-animal tests must be independently validated to prove that they can provide information that is relevant and reliable for hazard prediction in relation to specific types of toxicity in vivo. At the end of the 1980s, no scientific concept existed for the formal validation of in vitro toxicity tests, so a small group of European and American scientists met to develop a set of principles for experimental validation, which were first adopted by ECVAM in Europe in 1995, and, after harmonisation with experts from the USA and Japan, accepted internationally by the OECD in 1996. ECVAM has directly funded a number of validation studies, and a major breakthrough in the year 2000 was the acceptance for regulatory purposes in the EU of scientifically validated in vitro toxicity tests for phototoxic potential and for skin corrosivity. These, and other examples which are discussed, confirm that the internationally harmonised ECVAM/ICCVAM/OECD validation concept is a practical and effective way of making possible the replacement of regulatory testing in animals.

Animal Testing Alternatives↗
PubMed2004

The 2004 Aschoff/Pittendrigh lecture: Theory of the origin of the pineal gland--a tale of conflict and resolution.

A theory is presented that explains the evolution of the pinealocyte from the common ancestral photoreceptor of both the pinealocyte and retinal photoreceptor. Central to the hypothesis is the previously unrecognized conflict between the two chemistries that define these cells-melatonin synthesis and retinoid recycling. At the core of the conflict is the formation of adducts composed of two molecules of retinaldehyde and one molecule of serotonin, analogous to formation in the retina of the toxic bis-retinyl ethanolamine (A2E). The hypothesis argues that early in chordate evolution, at a point before the genes required for melatonin synthesis were acquired, retinaldehyde--which is essential for photon capture--was depleted by reacting with naturally occurring arylalkylamines (tyramine, serotonin, tryptamine, phenylethylamine) and xenobiotic arylalkylamines. This generated toxic bis-retinyl arylalkylamines (A2AAs). The acquisition of arylalkylamine N-acetyltransferase (AANAT) prevented this by N-acetylating the arylalkylamines. Hydroxyindole-O-methyltransferase enhanced detoxification in the primitive photoreceptor by increasing the lipid solubility of serotonin and bis-retinyl serotonin. After the serotonin --> melatonin pathway was established, the next step leading toward the pinealocyte was the evolution of a daily rhythm in melatonin and the capacity to recognize it as a signal of darkness. The shift in melatonin from metabolic garbage to information developed a pressure to improve the reliability of the melatonin signal, which in turn led to higher levels of serotonin in the photodetector. This generated the conflict between serotonin and retinaldehyde, which was resolved by the cellular segregation of the two chemistries. The result, in primates, is a pineal gland that does not detect light and a retinal photodetector that does not make melatonin. High levels of AANAT in the latter tissue might serve the same function AANAT had when first acquired- prevention of A2AA formation.

Animals↗
PubMed1997

Carrell-Krusen Symposium Invited Lecture-1997. Myotonic disorders in childhood: diagnosis and treatment.

The recent discoveries that mutations in the genes for the skeletal muscle sodium and chloride channels are responsible, respectively, for paramyotonia/hyperkalemic periodic paralysis and for myotonia congenita of Thomsen have made the classification, diagnosis, and treatment of these disorders much easier. The discovery that myotonic dystrophy results from an unstable [CTG]n trinucleotide expansion has permitted the accurate diagnosis of both symptomatic and asymptomatic individuals, and has led to major advances in preventive treatment, including prenatal and genetic counseling. Diseases that resemble the inherited myotonic disorders are now easier to identify, and as a result of genetic testing a new clinical disorder that is similar to but distinct from myotonic dystrophy has emerged. This new disorder, proximal myotonic myopathy, does not appear to be linked to the genes for the sodium or chloride channels, and has cataracts, myotonia, weakness, and no abnormal expansion of the [CTG]n repeat in the gene for myotonic dystrophy. This review discusses the diagnosis and treatment of these myotonic disorders.

Child↗
PubMed1999

Carrell-Krusen Symposium invited lecture. Clinical trials in motor neuron diseases.

Although there is no truly effective disease-specific therapy for any of the motor neuron diseases, rapid progress in our understanding of the pathophysiology of some of these disorders is being made. In addition to progress in neuroscience, clinical trials of agents that appear to slow the progress of at least one of these diseases, amyotrophic lateral sclerosis, are beginning to show promising results. The first clinical trials in spinal muscular atrophy are currently underway. A number of other developments have raised the quality of clinical trials, which should improve their productivity and efficiency in the future.

Acetates↗
PubMed1999

Paul Dyken Lecture of the Southern Pediatric Neurology Society. Inherited neurodegenerative disease: the evolution of our thinking.

The past 3 decades have witnessed impressive progress in our understanding of inherited neurometabolic diseases, promoted by the rapid development and application of molecular genetic strategies. Such progress has required the juxtaposition of clinical evaluations and basic science techniques. The central role of careful and complete assessment of affected children cannot be overemphasized and in no way has been diminished by technologic advances. Indeed, enhanced clinical and laboratory evaluations have led to important conceptual advances. Molecular genetics has elucidated those disorders with known metabolic defects through functional cloning and explained the variability of disease expression based on specific mutational events. Alternatively, positional cloning has identified molecular defects for those disorders with clear phenotypic patterns, but lacking a defined metabolic abnormality. Regarding heterogeneous expression, disorders with clearly different phenotypes can arise from different mutations within the same gene. The multiple variants of beta-hexosaminidase deficiency (Tay-Sachs disease) are, arguably, the best examples. Conversely, disorders with similar phenotypes are explainable by quite different mutational events. In addition, the identification of specific diseases exhibiting both biochemical abnormalities and disturbed organogenesis has blurred conventional dogma regarding separation of genetic disorders into strict metabolic and structural categories. Disorders of peroxisomal function and the neuronal ceroid lipofuscinoses are prototypes for the points noted above and raise important issues regarding our approaches to children with these disorders. These issues include a high index of suspicion for an inherited neurometabolic disease and an open mind to possible interrelations with other known and seemingly dissimilar conditions.

Child↗