RESUMEN
The multi-generation reproductive toxicity study (OECD TG 416 and USEPA 870.3800) has been extensively used internationally to assess the adverse effects of substances on reproduction. Recently the necessity of producing a second generation to assess the potential for human health risks has been questioned. The present standardized retrospective analysis of the impact of the second generation on overall study outcome combines earlier analyses and includes 498 rat multi-generation studies representing 438 different tested substances. Detailed assessment of study reports revealed no critical differences in sensitivities between the generations on the basis of a consideration of all endpoints evaluated. This analysis indicates that the second generation mating and offspring will very rarely provide critical information. These findings are consistent with the conclusions of previous retrospective analyses conducted by RIVM, USEPA and PMRA and support adoption of the proposed OECD extended one-generation reproductive toxicity study protocol in regulatory risk assessment testing strategies.
Asunto(s)
Fenómenos Fisiológicos Reproductivos/efectos de los fármacos , Proyectos de Investigación , Pruebas de Toxicidad , Envejecimiento , Animales , Relación Dosis-Respuesta a Droga , Desarrollo Embrionario/efectos de los fármacos , Determinación de Punto Final , Femenino , Fertilidad/efectos de los fármacos , Edad Gestacional , Lactancia , Tamaño de la Camada/efectos de los fármacos , Masculino , Exposición Materna , Exposición Paterna , Embarazo , Efectos Tardíos de la Exposición Prenatal , Ratas , Reproducción/efectos de los fármacos , Proyectos de Investigación/normas , Medición de Riesgo , Pruebas de Toxicidad/normasRESUMEN
BACKGROUND: Transcranial Doppler (TCD) is used to select children with sickle cell disease (SCD) for primary stroke prevention using regular blood transfusion. Whether it can also identify high stroke risk in adults with SCD is not known. METHODS: The authors examined 112 adult patients from two convenience population samples with SCD and 53 healthy control subjects to compare velocities in adults to those reported in children with SCD and to evaluate the influence of age and hematocrit on TCD. RESULTS: Adults with SCD had a higher mean time-averaged maximum mean velocity (110.9 +/- 25.7 cm/s) compared with healthy controls (71.1 +/- 12.0 cm/s), and the difference is approximately proportional to their anemia. No cases with velocities >/=200 cm/s (the threshold used in children for prophylactic treatment) were found in this sample. CONCLUSIONS: Transcranial Doppler velocities in adults with sickle cell disease (SCD) are lower than those in children with SCD. Velocity criteria used in children cannot be used to stratify risk of stroke in adults.