Alternative testing systems for evaluating noncarcinogenic, hematologic toxicity.

Abstract

Hematopoietic tissues are the targets of numerous xenobiotics. Clinical hematotoxicity is either a decrease or an increase in peripheral blood cell counts in one or more cell lineages-a cytopenia or a cytosis, respectively-that carries a risk of an adverse clinical event. The purpose of in vitro hematotoxicology is the prediction of these adverse hematologic effects from the effects of the toxicants on human hematopoietic targets under controlled experimental conditions in the laboratory. Building on its important foundations in experimental hematology and the wealth of hematotoxicology data found in experimental oncology, this field of alternative toxicology has developed rapidly during the past decade. Although the colony-forming unit-granulocyte/monocyte neutrophil progenitor is most frequently evaluated, other defined progenitors and stem cells as well as cell types found in the marrow stroma can be evaluated in vitro. End points have been proposed for predicting toxicant exposure levels at the maximum tolerated dose and the no observable adverse effect level for the neutrophil lineage, and several clinical prediction models for neutropenia have developed to the point that they are ready for prospective evaluation and validation in both preclinical species and humans. Known predictive end points are the key to successful comparisons across species or across chemical structures when in vitro dose-response curves are nonparallel. Analytical chemistry support is critical for accurate interpretation of in vitro data and for relating the in vitro pharmacodynamics to the in vivo pharmacokinetics. In contrast to acute neutropenia, anemia and acute thrombocytopenia, as well as adverse effects from chronic toxicant exposure, are much more difficult to predict from in vitro data. Pharmacologic principles critical for clinical predictions from in vitro data very likely will apply to toxicities to other proliferative tissues, such as mucositis.Environ Health Perspect 106(Suppl 2):541-557 (1998). http://ehpnetl.niehs.nih.gov/docs/1998/Suppl-2/541-557parchment/abstract.html

Synadenium umbellatum: citotoxicidade e danos ao DNA de células da medula óssea de camundongos

“…Devido à grande capacidade proliferativa do tecido hematopoiético, as células da medula óssea são alvos freqüentes da ação tóxica de xenobióticos (Yamaguchi et al, 1994). Desta forma, a avaliação da integridade das células hematopoiéticas é um parâmetro importante para o entendimento dos mecanismos envolvidos na alteração da produção de células sanguíneas e como estas mudanças coletivamente irão impactar o sistema imuno-hematopoiético (Deldar et al, 1988;Parent-Massin, Thouvenot, 1993;Yamaguchi et al, 1994;Parchment, 1998;Gribaldo et al, 2000;Negro, Bonato, Gribaldo, 2001;Pessina et al, 2001;Gribaldo, 2002;Pessina et al, 2003;Diodovich et al, 2004).…”

CFU‐GM Assay for Evaluation of Drug Myelotoxic Activity

“…The concept of a prediction model has evolved from recent studies that sought to correlate in vitro and in vivo data by relating acute exposure to anticancer agents, the inhibition of CFU-GM in vitro, and the depth of the ANC nadir in vivo (Parchment et al, 1994;Volpe et al, 1996;Erickson-Miller et al, 1997;Deldar and Parchment, 1997;Parent-Massin and Parchment, 1998;Parchment, 1998;Pessina et al, 2001Pessina et al, , 2003. The prediction model suggested here has been applied in a prevalidation study (Pessina et al, 2001) to correlate the inhibition of CFU-GM in vitro and the depth of ANC nadir in vivo.…”

“…Toxicant-induced neutropenia can be described clinically by different hematology parameters, but predicting neutropenia for a xenobiotic by means of in vitro testing requires an accurate prediction for each parameter (Parchment and Murphy, 1997;Parchment, 1998). Currently, the clinical prediction models for the depth of the neutrophil nadir published in literature are complex, and differ in the amount of pharmacological information required to make predictions as well as in the accuracy of those predictions (Parchment et al, 1993;Parchment and Murphy, 1997;Parchment, 1998;Parchment et al, 1998). For the purpose of regulating exposure levels for thousands of xenobiotics, the most generally useful model requires the least amount of specialized pharmacological information (Parchment, 2000;Pessina et al, 2000).…”

Hematotoxicity: In Vitro and Ex Vivo Compound Profiling

“…Therefore, the trust level of this assay to embrace a wide range of predictable events is not as high as it is for the CFU assay. It is then advisable to confirm some key findings of the tier 1 stage, by the more elaborated and more validated CFU assay [43][44][45][46][47][48][49].…”