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1.
Arch Toxicol ; 97(4): 991-999, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36800004

RESUMO

The mode of action (MoA) of the 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitor herbicides in mammals is well described and is generally accepted to be due to a build-up of excess systemic tyrosine which is associated with the range of adverse effects reported in laboratory animals. What is less well accepted is the basis for the marked difference in the effects of HPPD inhibitors that has been observed across experimental species and humans, where some species show significant toxicities whereas in other species exposure causes few effects. The activity of the catabolic enzyme tyrosine aminotransferase (TAT) varies across species including humans and it is hypothesized that this primarily accounts for the different levels of tyrosinemia observed between species and leads to the subsequent differences in toxicity. The previously reported activities of TAT in different species showed large variation, were inconsistent, have methodological uncertainties and could lead to a reasonable challenge to the scientific basis for the species difference in response. To provide clarity, a new method was developed for the simultaneous and systematic measurement of TAT in vitro using robust methodologies in a range of mammalian species including human. The results obtained showed general correlation between high TAT activity and low in vivo toxicity when using a model based on hepatic cytosol and a very convincing correlation when using a primary hepatocyte model. These data fully support the role of TAT in explaining the species differences in toxicity. Moreover, this information should give greater confidence in selecting the most appropriate animal model (the mouse) for human health risk assessment and for key classification and labeling decision-making.


Assuntos
4-Hidroxifenilpiruvato Dioxigenase , Herbicidas , Humanos , Animais , Camundongos , 4-Hidroxifenilpiruvato Dioxigenase/metabolismo , 4-Hidroxifenilpiruvato Dioxigenase/farmacologia , Especificidade da Espécie , Tirosina/farmacologia , Modelos Animais , Fígado , Inibidores Enzimáticos/farmacologia , Herbicidas/toxicidade , Mamíferos/metabolismo
2.
Regul Toxicol Pharmacol ; 125: 105024, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34364928

RESUMO

Historical control data (HCD) consist of pooled control group responses from bioassays. These data must be collected and are often used or reported in regulatory toxicology studies for multiple purposes: as quality assurance for the test system, to help identify toxicological effects and their effect-size relevance and to address the statistical multiple comparison problem. The current manuscript reviews the various classical and potential new approaches for using HCD. Issues in current practice are identified and recommendations for improved use and discussion are provided. Furthermore, stakeholders are invited to discuss whether it is necessary to consider uncertainty when using HCD formally and statistically in toxicological discussions and whether binary inclusion/exclusion criteria for HCD should be revised to a tiered information contribution to assessments. Overall, the critical value of HCD in toxicological bioassays is highlighted when used in a weight-of-evidence assessment.


Assuntos
Bioensaio/métodos , Bases de Dados Factuais , Toxicologia/métodos , Toxicologia/normas , Relação Dose-Resposta a Droga , Medição de Risco
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