• 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 5,8,11-Eicosatriynoic Acid sale br Conclusions There is sign


    Conclusions There is significant interest in understanding the contribution of biological mechanisms to the non-linear/bilinear dose–response curves for DNA-reactive agents. Model monofunctional alkylating agents have datasets amenable to PoD determination for genotoxic effects in both in vitro and in vivo tests systems; these findings were supported by robust statistical analysis of in vitro and in vivo datasets [27], [28], [29], [30]. Such new experimental and computational approaches will help develop mechanistic evidence to support the necessary, biological understanding of the MOA for empirically demonstrated PoDs for DNA-reactive agents. The biological evidence for alkylating agents points to multiple DNA repair systems and DDR pathways acting together to prevent mutation, giving rise to non-linear/bilinear dose–responses for genotoxicity. Complex interactions within a particular DNA repair pathway, as well as interplay between different DNA repair and DDR pathways, counteract the effects of ever-present background DNA damage. Together, these pathways appear sufficient to counteract mutation at low exposures/doses and/or the propagation of 5,8,11-Eicosatriynoic Acid sale harboring significant DNA damage. The interplay of these biological processes serves as the basis of non-linear/bilinear dose–responses for genotoxic effects. Continuing efforts should be increasingly focused on the biological underpinnings of PoDs in order to show the biological pathways/networks involved in repair and homeostatic processes for various types of DNA damage. Hence, the examination of these key cellular, mechanistic responses should be integrated into the designs of the MOA studies to demonstrate the PoDs for genotoxic effects for various types of DNA-reactive agents. These diverse data streams can then be applied to risk assessment for genotoxic chemicals to reduce overall uncertainty in the process, specifically for risk characterization and uncertainties surrounding exposures at environmentally-relevant concentrations.
    Conflict of interest
    Introduction Pharmaceutical regulatory authorities have shown increased concern about impurities - especially genotoxic impurities (GTIs) – in active pharmaceutical ingredients (APIs) due to their adverse effects on human health [1, 2]. Sources for organic impurities in APIs include unreacted starting materials and reagents, intermediary products, catalysts, by-products formed, and degradation and storage products [3, 4]. The best route to prevent GTI presence in the final formulations is their elimination from synthetic pathways. However, when the formation of GTIs in APIs production cannot be prevented, purification of the API must be performed until the GTI is removed to satisfying levels: a Threshold of Toxicological Concern (TTC) value of 1.5 μg/day imposed by strict regulatory guidelines [1, 2]. Conventional separation techniques used in API purification include crystallization, filtration, distillation, the use of adsorbents, resins and column chromatography [[4], [5], [6]]. However, since these operation units are not GTI selective, significant amounts of API can be lost with great economic impact for pharmaceutical companies [5]. More recently, the use of organic solvent nanofiltration (OSN) [[5], [6], [7], [8], [9]], molecular imprinting techniques [[10], [11], [12]] and combinations thereof [[13], [14], [15]] have been suggested to address this challenge, based on size discrimination and specific interactions to target molecules. Reactive resins as adsorbents, bearing specific functional groups, are versatile and robust materials with vast application in aqueous systems [[16], [17], [18], [19], [20], [21]]. Nevertheless, API manufacturing synthetic processes often take place in organic solvent media, rendering their application challenging. For this reason, the development of a versatile organic solvent compatible material, for DNA alkylating agents scavenging, is a huge achievement with promising successful applications in pharmaceutical industry, ultimately contributing for API patients' wellbeing.