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When toxic substances penetrate the human body, they disseminate to various tissues, undergoing metabolic changes. This process yields reactive metabolites that may covalently bind with specific target molecules, resulting in toxicity.
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Drug toxicities can be stratified into pharmacological, pathological, or genotoxic based on their mechanisms. The incidence and severity of these toxicities generally increase with the drug's concentration in the body and exposure time.Pharmacological toxicity is evident when the therapeutic effects of drugs overshoot into adverse reactions in a predictable, dose-dependent manner. Central nervous system (CNS) depression from barbiturates is a classic example, with effects escalating from...
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Studies that assess how a drug is absorbed, distributed, metabolized, and excreted (ADME) at toxic doses are termed toxicokinetics. Understanding toxicokinetics helps predict adverse drug reactions (ADRs) and manage toxicity in humans.Toxicokinetics differs from pharmacokinetics mainly in the dose levels studied, with toxicokinetics focusing on higher toxic doses. The kinetics at these levels can be non-linear due to altered physiological processes. Toxicodynamics examines the relationship...
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Humans continually engage with an environment rich in potentially harmful chemicals. These are introduced to our bodies through inhalation, ingestion, or skin contact. These chemicals exist in various forms, such as air and environmental pollutants, agricultural chemicals, organic solvents, and heavy metals.
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Drug toxicity quantifies the harm a compound causes to an organism, varying by dose and potentially impacting whole systems or specific organs like the liver. Toxic reactions may arise from venomous insect or spider bites, with effects ranging from mild symptoms to severe outcomes such as brain damage or death. Common forms of acute poisoning include ethanol intoxication and overdose of pain or fever medications, with substances like GHB and heroin being particularly lethal at doses close to...
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Bioactivation is a metabolic process that transforms less reactive substances into highly reactive metabolites, initiating tissue toxicity. This transformation can lead to various toxic effects, including carcinogenesis and teratogenesis. Reactive metabolites are classified into two main types: electrophiles and free radicals.Electrophiles are electron-deficient species and are produced primarily by the enzyme cytochrome P-450 during the metabolism of compounds containing carbon, nitrogen, or...
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Pathways of Toxicity.

Andre Kleensang1, Alexandra Maertens, Michael Rosenberg

  • 1Johns Hopkins University, Bloomberg School of Public Health, Center for Alternatives to Animal Testing, Baltimore, MD, USA.

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|October 16, 2013
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Summary
This summary is machine-generated.

Developing Pathways of Toxicity (PoT) is crucial for modern toxicology. This workshop defined PoT and explored resources needed for systems biology approaches in hazard identification.

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Area of Science:

  • Toxicology and Risk Assessment
  • Systems Biology
  • Computational Toxicology

Background:

  • A consensus exists on transforming toxicology and risk assessment to align with advancements in life sciences.
  • Significant challenges remain in establishing a mechanistic foundation for toxicology.
  • Systems biology offers a promising avenue for this transformation, particularly in hazard identification.

Purpose of the Study:

  • To explore the development of Pathways of Toxicity (PoT) as a key tool for hazard identification.
  • To define the concept of PoT and its relationship with other toxicological pathway concepts like mode of action (MoA).
  • To identify necessary resources and approaches for creating a comprehensive PoT information resource.

Main Methods:

  • A workshop was convened to discuss and define Pathways of Toxicity (PoT).
  • Exploration of existing and needed public and commercial resources for PoT data, tools, and analyses.
  • Discussion on how systems biology can inform pathway annotation and resource accessibility for diverse users.

Main Results:

  • A preliminary definition of PoT was established: 'A molecular definition of cellular processes shown to mediate adverse outcomes of toxicants'.
  • Recognition that perturbed physiological pathways can function as PoT.
  • Identification of resource needs for PoT information, including data, visualization, tools, and use-cases.

Conclusions:

  • The formal definition and development of Pathways of Toxicity are essential steps towards a mechanistic toxicology foundation.
  • Systems biology approaches are vital for informing PoT annotation and integrating diverse data.
  • Collaborative efforts are needed to build and utilize comprehensive PoT resources for improved hazard identification.