particle toxicology

• What is toxicology?

  It is the study of the adverse effects of chemical substances on living organisms.
• How do soluble toxins affect the body?

  They lead to systemic exposure through the bloodstream and detoxification in the liver.
• What is the detoxification ability of the liver?

  • Expression of a variety of xenobiotic bio transforming enzymes
  • Converts lipophiles into water-soluble metabolites for elimination
  • Phase 1: Cytochrome P450 family catalyzes oxidation, reduction, and hydrolysis
  • Phase 2: Conjugation of functional groups by glutathione, sulphate, and glycine
• What is the aim of particle toxicology?

  To investigate the characteristics of particles that determine their ability to cause harm.
• What are the specific challenges of particle toxicology?

  • Different routes of exposure: inhalation, ingestion, skin contact
  • Different defense mechanisms
  • Diverse mechanisms of toxicity
• What are some sources of inhaled particles?

  Environmental:

  • Air pollution
  • Vehicle exhaust
  • Tyre wear, brake pads
  • Fossil fuel burning
  • Wild fires
  • Volcanic dust
  • Smoking

  
  

  Occupational:

  • Mining
  • Construction
• How did the industrial revolution affect exposure to inhaled particles?

  It accelerated the exposure to inhaled particles.
• When was the first line drawn between exposure to dust particles and lung disease?

  In the 15th and 16th centuries.
• Who wrote about the effects of dust in mining in the 16th century?

  Georgius Agricola.
• What did Georgius Agricola recommend for miners?

  He recommended wearing primitive dust masks in the form of veils.
• What is the core tenant of toxicology according to Paracelsus?

  All things are poison; solely the dose determines that a thing is not a poison.
• What are the big three of particle toxicology?

  • Quartz
  • Asbestos
  • Coal dust
• What causes coal workers' pneumoconiosis?

  Large accumulations of coal dust-laden macrophages.
• What cardiovascular effects are linked to air pollution exposure?

  • General morbidity and mortality due to respiratory and cardiovascular diseases
  • Acute exposure linked to adverse cardiovascular events
  • Long-term exposure increases risk of death from coronary heart disease
• How does inhalation of particles lead to systemic effects?

  Inhalation leads to pulmonary inflammation and can translocate particles into circulation.
• What systemic effects can inhaled particles cause?

  • Increased thrombogenicity and arterial rigidity
  • Increased blood pressure and impaired renal blood flow
  • Endothelial dysfunction and insulin resistance
  • Pre-eclampsia and placental damage
  • Inflammation and oxidative stress leading to cancer
  • Translocation across the blood-brain barrier leading to dementia
• What is the traditional approach to toxicology?

  • Observe disease
  • Work backwards to understand the mechanism and driving force
• What is the need for a paradigm shift in toxicology?

  • Shift from classic toxicology to predictive toxicology
  • Build on knowledge from particle toxicology studies
  • Identify and assess risks for novel materials
• What defines nanomaterials?

  • Having at least one diameter less than 100 nm
  • Raises concerns for human and environmental health
• What are common mechanisms of particle toxicology?

  • Dissolution and release of toxic metal ions
  • Cationic injury to membranes
  • Frustrated phagocytosis and inflammation
  • Reactive surfaces leading to membrane disruption
  • Bio transformation responses in nanoparticles
• What are the effects of ultra-high reactivity and metal ion shedding?

  • Oxidative stress
  • Cytotoxicity
  • Cellular stress
  • Inflammation
  • Heavy metal overload
  • pH balance and electrolyte disorders
• What happens with cationic nanomaterials?

  • Cell and lysosomal membrane interruption
  • Compromised membrane integrity
  • Cytotoxicity and immune activation
• What are the effects of long aspect ratio nanomaterials?

  • Frustrated phagocytosis and lysis
  • Lysosome disruption
  • Cell death and inflammation
  • Cytokine release and inflammasome activation
• What is a structure-activity relationship (SAR)?

  • Describes physical and chemical properties driving toxicity
  • Links physiochemical characteristics to biological reactivity
  • Can predict toxicity of novel materials
• What did Stanton et al propose in the 1970s regarding fibre pathogenicity?

  • Carcinogenicity is related to fibrous structure
  • Particularly for fibres below 2.5 µm in diameter and between 10 to 80 µm in length
• What are the effects of long fibres in terms of clearance?

  • Failure of passive clearance through stomata
  • Failure of active clearance by immune cells
• How do short fibres behave in the body?

  • Can be fully cleared by phagosomes
  • Can drain through pleural fluid to lymphatic system
• What is the biopersistence of asbestos compared to glass and mineral fibres?

  • Asbestos is very biopersistent
  • Glass and mineral fibres dissolve in low pH and are cleared
• What is the relationship between high aspect ratio nanoparticles and mesothelioma?

  High aspect ratio nanoparticles like carbon nanotubes can cause asbestos-like mesothelioma.
• What is the histology of mesothelium?

  • Single layer of squamous-like cells
  • 25 µm diameter
  • Nucleus round and raised above cytoplasm
  • Lines pleural cavity
  • Protects lungs from infectious agents
• What are the common molecular signatures in long fibre-induced lesions?

  • Changes in mRNA in diaphragm lysate
  • Common gene expression signature between long CNT and asbestos lesions
  • Involves inflammatory processes and macrophage recruitment
• What is the IARC classification for Mitsui-7?

  It is classified as a group 2B possible human carcinogen.
• What is the biologically effective dose in toxicology?

  • Exposure limits for most dusts set by mass
  • Entity within any dose of particles that drives critical pathophysiological responses
• What is the gene expression signature associated with LFA and LNT induced lesions?

  It involves pathways related to inflammatory processes, macrophage recruitment, and cytokine production.
• How does the activation of kinas signaling pathways vary?

  It is length dependent.
• What are the molecular mechanisms underlying lesion development at early stages for long CNT and asbestos?

  They are identical.
• What type of cancer is observed in mice exposed to long CNT?

  Mesothelioma.
• What is a feature of human mesothelioma related to the CDKN2A gene?

  Silencing of the CDKN2A tumor suppressor gene.
• What is the fibre pathogenicity paradigm?

  • It relates to the classification of fibers based on their potential to cause disease.
  • It includes the assessment of their biological effects and mechanisms of action.
• What classification does one MWCNT have according to IARC?

  It is classified as a group 2B possible human carcinogen.