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Table 1 Objectives and design for rodent inhalation studies of different duration, modified from [84]

From: Particle toxicology and health - where are we?

Acute /Subacute
5-28 days)
Subchronic
(90 days)
Chronic
(2 years)
• To obtain hazard ID and ranking (ideally compared to positive and negative controls)
• May be preceded by i.t. instillation or 1 day inhalation with range of doses to estimate inhaled concentration with MPPD model
• Ensure rodent-respirable aerosol stability over a range of concentrations
• If available use workplace or consumer exposure data to inform aerosol generation
• To determine concentrations for 90-day exposures (range-finding)
• To collect biokinetic data for portal of entry, and possibly identification of secondary target organs, incl. pleura, and fetus
• To provide guidance of dose levels for mechanistic in vitro testing, incl. secondary organs
• Post-exposure observation period desirable (~2 months)
• To derive NOAEL
• Use minimum 3 concentrations, including known or expected human exposure levels; both sexes optional
• If no effect at 50 mg/m3 rodent respirable aerosol, then no need to do chronic study
• To identify hazard: total respiratory tract, pleura, cardiovascular, central nervous system (CNS), bone marrow
• To identify target organs
• To select concentration for chronic study
• Detailed biokinetics: retention, clearance, organ accumulation,
• To predict long-term effects
• To inform human risk assessment via dosimetric extrapolation
• Post-exposure observation period to assess progression-regression (~3 months)
• To determine long latency effects (cancer); life shortening; extrapulmonary target organs
• 3 concentrations based on 90-day or range-finding study results; include human exposure level; high dose: MTD; low dose: no significant effect
• To assess total respiratory tract, pleura and systematic effects, nose to alveoli, cardiovascular, CNS, bone marrow, others (reproductive?)
• To determine detailed biokinetics: respiratory tract retention, clearance, organ accumulation
• To perform extrapolation to human for risk assessment
• Post exposure observation period up to a total study duration of 30 months (if survival of ≥20%)