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