New Approach Methodology for Assessing Inhalation Risks of a Contact Respiratory Cytotoxicant: Computational Fluid...

Area of Science:

• Toxicology
• Computational modeling
• Inhalation exposure science

Background:

• Regulatory agencies seek alternatives to animal testing for inhalation toxicity assessments.
• In vitro and in silico methods are emerging as viable alternatives.
• Fungicides like chlorothalonil require robust risk assessment for human and environmental safety.

Purpose of the Study:

• To develop computational fluid-particle dynamics (CFPD) models for estimating inhaled aerosol deposition in rats and humans.
• To compare deposition patterns in rats with existing inhalation toxicity data.
• To provide data for human in vitro toxicity studies and reduce reliance on animal testing.

Main Methods:

• Development of CFPD models to simulate aerosol deposition in rat and human respiratory tracts.
• Simulation of various aerosol sizes (1-50 µm) under different breathing conditions (nasal/oral).
• Application of the International Commission on Radiological Protection (ICRP) clearance model to calculate local tissue dose metrics.

Main Results:

• In rats, deposition was highest in the anterior nasal regions, larynx, and transitional epithelium.
• In humans, aerosols of 1-5 µm penetrated deep into the lungs, while larger aerosols (>10 µm) deposited primarily in the upper airways.
• Deposition in the pharynx, larynx, trachea, and bronchi was greatest for 10-20 µm aerosols; larger aerosols showed limited penetration.

Conclusions:

• CFPD models accurately predict inhalation exposure relevant to in vitro and in silico toxicology.
• Estimated human equivalent concentrations derived from deposition data reduce the need for animal studies in risk assessment.
• This approach supports regulatory acceptance of non-animal testing methods for inhalation toxicity.