STP Position Paper

Abstract

The Scientific and Regulatory Policy Committee of the Society of Toxicologic Pathology (STP) appointed a working group to address risk assessment for increases in alveolar macrophages following inhalation of pharmaceutical materials. This position paper provides recommendations for inhalation study-specific terminology and interpretation based on literature and information from marketed inhaled drugs. Based on a weight-ofthe-evidence approach, and with appropriate consideration of the physical and pharmacological characteristics of the compound, uncomplicated increases in the size or number of alveolar macrophages in nonclinical species are interpreted as nonadverse.

Toxicological assessment of a prototype e-cigaret device and three flavor formulations: a 90-day inhalation study in rats

“…Even for small amounts of respirable particulates that do not overload macrophages, the pulmonary clearance half-life is approximately 100 days in the rat lung (Oberdörster et al, 1992 ). According to the criteria established by the Society of Toxicologic Pathology Working Group and published by Nikula et al ( 2014 ), such a response should be considered a normal adaptive response of the lung since “findings suggest that even in susceptible populations, there is no evidence for any functional adverse effect due to increased alveolar macrophages”.…”

Clinical potential of oligonucleotide-based therapeutics in the respiratory system

“…Macrophage recruitment and enlargement (hystiocytosis; foamy macrophage phenotype) in the parenchyma and tracheobronchial lymph nodes was observed in both species, persisting for 13 weeks. Dosedependent pro-inflammatory infiltrates were reported only in mice, with hystiocytosis ascribed to 'normal' alveolar macrophage function as defined by Nikula et al (Nikula et al, 2014…”

Morphometric Characterization of Rat and Human Alveolar Macrophage Cell Models and their Response to Amiodarone using High Content Image Analysis

“…Airway diseases such as asthma and chronic obstructive pulmonary disease (COPD) are an area of unmet clinical need despite considerable investment in developing new therapeutics in this area [ 1 , 2 ]. New inhaled medicines require extensive non-clinical safety assessment before progressing to the clinic for evaluation of safety and efficacy in humans [ 1 – 6 ].…”

“…Airway diseases such as asthma and chronic obstructive pulmonary disease (COPD) are an area of unmet clinical need despite considerable investment in developing new therapeutics in this area [ 1 , 2 ]. New inhaled medicines require extensive non-clinical safety assessment before progressing to the clinic for evaluation of safety and efficacy in humans [ 1 – 6 ]. It is not uncommon for alveolar macrophage responses to be observed in histological lung slices of animals during non-clinical inhalation toxicology studies: these are typically characterised by a highly vacuolated appearance and larger cell size [ 2 , 3 ].…”