Evaluation of neural reflex activation as a potential mode of action for respiratory and cardiovascular effects of fine particulate matter.

Objectives: Mortality from respiratory and cardiovascular health conditions contributes largely to the total mortality that has been associated with exposure to PM_2.5 in epidemiology studies. A mode of action (MoA) for these underlying morbidities has not been established, but it has been proposed that some effects of PM_2.5 occur through activation of neural reflexes.

Materials and methods: We critically reviewed the experimental studies of PM_2.5 (including ambient PM_2.5, diesel exhaust particles, concentrated ambient particles, diesel exhaust, and cigarette smoke) and neural reflex activation, and applied the principles of the International Programme on Chemical Safety (IPCS) MoA/human relevance framework to assess whether they support a biologically plausible and human-relevant MoA by which PM_2.5 could contribute to cardiovascular and respiratory causes of death. We also considered whether the evidence from these studies supports a non-threshold MoA that operates at low, human-relevant PM_2.5 exposure concentrations.

Results and discussion: We found that the proposed MoA of neural reflex activation is biologically plausible for PM_2.5-induced respiratory effects at high exposure levels used in experimental studies, but further studies are needed to fill important data gaps regarding the relevance of this MoA to humans at lower PM_2.5 exposure levels. A role for the proposed MoA in PM_2.5-induced cardiovascular effects is plausible for some effects but not others.

Conclusions: Further studies are needed to determine whether neural reflex activation is the MoA by which PM_2.5 could cause either respiratory or cardiovascular morbidities in humans, particularly at the ambient concentrations associated with total mortality in epidemiology studies.