Comparative Aspects of Ricin Toxicity by Inhalation

Abstract

The pathogenesis of ricin toxicity following inhalation has been investigated in many animal models, including the non-human primate (predominantly the rhesus macaque), pig, rabbit and rodent. The toxicity and associated pathology described in animal models are broadly similar, but variation appears to exist. This paper reviews the published literature and some of our own unpublished data and describes some of the possible reasons for this variation. Methodological variation is evident, including method of exposure, breathing parameters during exposure, aerosol characteristics, sampling protocols, ricin cultivar, purity and challenge dose and study duration. The model species and strain used represent other significant sources of variation, including differences in macro- and microscopic anatomy, cell biology and function, and immunology. Chronic pathology of ricin toxicity by inhalation, associated with sublethal challenge or lethal challenge and treatment with medical countermeasures, has received less attention in the literature. Fibrosis may follow acute lung injury in survivors. There are advantages and disadvantages to the different models of pulmonary fibrosis. To understand their potential clinical significance, these factors need to be considered when choosing a model for chronic ricin toxicity by inhalation, including species and strain susceptibility to fibrosis, time it takes for fibrosis to develop, the nature of the fibrosis (e.g., self-limiting, progressive, persistent or resolving) and ensuring that the analysis truly represents fibrosis. Understanding the variables and comparative aspects of acute and chronic ricin toxicity by inhalation is important to enable meaningful comparison of results from different studies, and for the investigation of medical countermeasures.

Short- and long-term outcomes of pulmonary exposure to a sublethal dose of ricin in mice

“…The damage to the lung that we observed during the early time points post-sublethal exposure, included marked interstitial pneumonia, neutrophil infiltration, pro-inflammatory cytokine response, alveolar macrophage and alveolar epithelia type II cell death and edema. These observations stand in line with previous studies, where a lethal dose was used by intranasal instillation 8 , 9 , 28 , 29 , 35 , 36 , which also corresponded with other studies in rodents following inhalation exposure 34 , 42 , 43 . Altogether, our findings further substantiate intranasal instillation as a solid alternative respiratory exposure route for ricin intoxication in mice.…”

“…This sub-lethal intoxication dose is within the range that was used in other studies, using rodent models, where aerosolized inhalation or intratracheal instillation were used. We show here that the damage during the acute phase of our study recapitulates the damage caused by sublethal dose of ricin which was applied by aerosolized inhalation 15 , 20 , 21 , 23 , 34 . In the past, we determined ricin intranasal instillation LD 50 of rodents in the range of 3.5–4.8 µg/kg 8 , 9 , 28 , 29 , 36 .…”

“…However, research on lung deposition in other models has shown differences between aerosol inhalation exposure and intranasal instillation 41 . Despite the possible differences in toxin deposition, the overall damage in the lung following the two exposure routs is similar 11,34,42 . The damage to the lung that we observed during the early time points post-sublethal exposure, included marked interstitial pneumonia, neutrophil infiltration, pro-inflammatory cytokine response, alveolar macrophage and alveolar epithelia type II cell death and edema.…”

“…The individuals exposed to a low dose will inevitably pose a substantial logistical burden on medical care systems. These individuals are also most likely to be aided by administration of medical countermeasure 21 , 34 . Several studies investigated the effects of inhalation exposure to a sublethal dose of ricin in rodents and non-human primates.…”

Physiologically based pharmacokinetic model for predicting the biodistribution of albumin nanoparticles after induction and recovery from acute lung injury

“…Acute lung injury (ALI) is a severe clinical syndrome that, at the most critical stage of the disease spectrum, can cause acute respiratory distress syndrome (ARDS) [ [1] , [2] , [3] , [4] , [5] ]. The common causes of ALI are sepsis [ [6] , [7] , [8] , [9] ], pneumonia [ 10 , 11 ], trauma [ [12] , [13] , [14] , [15] , [16] ], aspiration [ [17] , [18] , [19] ], inhalation of toxic molecules [ [20] , [21] , [22] , [23] , [24] ], treatment-related adverse effects [ 25 , 26 ], and pancreatitis [ [27] , [28] , [29] ]. Despite advances in critical care, there is currently no effective medication targeting the underlying pathophysiology of ALI, and management of this disease remains supportive, mostly focusing on addressing the inciting cause [ 30 ].…”