Nettle Agent Phosgene Oxime Toxicity and Related Mechanism from its Dermal Exposure
Authors: Singh Satyendra Kumar , Goswami Dinesh Giri , Croutch Claire R. , Agarwal Rajesh , Noland Erica L. , Tewari-Singh Neera 
Published: April 2020

Phosgene Oxime (dichloroform oxime; CX), an urticant or nettle agent categorized as a vesicant, is a potential chemical threat agent. Its exposure causes rapid toxicity, severe pain with dermal symptoms including erythema (redness), urticaria, blanching, itching hives, necrosis and systemic effects. Due to its fast penetration, severe dermal injury, and instant lethal toxic effects resulting in high mortality, CX could be weaponized with other chemical threat agents to enhance their deleterious effects. Skin damage with erythema, necrosis and inflammation following cutaneous exposure to CX and vesicants, e.g. sulfur mustard (SM; mustard gas), nitrogen mustard (NM) and lewisite (L), is similar; however, CX also causes severe skin injury with immediate urticaria and blanching as well as mortality. The skin urticaria from CX resembles urticaria caused by allergic and non‐allergic reactions to various environmental substances and can occur alone or can be associated with lethal allergic reaction, anaphylaxis. CX is one of the least studied vesicating agent with no effective treatment available. In the present study, we exposed the dorsal skin of SKH‐1 hairless mice with neat CX for 0.5 and 1.0 min using two 12 mm vapor caps, and studied different parameters associated with its pathophysiology. Clinical data from our study showed that CX exposure leads to acute skin lesions (edema, erythema, necrosis, urticaria and blanching) as well as decreases in heart and respiratory rate, drop in body temperature, vasculature dilation and blood congestion in multiple organs indicating urticaria and anaphylaxis. Histopathological analysis showed a CX‐induced increase of over 2‐fold in the mouse skin epidermal thickness at 2 hr and 14 days following 0.5 min and 1.0 min exposures, respectively. Similarly, 1.5–2.0‐fold increase in dermal plus hypodermal thickening was observed at all study time points following 0.5 and 1.0 min CX exposures. Dermal fibrosis, necrotic blood vessels, hyperkeratosis, cell death and an increase in inflammatory cells was also observed at day 1 and 14 following 0.5 min CX exposure. Edema, necrosis and dying fat cells were observed within 2 hr in the skin of both the CX exposure groups. CX induced an increase in mast cell degranulation within 30 min of its exposure which peaked to over 90% at 24 hr post exposure and was associated with increased histamine and tryptase levels. In addition, an increase in the level of MMP9 and DNA damage maker (pH2AX) in skin tissues was also observed. The results from our completed studies suggest that mast cells could be important players in CX‐ and probably other vesicating agents‐induced toxicity. Hence, molecular markers and cytokines associated with CX‐induced mast cell degranulation as well as inflammatory and DNA damage responses are being evaluated to identify the signaling pathways and key molecular targets for further therapeutic approaches to counteract toxicity from CX cutaneous exposure in case of a chemical emergency.