Page 108 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

Chemicals of Terrorism Chapter | 5 75

VetBooks.ir and vapor is rapid, and mustard causes both localized apoptosis by activating endonucleases, proteases, and
phospholipases (Smith et al., 1995). Mustard gas may also
cellular and systemic damage (NATO, 1973). Mustard
exert its toxicity via depletion of glutathione. Without
penetrates down hair follicles and sweat glands within
minutes. Dermal absorption of mustard varies by species. glutathione, reactive oxygen species react with membrane
About 20% of a dermal dose is absorbed through human phopholipids causing loss of membrane function, fluidity,
skin, while up to 75% is absorbed through the skin in rats and integrity. Inflammation and sulfur mustard-increased
(Smith, 1999). Ocular absorption also happens within proteolytic activity are also implicated in contributing to
minutes. The latent period for absorption is inversely mustard pathology (Cowan et al., 1998).
related to the dose, temperature and humidity (NATO,
1973). Lesions develop within 2 3 h with high-level
exposures, and 8 10 h after milder exposures (Requena Toxicity
et al., 1988).
The chemical reaction with biological tissue occurs Mustard gas is a radiomimetic, as it produces lesions sim-
rapidly but symptoms are typically delayed by several ilar to radiation (Sidell et al., 1997). Tissues with high
hours (Grant and Schuman, 1993; Sidell et al., 1997). cell turnover are the most affected. Being a vesicant, mus-
Dog studies show that equilibrium between blood and tis- tard gas can produce erythema, severe pruritus, blistering,
sues was achieved within 5 min after inhalation (IARC, ulceration, and necrosis of exposed skin (Borak and
1975). Once inside the body, mustard accumulates (in Sidell, 1992; Budavari, 2000). With dermal exposure, the
descending order) in fat, skin with subcutaneous fatty skin initially appears pale and then becomes erythematous
tissue, brain, kidney, muscle, liver, cerebrospinal within a few hours of exposure (Requena et al., 1988).
fluid, spleen, and lung (Drasch et al., 1987; Somani and Blistering usually starts on the second day and progresses
Babu, 1989). Urine is the major route of excretion in rab- for several more days. Erythema disappears in 3 7 days,
bits, mice, and rats. After IV administration in rats and while the ulcers take 6 8 weeks to heal (Garigan, 1996;
mice, the majority is excreted in 72 96 h (Maisonneuve Sidell et al., 1997). Brown or black hyperpigmentation
et al., 1993). Only about 6% is eliminated in the feces usually occurs after resolution of the burns, especially in
(IARC, 1975). Bone marrow damage is not evident for areas with thinner skin. Skin involvement is most severe
3 top 5 days and leukopenia usually occurs at day 7 10 at warm and moist sites (genitalia, perineal regions, groin,
following exposures (Garigan, 1996). skin folds, and axillae). This is due to the high number of
sweat glands in these areas.
The eyes are very sensitive to the effects of mustard
Mechanism of Action
gas (NATO, 1973; Borak and Sidell, 1992). Pain, lacrima-
The mechanism of action for cellular damage by mustard tion, corneal ulceration, along with photophobia, swelling,
is unknown, but four theories have been proposed: alkyl- blepharospasm, and blindness can be seen (Garigan,
ation of deoxyribonucleic acid, oxidative stress upon cell 1996). Conjunctivitis appears early, developing 4 6h
components, depletion of glutathione, and an inflamma- after exposure. Eye lesions have been reported at a Ct
tory response (Smith et al., 1995). Mustard gas is a (concentration 3 time) of 10 mg-min/m 3 (Sidell et al.,
bifunctional alkylating agent. It forms covalent cross- 1997). Porcelain-white areas in the episcleral tissues adja-
links between the double strands of DNA which inhibits cent to the cornea and formation of large, tortuous,
DNA synthesis. Mustard-induced blistering appears to be sausage-shaped varicose veins are pathognomonic signs
correlated to DNA damage in the basal cells (Cowan of mustard gas poisoning (Grant and Schuman, 1993).
et al., 1998). Mustard penetrates the skin and damages the Chronic conjunctivitis and keratopathy has been reported
cells separating the epidermis from the dermis. Mustard in people (Blodi, 1971).
disrupts the hemidesmosomes leading to blister formation The main nondermal toxic effects are on the respira-
between the two layers (Sidell et al., 1997). Skin biopsies tory tract. Irritation or ulceration of the respiratory tract
from mustard gas blisters revealed a separation of the can occur (Borak and Sidell, 1992; Budavari, 2000).
basal cells from one another and the development of mul- Cough, dyspnea, and pulmonary edema may occur up to
tinucleated cells (Bismuth et al., 1995). 24 h after inhalation. One ppm in air is a lethal concentra-
Mustard also causes oxidative stress on intracellular tion for dogs and 0.650 ppm mustard results in a 33%
molecules. Mustard forms an electrophilic ethylene epi- mortality rate in rabbits (OHM/TADS, 2005). See
sulfonium intermediate in the aqueous of the cytosol Table 5.2 for LD 50 information in various species by mul-
(Smith, 1999). The episulfonium ion reacts with sulfhy- tiple routes of exposure. Mild pulmonary exposures pro-
dryl groups leading to increased intracellular calcium. duce rhinorrhea, sneezing, epistaxis and cough within
The increased calcium level breaks down the microfila- 12 24 h of exposure. Large exposures can cause pulmo-
ments needed to maintain cell integrity and induces nary damage. In severe cases, hypoxia and respiratory