Appendix C

Review of Literature on Known Project SHAD Agents, Simulants, Tracers, and Decontaminants

At the committee’s request, the Institute of Medicine (IOM) research librarian carried out targeted literature searches on the following agents, simulants, tracers, and decontaminants¹:

1. Bacillus globigii (BG)
2. Betapropiolactone (beta-propiolactone; BPL)
3. Calcium hypochlorite
4. Calcofluor
5. Coxiella burnetii (CB, Q fever)
6. Diethylphthalate (DEP)
7. Escherichia coli (E.coli; EC)
8. Methyl acetoacetate (MAA)
9. Pasteurella tularensis (Francisella tularensis)
10. Phenol
11. Sarin
12. Serratia marcescens (SM)
13. Staphylococcal enterotoxin type B (SEB)
14. Sulfur dioxide
15. Trioctyl phosphate (TOF)
16. Uranine
17. VX nerve agent (VX)
18. Zinc cadmium sulfide

These searches were conducted to determine whether new information was available to update the reviews of these materials that had been prepared in 2004 for the SHAD I study (IOM, 2007b).² The searches were designed to identify peer-reviewed literature published

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¹ The SHAD I (IOM, 2007b) review included bis-hydrogen phosphite and phosphorus-32, but these substances were not included in the updated review of literature for this study. These tracers were disseminated with VX over a barge in the Flower Drum II test. No personnel have been identified as participants in this test.

² The SHAD I report is available for free download at http://iom.nationalacademies.org/Reports/2007/Long-TermHealth-Effects-of-Participation-in-Project-SHAD-Shipboard-Hazard-and-Defense.aspx (accessed December 7,

between January 2001 and January 2012 on studies in vitro, in animals, or in humans that evaluated the safety or potential long-term health effects of exposure to the substances. The committee did not examine papers reporting use of a given substance in laboratory procedures without evaluation of health effects, papers in which the substance was not the focus of the study, or papers that did not address potential long-term effects of exposure. The databases searched were Medline, Toxline, Embase, Science Citation Index within the Web of Science, Chemical Carcinogenesis Research Information System (CCRIS), Hazardous Substances Data Bank (HSDB), and Integrated Risk Information System (IRIS). The searches used the substance name, synonyms, and the Chemical Abstracts Service (CAS) registry number, as appropriate.

The descriptions that follow summarize findings from background papers prepared by the Center for Research Information (CRI) for the SHAD I study (IOM, 2007b). They also reflect new findings or additional information drawn from the supplemental literature searches. The committee sought to generate hypotheses that it could use to provide some focus for a portion of its analysis. In these descriptions, the committee notes instances where the available literature provides at least some evidence that an exposure might be associated with an increased risk of certain long-term health effects. The committee is using “long-term” to mean persisting, recurring, or appearing several years or more after exposure. The committee’s identification of a health effect means that it was judged to warrant investigation as an a priori hypothesis to be tested; it does not constitute an assertion by the committee that the evidence is conclusive that the health effect could result from the relatively short-term exposures to the substance that occurred in SHAD tests.

Bacillus globigii (B. globigii or BG) [biological simulant]

B. globigii is a Gram-positive spore-forming bacterium commonly found in dust, soil, and water and frequently used as a tracer and simulant for spore-forming bacteria such as Bacillus anthracis (e.g., Clark Burton et al., 2005; Duncan et al., 2009) or other bacterial spores (Probst et al., 2010). It has also been called B. subtilis var niger and B. lichenformis, but it is now referred to as B. atrophaeus. BG was used as a simulant in SHAD testing.

The literature search for BG/B. atrophaeus did not identify new information on potential long-term health effects from BG exposure or reports of long-term persistence or delayed manifestations of infection. As a result, the committee did not find it necessary to augment the information reported for the SHAD I study (IOM, 2007b) on the potential pathogenicity of BG. As noted in that report, BG was previously considered to be a largely harmless agent, but it is now recognized as a human pathogen. Infection is most often associated with invasive trauma or a weakened health state. Reported effects include ocular infections, bacteremia, sepsis/septicemia, ventriculitis, and peritonitis. Gastrointestinal (GI) effects may occur with consumption of contaminated food. Although these reported short-term health effects can be serious, there are no reports to indicate persistent health consequences once short-term effects have resolved (CRI, 2004a).

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2015). A set of commissioned papers that reviewed the health-effects literature on these substances were prepared by the Center for Research Information for the first IOM SHAD study and are available at this same website. These commissioned papers are cited in this report as (CRI, 2004[x]).

Studies of B. globigii, B. subtilis var niger, B. lichenformis, and B. atrophaeus provided no evidence for identifying specific long-term health effects that might be associated with exposure during SHAD testing.

Betapropiolactone (BPL) [decontaminant]

BPL is a colorless liquid with a pungent odor that was used in Project SHAD as a decontaminant. Its short-term effects are irritation of the skin, eyes, and respiratory and digestive systems. Dermal exposure can cause blisters and burns, and animal testing has indicated that ocular administration results in pain and corneal opacity. Animal testing has also shown an association between respiratory exposure and inflammation of the respiratory tract.

Human testing to evaluate BPL as an anti-hepatitis disinfectant for plasma transfusion took place at the Henry Ford Hospital in the 1950s and 1960s (Kelly et al., 1957, and LoGrippo, 1964, as cited in CRI, 2004f). No chronic toxic effects were reported in the 995 recipients of treated plasma who were followed for periods ranging from 6 months to 5 years; however, related animal experiments demonstrated cumulative toxicity manifested in weight loss and necrosis of the liver and kidney tubules (Kelly et al., 1957, and LoGrippo, 1964, as cited in CRI, 2004f).

BPL is categorized as a possible human carcinogen (Group 2B) by the International Agency for Research on Cancer (IARC, 1999a), and it is a confirmed animal carcinogen, frequently used in animal experiments to induce cancer (CRI, 2004f). The National Toxicology Program (NTP) categorizes BPL as “reasonably anticipated to be a human carcinogen,” based on evidence of carcinogenicity from studies in animals (NTP, 2011, p. 366). Tumor sites reported in experimental animal studies vary with the route of exposure. Oral exposure caused cancer of the stomach, dermal exposure caused benign and malignant skin tumors, and subcutaneous injection caused cancer at the injection site. Lymphoma and liver tumors were also observed following injection. Intrarectal exposure caused benign colon tumors, and inhalation exposure caused cancer of the nasal cavity. The NTP review reported that no epidemiological studies were identified that evaluated the association between exposure to BPL and risk of cancer in humans (NTP, 2011).

The committee’s literature search for publications since 2001 did not identify new information on potential long-term health effects from BPL exposure beyond those noted in the review for the previous SHAD report (CRI, 2004f).

Because betapropiolactone is considered a possible human carcinogen, the committee tested the hypothesis that exposure is associated with an increased risk among SHAD test participants for the following conditions:

• Any cancers

Calcium Hypochlorite [decontaminant]

Calcium hypochlorite is a yellowish-white solid with formula Ca(ClO)₂ and CAS number 7778-54-3. It smells strongly of chlorine. It is an ingredient in bleaching powder, and it is used in household cleaners and disinfectants, drinking and wastewater purification systems, and disinfection systems for swimming pools (ATSDR, 2011). It was reported to have been used as a decontaminant in at least two tests carried out as part of Project SHAD.

Calcium hypochlorite was not among the substances for which a literature review was carried out for the first IOM study on the potential long-term health effects from participation in Project SHAD. The literature search for the SHAD II study found limited information available from sources such as the Agency for Toxic Substances and Disease Registry (ATSDR), International Agency for Research on Cancer (IARC), and HSDB. Calcium hypochlorite can be an irritant to the eyes, skin, respiratory tract, and GI tract. At high concentrations it can cause severe damage to these tissues or even death. Dermal exposure to Ca(ClO)₂ at high concentrations can cause pain, inflammation, and blisters. Exposure of the eyes can result in effects that range from mild irritation to severe injury, depending on the exposure concentration (ATSDR, 2011). Exposure to chlorine gas released from concentrated calcium hypochlorite solutions can lead to coughing, nasal irritation, and sore throat. Little evidence is available regarding the carcinogenicity of hypochlorite salts in animals, and no data on carcinogenicity were available from human studies. As a result, IARC (1997) determined that calcium hypochlorite is not classifiable regarding its carcinogenicity.

Available studies of calcium hypochlorite provided no evidence for identifying specific long-term health effects that might be associated with exposure during SHAD testing.

Calcofluor [tracer]

Calcofluor is a fluorescent whitening agent used to brighten items such as paper and textiles. It is also used as a laboratory stain and as a fluorescent tracer in the environment. It was used as a tracer in the SHAD tests designated Half Note and Test 69-32.

The IOM search for references relevant to potential long-term human health effects from exposure to calcofluor did not identify relevant journal articles published since the literature review carried out for the first SHAD study. That review found that the toxicity of calcofluor is low, based on oral and dermal toxicity studies in fish, mammals, and humans (CRI, 2004g). It has not been found to be carcinogenic or mutagenic to humans.

Studies of calcofluor provided no evidence for identifying specific long-term health effects that might be associated with exposure during SHAD testing.

Coxiella burnetii (C. burnetii or CB) [active biological agent]

C. burnetii is a bacterium that is the causative agent of Q fever. It was investigated as a potential biological warfare agent during SHAD testing in the 1960s. Its primary natural reservoirs are animals such as cattle, sheep, and goats. Transmission from these animals to humans most frequently occurs through inhalation of aerosolized bacteria shed by animals (CDC, 2011, 2012). The bacterium has an extracellular form that is metabolically inactive, can be transmitted through air and dust, and remains infectious for several weeks in natural environments (CRI, 2004b). Aerosolized C. burnetii was used as part of Project SHAD in the test called Shady Grove.

Infection with C. burnetii can cause various acute and chronic health effects. However, only about 40 percent of people infected with it report clinical symptoms (CRI, 2004b). According to the Centers for Disease Control and Prevention (CDC), roughly 3 percent of the healthy U.S. population and 10-20 percent of persons in high-risk occupations (veterinarians, farmers, etc.) have antibodies to C. burnetii (CDC, 2012).

The acute form of Q fever typically arises 10-17 days after exposure, with common modes of presentation including pneumonia, hepatitis, or an influenza-like febrile illness (IOM, 2007a). Long-term effects from infection with C. burnetii have been observed. Neurologic deficits sometimes develop during the acute phase of the illness and can continue over the long term. In addition, the scientific literature links five chronic syndromes with C. burnetii infection: endocarditis, vascular infection, chronic hepatitis, osteomyelitis, and a post-Q fever fatigue syndrome (IOM, 2007a). Among these conditions, endocarditis and vascular infection appear to be the most common (Raoult et al., 2000). Of note, acute Q fever is not a necessary precursor for Q fever endocarditis. In a large case series in France only one-third of Q fever endocarditis patients reported potential Q fever in the year before the start of endocarditis symptoms (Raoult et al., 2000). Q fever endocarditis is most common in those with abnormal or prosthetic cardiac valves or underlying cardiac valvular lesions (IOM, 2007a).

The SHAD II committee’s examination of the relevant recent literature reinforced the association of C. burnetii infection with endocarditis and vascular infection (e.g., Alshukairi et al., 2006; Angelakis and Raoult, 2010). Recent Q fever outbreaks in the Netherlands (Kampschreur et al., 2012) and increasing awareness of the disease elsewhere (Bacci et al., 2012) are providing more information about the natural history and prevalence of the disease. However, long-term effects from C. burnetii infection are difficult to study because infection is at times asymptomatic and results of serological testing to identify past infections can vary across reference laboratories using the same immunological test (Healy et al., 2011). Active research on the natural history of C. burnetii infection and potential chronic effects of infection is ongoing (Hartzell et al., 2008; Raoult et al., 2005; van der Hoek et al., 2012).

Based on the evidence available regarding potential long-term health effects associated with exposure to C. burnetii, the committee tested the hypotheses that participation in SHAD tests that used C. burnetii may be associated with increased risk for the following conditions:

• Endocarditis
• Vascular infection
• Chronic hepatitis
• Osteomyelitis
• Post Q-fever fatigue syndrome

Diethylphthalate (DEP) [chemical simulant]

DEP is a liquid chemical widely used in industrial and consumer products, including automobile parts, toothbrushes, tools, food packaging, aspirin, insecticides, and cosmetics (CRI, 2004h). It is frequently used to make plastics more flexible (e.g., medical tubing), and in this role is known as a “plasticizer.” It was used in Project SHAD as a simulant for VX nerve agent.

Because of wide human exposure to this compound, many studies have been carried out to evaluate its toxicity. Dermal sensitization to DEP has been described but seems to be rare (WHO, 2003). Other than producing irritation of mucous membranes and the lungs and a general anesthetic effect at high doses (CRI, 2004h), it has shown very low toxicity.

Studies in animals of the potential for low doses of phthalates such as DEP to influence immune and allergic responses have not provided consistent answers (Kimber and Dearman, 2010). Recent concerns about the potential for phthalates to disrupt endocrine signaling have led to additional studies evaluating the potential for altered reproductive effects. However, in a study

of the comparative toxicology of nine phthalate diesters (including DEP) and five monoesters administered to male rats at high doses, DEP showed only few and subtle effects compared to the other compounds (Kwack et al., 2009). Exposure to DEP in utero did not alter sexual differentiation in male rat pups (Gray et al., 2000). However, a study in which male Wistar rats were fed DEP dissolved in the diet daily for 5 months showed dose-dependent changes in liver histology (Pereira et al., 2006) and Wistar rats continuously exposed to DEP through diet over three generations showed fatty degeneration of the liver, particularly in the third (F2) generation (Pereira et al., 2007). DEP is not among phthalates that have been banned from cosmetics or children’s toys by the United States or the European Union (EurActiv, 2004).

Studies of DEP provided no evidence for identifying specific long-term health effects that might be associated with exposure during SHAD testing.

Escherichia coli (E. coli or EC) [biological simulant]

E. coli is a Gram-negative bacterium that belongs to the Enterobacteriacae family. Large numbers of strains of E. coli are known to exist. Many strains are harmless, including ones that commonly inhabit the human intestines (enteric bacteria), and E. coli is widely used in laboratories for research. However, certain strains can be significantly pathogenic. E. coli was used in Project SHAD as a simulant to study the decay of biological agents in a marine or shipboard environment. Records available to the committee did not specify the strain of E. coli used in the SHAD tests, but its use as a simulant suggests avoidance of any strains known to be pathogenic.

Oral exposure to pathogenic strains of E. coli can cause diarrhea and nausea, which typically resolve in 1-2 days. E. coli is a common source of hospital-acquired infection, as well as a frequent cause of urinary tract and blood infections. Some forms of pathogenic E. coli can cause severe and even fatal illness.

The literature search seeking new references since the CRI’s 2004 review found several articles of note on health effects of infection with pathogenic forms of E. coli. Berger et al. (2010) found risk factors for E. coli bacteremia to include vascular catheters, malignancy, and cytoreductive or immunosuppressive therapy. In another study, risk factors for recurrent E. coli infections of the bloodstream included being male, the presence of hematologic malignancy, and inadequate antibiotic treatment (Sanz-Garcia et al., 2009). Smith and Bayles (2007) noted that E.coli is among several foodborne pathogens commonly associated with postinfectious irritable bowel syndrome. A considerable literature surrounds potential sequelae from infection by the E. coli O157:H7 strain. The highly pathogenic E. coli O157:H7 was not recognized until the 1980s and is not likely to be relevant to potential effects from Project SHAD exposures.

The use of E. coli in SHAD tests as a simulant would seem to suggest that the intention was to select a nonpathogenic strain for this purpose. However, because the specific strain used is not known, the committee considered evidence regarding potential long-term health effects associated with exposure to certain pathogenic strains of E. coli. Based on that evidence, the committee tested the hypotheses that participation in SHAD tests that used E. coli may be associated with increased risk for the following condition:

• Irritable bowel syndrome

Methyl Acetoacetate (MAA) [chemical simulant]

MAA is a colorless liquid frequently used in the fragrance industry. The general population may be exposed through breathing wood smoke (HSDB citing NIOSH, 1983). It was used in Project SHAD as a simulant for the nerve agent sarin.

Methyl acetoacetate is considered to be a mild irritant: exposure may cause swelling, redness, or pain, particularly at mucous membranes (CRI, 2004i), and may cause corrosive effects to the eye. It is not considered to be mutagenic nor has it shown reproductive or developmental effects in the rat (CRI, 2004i; HSDB, 2005). However, studies of the toxicity of MAA are limited. The literature search seeking new reports since the review for the first IOM SHAD study identified only HSDB (2005) information and a summary of mutagenicity studies in CCRIS (2010). All but one of the mutagenicity studies were negative. The positive results in the one study are thought to be an artifact of problems with the pH of the test system (CRI, 2004i).

Studies of MAA provided no evidence for identifying specific long-term health effects that might be associated with exposure during SHAD testing.

Pasteurella tularensis (Francisella tularensis) [active biological agent]

Pasteurella tularensis, which has been renamed Francisella tularensis, is a Gram-negative coccobacillus that is the causative agent for the disease tularemia. It is carried by animals, and its transmission to humans is associated with being in contact with animals or with tick bites. It is also considered to be a possible bioterror agent because of its ability to cause debilitating or fatal illness. Aerosolized F. tularensis was used as part of Project SHAD in the test called Shady Grove.

Infection with F. tularensis typically results in fever, with additional symptoms such as chills, headaches, weight loss, emesis, diarrhea, muscle aches, joint pain, cough, hepatitis, and jaundice. Local enlargement of the lymph glands, skin eruptions, and ulcerations often occur at the site of initial inoculation. The more common manifestations are in skin, lymph, lungs, and liver. Sometimes patients experience atypical signs and effects such as neuropathies, meningeal involvement, and pericarditis. The typical course of infection is 1 month of fever, 1 month of weakness, and 6 weeks of gradual but complete recovery (CRI, 2004c). However, exposure to aerosolized F. tularensis can lead within days or weeks to respiratory failure and death if the infection is untreated (Dennis et al., 2012). Several clinical syndromes have been described and include glandular, pneumonic, and typhoidal forms (CIDRAP, 2010).

Tularemia is considered a “strictly acute disease” (CRI, 2004c, p. 2). Although one case report documents recurrences of fever and ulcerations over a decade, there are no reports of symptoms first appearing months or years after initial infection.

The literature search seeking new references since the CRI review (2004c) did not identify additional papers relevant to potential long-term effects from infection with F. tularensis.

Studies of F. tularensis and tularemia provided no evidence for identifying specific long-term health effects that might be associated with exposure during SHAD testing.

Phenol [noted as component in preparation of simulant BG in Half Note test]

Phenol is an organic compound with the chemical formula C₆H₆O and a sweet and tarry odor. It is manufactured in large amounts in the United States. It is used in the manufacture of plastics, in household cleaning products, and in consumer products such as mouthwashes, gargles, throat lozenges, and throat sprays. It is also released into the air in automobile exhaust, cigarette smoke, and smoke from burning wood. Low levels are found in certain smoked and fried foods (ATSDR, 2008). It is used medically as a treatment for spasticity (Cullu et al., 2005; Goktepe et al., 2002; Jarrett et al., 2002; Kolaski et al., 2008; Pinder et al., 2008) and for certain dermatological conditions (Iglesias et al., 2008; Kaminaka et al., 2009a,b). It is also sometimes used as a preservative in vaccines and biologics (Geier et al., 2010). A report on one SHAD test (DTC, 1968) noted that it was added at 1 percent to slurry preparations of BG.

Phenol was not among the substances for which a literature review was carried out for the first IOM study on Project SHAD. The literature search for the current study found an array of publications about health effects of phenol exposure. Most of these reports, such as ATSDR (2008) and HSDB (2003a) summaries, emphasize short-term hazards. Phenol is caustic to tissues, and toxicity can result from oral, dermal, or inhalation exposure. Ingestion of concentrated phenol can cause GI damage and even death. When concentrated phenol is applied to the skin, it can cause burns and other skin damage, as well as liver and kidney toxicity. The National Institute for Occupational Safety and Health (NIOSH, 2011) has assigned a special skin notation for phenol because skin contact can be life-threatening as well as injurious to the skin. Inhalation can result in pulmonary irritation and edema. At high doses dermal absorption can lead to systemic toxicity, including cardiovascular effects, pulmonary depression, and central nervous system effects (NIOSH, 2011). Phenol is considered a weak clastogen (cause of breaks in chromosomes) based on studies in mice (Bruce et al., 2001).

Assessments by IARC (1999b) and Bruce et al. (2001) examined data regarding cancer and other potential long-term endpoints. Phenol has not been shown to be a carcinogen in animals or humans (IARC, 1999b). Information about other potential long-term effects from studies in humans is very limited, but includes reports suggesting the potential for suppression of immune response, altered hematological parameters, and increased liver enzymes in workers (Bruce et al., 2001).

Taken together, the available studies of phenol provided no evidence for identifying specific long-term health effects that might be associated with exposure to phenol during SHAD testing.

Sarin [active nerve agent]

Sarin is an organophosphate compound and chemical warfare agent developed by German scientists in the late 1930s. It is a nerve agent that inhibits enzymes known as acetylcholinesterases (AChEs), which are responsible for breaking down the neurotransmitter acetylcholine into choline and acetic acid. With inhibition of the enzymes, the neurotransmitter builds up at nerve synapses to overstimulate nerve receptors. It was a test agent in the SHAD test Flower Drum I.

Health effects from sarin depend on the amount, timing, and route of exposure. Short-term (acute) effects of exposure to sarin at low concentrations include ocular pain, blurred or dimmed vision, miosis (constricted pupils), tearing, runny nose, and sweating. At high

concentrations, the effects include convulsions, loss of consciousness, paralysis, and respiratory failure possibly leading to death.

Long-term effects in humans from exposure to sarin have been studied in several populations: those exposed through the terrorist use of sarin in Japan in 1994 and 1995, intentionally exposed military volunteers, accidentally exposed industrial workers, and Gulf War veterans. These studies are reviewed in two IOM reports prepared as part of the Gulf War and Health series (IOM, 2000, 2004). Many methodological challenges accompany epidemiologic studies of exposed populations. Exposure levels are typically uncertain or approximate, and studies have frequently relied on self-report to assess health outcomes. Taking into account the evidence available on the effects of high-dose exposures, the IOM Gulf War and Health committee found “limited/suggestive evidence of an association between exposure to sarin at doses sufficient to cause acute cholinergic signs and symptoms and a variety of subsequent long-term neurological effects” (IOM, 2004, p. 93).

With regard to long-term effects from low doses of sarin (exposures “insufficient to cause acute cholinergic signs and symptoms”), the IOM Gulf War and Health committee found “inadequate/insufficient evidence to determine whether an association does or does not exist between exposure” and subsequent long-term adverse neurological health effects (IOM, 2004, p. 96). The review examined evidence on a wide array of general neurological effects (e.g., changes in memory, difficulty in sleeping, cognitive dysfunction) as well as posttraumatic stress disorder. That committee did not believe that it was possible to extrapolate the long-term, low-level effects of organophosphorus (OP) compounds used as insecticides to the case of sarin (IOM, 2004, p. 97).³

Since that review, various studies have provided additional data from human studies of long-term effects from sarin exposure. A survey by Kawada et al. (2005) of victims of the Tokyo subway sarin release has observed poorer sleep quality among those in the exposed group compared to a control group. A report by Miyaki et al. (2005) describes decrements in results for certain neurobehavioral tests in a small sample of Tokyo sarin victims 7 years after the sarin exposure. Yamasue et al. (2007) examined the brain morphology of a subset of victims of the

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³ Sarin and VX share a mechanism of action with organophosphate compounds used as insecticides: the inhibition of cholinesterases, enzymes that act to break down acetylcholine at nerve synapses. The resulting buildup of acetylcholine leads to some shared symptoms upon exposure to OP insecticides and nerve agents such as sarin and VX. As a result, the potential long-term health effects of low-dose exposure to organophosphate insecticides are of interest.

The IOM committee responsible for Gulf War and Health, Volume 2: Insecticides and Solvents (IOM, 2003) reviewed the epidemiologic literature on OP compounds, and found limited/suggestive evidence of associations between chronic exposure to OP insecticides and both non-Hodgkin’s lymphoma and adult leukemia. More recently, data from the Agricultural Health Study showed leukemia risk to be elevated in those with highest exposure to fonofos, an organothiophosphate, and identified a significant dose-response trend for lifetime exposure-days and risk of prostate cancer among pesticide applicators with a family history of prostate cancers (Mahajan et al., 2006). Prostate cancer risk was unrelated to fonofos use overall. Mills and Yang (2003) observed an association between increased prostate cancer risk and relatively high levels of several different pesticides, including the organophosphate dichlorvos. A connection between organophosphate pesticides and cancer remains uncertain, and the implications for cancer risk from sarin and VX exposure are also uncertain. As noted, the IOM Committee on Gulf War and Health: Updated Literature Review of Sarin did not believe that it was possible to extrapolate the long-term, low-level effects of OP insecticides to the case of sarin and cyclosarin (IOM, 2004). “Although the OP insecticides and the OP nerve agents are known to share a mechanism of action underlying their acute effects (inhibition of cholinesterase), the mechanism that underlies any potential low-level effects of OP insecticides is less established” (IOM, 2004, p. 97).

1995 subway attack who had been treated in the emergency room for sarin intoxication. Compared to controls, the subjects with sarin exposure had smaller than normal volumes in certain brain regions, correlating with decreased serum cholinesterase levels and the severity of chronic somatic complaints. A report by Yanagisawa et al. (2006) noted the continuation of psychological symptoms after 5 years in some victims of the Matsumoto and Tokyo subway terrorist events.

Experimental studies in animals of long-term effects from sarin exposures have suggested the potential for alterations in muscarinic receptors, suggestive of a potential mechanism through which sarin could cause long-term effects on the nervous system (Henderson et al., 2002; IOM, 2004). Some other changes have been observed in brain histopathology and electroencephalogram (EEG) patterns that persisted for months or up to 1 year. However, these changes did not appear to be associated with behavioral changes or clinically relevant results (IOM, 2004), and it is not clear how to interpret these findings for humans. Experimental studies in animals have not provided evidence of reproductive or developmental toxicity, or of carcinogenicity (CRI, 2004j; IOM, 2004; Munro et al., 1994).

Based on the evidence available regarding potential long-term health effects associated with exposure to sarin, the committee tested the hypotheses that participation in SHAD tests that used sarin may be associated with increased risk for the following conditions:

• Neurological effects
• Psychological symptoms

Serratia marcescens (S. marcescens or SM) [biological simulant]

S. marcescens is a rod-shaped, Gram-negative bacterium found frequently in soil, water, sewage, foods, and various animals. It is a saprophyte, obtaining nutrients from dead organic material, and is commonly found growing in damp spaces such as bathrooms, where its growth can manifest as a pinkish film. S. marcescens was used in Project SHAD to measure the degradation of an aerosolized bacterium as a result of sun exposure in a marine environment. At the time of the SHAD tests it was seen as harmless, but its potential to cause opportunistic infections has since been recognized.

As reviewed by CRI (2004d) for the SHAD I report, S. marcescens infection is seen most often as an opportunistic infection in health care settings. It is frequently associated with use of invasive devices or procedures or found in persons with compromised or suppressed immune systems. The infection can result in a variety of health effects involving nearly every physiological system (reviewed in Mahlen, 2011). These effects can include septicemia, urinary tract infections, endocarditis, otitis media, and soft-tissue or skin infections such as necrotizing fasciitis. S. marcescens can survive on soft contact lenses and can cause conjunctivitis and infective keratitis. S. marcescens strains are frequently resistant to antibiotics. The infections can be lethal.

The new literature search primarily identified reports of cases of S. marcescens infection in patients, often with compromised immunity. The conditions reported include skin and other abscesses (Baggish and Nadiminti, 2007; Friedman et al., 2003; Friend et al., 2009; Langrock et al., 2008; Soria et al., 2008; Yoshida et al., 2009), necrotizing fasciitis (Bachmeyer et al., 2004; Liangpunsakul and Pursell, 2001; Wen, 2012), endocarditis (Dokic et al., 2004), granuloma (Yoshihiro et al., 2010), eye infections (Hume and Willcox, 2004; Mah-Sadorra et al., 2005), and

central nervous system infections (Huang et al., 2001). The committee did not identify additional evidence of long-term health effects from S. marcescens infection that are not connected with an acute or recurring infection.

Studies of S. marcescens provided no evidence for identifying specific long-term health effects that might be associated with exposure during the SHAD testing.

Staphylococcal enterotoxin type B (SEB) [active biological agent]

SEB is produced by the infectious pathogen Staphylococcus aureus. Because of this toxin’s ability to cause acute incapacitating illness, it was part of the U.S. biological weapons stockpile. According to DoD (2002), it was used in Project SHAD in the test Speckled Start.

As noted in the literature review for the first SHAD report (CRI, 2004e; IOM, 2007b), SEB can cause adverse health effects through oral, inhalation, and dermal routes of exposure. Oral exposure to SEB can result in symptoms of nausea, vomiting, cramping abdominal pain, and diarrhea. Fever, tachycardia, hypotension, and diffuse abdominal pain are among other possible symptoms. Symptoms from oral exposure typically appear within 1 to 6 hours and resolve within as little as 24 hours. Exposure through inhalation also usually results in symptoms within a few hours, but they last 1 to 2 weeks. High fever is typically followed by myalgia, headache, chills, chest pain, rales, dyspnea, and a nonproductive cough. Nausea and vomiting may also occur. Death is uncommon, although severe and even fatal septic shock is possible as a result of exposure to large doses (CRI, 2004e).

Seemingly independent of its acute effects, SEB acts as a “superantigen” (Fraser, 2011). At minutely low (picomolar) concentrations it strongly activates the immune system (both T-lymphocytes and antigen-presenting cells). SEB exposure can also induce unresponsiveness in memory T-cells and programmed death in cells that initially proliferate. This may be a mechanism through which S. aureus evades the immune system (CRI, 2004e).

Long-term effects of SEB exposure may include the start or exacerbation of allergic diseases such as atopic dermatitis, psoriasis vulgaris, vernal keratoconjunctivitis, and atopic keratoconjunctivitis. It has also been associated with the induction of autoimmune diseases such as Graves’ disease, rheumatoid arthritis, and multiple sclerosis (CRI, 2004e).

Since the review by CRI, several publications have reiterated or further explored the risk for allergic disease as a potential long-term effect from SEB exposure. For example, J. H. Lee et al. (2005) demonstrated an association between sensitization to Staphylococcal enterotoxin type A (SEA) and SEB and an increased risk for allergic airway disease such as bronchial asthma. Findings of Liu et al. (2006a,b) supported the potential relationship of SEB with TH2 immune responses in sinusitis and with food allergy. Rajagopalan et al. (2006a,b) demonstrated in mice that intranasal and conjunctival exposure to SEB can cause systemic immune activation. A report based on occupational exposures at the U.S. Army Medical Research Institute of Infectious Diseases notes three cases in which ocular exposures to SEB resulted in conjunctivitis and localized swelling (Rusnak et al., 2004). Tomi et al. (2005) found that the severity of atopic dermatitis and psoriasis correlated with enterotoxin production by S. aureus strains isolated from the skin of patients.

Based on the evidence available regarding potential long-term health effects associated with exposure to SEB, the committee identified as possible hypotheses that participation in SHAD tests that used SEB may be associated with increased risk for the following conditions that may reflect heightened allergic responses:

• Asthma
• Rheumatoid arthritis
• Graves’ disease
• Multiple sclerosis

However, the committee was not able to test this hypothesis because the study population included too few individuals from the test in which SEB was used.

Sulfur dioxide (SO₂) [chemical simulant]

SO₂ is a colorless gas with a pungent odor. It has many industrial uses and is a component of air pollution. It is also used as a biocide and preservative in the agriculture and food industries (IARC, 1992). It was used as a simulant for the nerve gas sarin in Project SHAD.

Typical exposure to SO₂ is through inhalation. At levels higher than the odor threshold, exposure can lead to short-term responses of lung irritation, bronchoconstriction, asthma-like symptoms, and respiratory distress. At sufficiently high levels, exposure can lead to permanent impairment of lung function in the form of reactive airways dysfunction syndrome (RADS), chronic obstructive pulmonary disease (COPD), or enhanced sensitivity in asthmatics (CRI, 2004k). SO₂ has also been linked to damage to developing fetuses and the reproductive system, and, with long-term exposure, to low birth weights and in adults to cerebrovascular and heart disease, pulmonary disorders, and increased morbidity and mortality (CRI, 2004k).

Research in cell systems and animals has indicated that SO₂ exposure can decrease levels of antioxidant enzymes, cause chromosome breakage, and be mutagenic or comutagenic (CRI, 2004k). The most recent assessment of sulfur dioxide by IARC (1992) found inadequate evidence to determine its carcinogenicity in humans and limited evidence for its carcinogenicity in animals.

The literature search seeking new reports since the 2004 CRI review found continued active research into the health effects of exposure to SO₂. Many studies have been done in cell systems or animals. Studies in cultured human bronchial epithelial cells (Li and Meng, 2007, Li et al., 2007a) and male Wistar rats (Li et al., 2007b, 2008) suggest that SO₂ increases the expression of certain genes related to asthma, which might be a mechanism through which SO₂ aggravates asthma. A series of studies in mice by the same group indicates that SO₂ can enter lungs and other organs, such as the heart (Meng et al., 2005), and cause oxidative damage (Meng et al., 2003) and damage to DNA (Meng et al., 2004, 2005). These researchers also found SO₂ inhalation to lead to chromosomal aberrations in bone marrow cells (Meng and Zhang, 2002). In contrast, the results of a study by Ziemann et al. (2009) indicated an absence of mutagenicity in a bone marrow micronucleus test with NMRI mice. Studies in rats by Sang et al. (2009, 2010, 2011) have explored the potential mechanisms of neurotoxicity of SO₂, finding a likely role for free radicals generated by SO₂ metabolism. Zhang et al. (2006a,b) found indications of oxidative stress in the testes of adult male rats exposed to 15 parts per million of SO₂ in air for 4 hours per day.

Studies of health effects in humans from exposures to SO₂ include observing an increase in the incidence of asthma in workers who experienced repeated peak exposures to SO₂ during work at sulfite pulp mills (Andersson et al., 2006). In addition, higher estimated mean exposure to outdoor SO₂ was associated with greater lifetime prevalence of asthma diagnosed by a doctor

in a study of Czech and Polish school children (Pikhart et al., 2001). A small study of exposure to SO₂ over a season of apricot sulfurization indicated a lack of a chronic effect on the workers (Ermis et al., 2010). In a large study of workers in the pulp and paper industry, exposure to SO₂ was associated with increased lung cancer mortality risk compared with unexposed workers; however, the duration of exposure and time since first exposure were not associated with mortality (W. J. Lee et al., 2002). A literature review evaluating evidence of reproductive and developmental effects (Kaufman et al., 2011) found associations with increased incidence of preterm birth, low birth weight, and other measures of reduced fetal growth when evaluating results from more than 50 studies in humans and 14 in animals. The State of California has listed SO₂ among chemicals known to cause reproductive toxicity because of its developmental toxicity (OEHHA, 2011).

Studies of SO₂ provided no evidence for identifying specific long-term effects that might be associated with exposure during SHAD testing.

Trioctyl Phosphate (TOF or TEHP) [chemical simulant]

TOF is also known as Tris(2-ethylhexyl) phosphate, or TEHP. It is used as a solvent and as a fire retardant or plasticizer for polyvinyl chloride. Exposure to the general population occurs principally via food and drinking water. TOF was used in Project SHAD as a simulant for the chemical warfare nerve agent VX.

Short-term health effects from exposure to TOF appear to be limited. In animals it induces mild temporary irritation of the skin, eye, and respiratory system. A skin test on a small number of human volunteers resulted in redness but no signs of significant skin irritation (WHO, 2000, citing Kimmerle, 1958).

Longer-term studies in animals show a mild chronic inflammation in dogs’ lungs after 3 months of regular exposures averaging 85 mg/m³ (WHO, 2000, citing MacFarland and Punte, 1966). This effect was not seen in rhesus monkeys, and no other toxic effect was seen in the testing. Neurotoxicity and cytotoxicity studies have been negative. TEHP did not inhibit cholinesterase. It had a dose-related effect on the trained behavior of dogs but not monkeys (WHO, 2000, citing MacFarland and Punte, 1966). There is no evidence of genotoxicity from tests for sister-chromatid exchanges or chromosomal aberrations, and mutagenicity tests have been negative (CRI, 2004l).

NTP studies carried out in 1984 produced several negative results in tests of carcinogenicity in rats and mice, with the exception of positive findings for liver adenoma and carcinoma in female B6C3F1 mice and phaeochromocytomas in male rats (NTP, 1984). There was a dose-related increase in follicular cell hyperplasia of the thyroid in mice, but no dose-related increase in thyroid tumors (HSDB, 2003b). These findings have not been considered sufficient evidence for concluding that exposure is associated with a significant risk of human carcinogenicity. No studies on potential reproductive effects have been identified.

The search for newer literature on TOF/TEHP identified few studies published since the CRI review (2004l), and the articles that were identified did not provide new information concerning potential long-term health effects from exposure to the compound.

Studies of TEHP provided no evidence for identifying specific long-term health effects that might be associated with exposure during SHAD testing.

Uranine [tracer]

Uranine, also known as sodium flourescein, is a dye that is used as a fluorescent tracer in medical and environmental studies. For example, it is regularly used in ophthalmologic procedures to evaluate blood flow. It was used in the SHAD test designated Speckled Start.

The new literature search primarily identified reports related to medical uses of uranine as a tracer or contrast agent. Intravenous administration of uranine is in rare instances associated with anaphylactic shock (e.g., Bearelly et al., 2009) and more commonly with nausea (L. R. Lee et al., 2001). It is also being used in confocal laser endomicroscopy (CLE) of the GI tract. No serious adverse effects were observed in a multicenter study of CLE that included 2,252 patients (Wallace et al., 2010). Localized dermal application of uranine does not appear to be associated with health effects (O’Goshi and Serup, 2006). Only one study (in rats) was identified that was relevant to exposure through inhalation (Sakagami et al., 2003), which is the most likely manner in which the SHAD veterans who participated in the Speckled Start test may have been exposed. In rats that received nose-only inhalation exposures to uranine, absorption occurred in the nasal passages, the lungs, and the GI tract. Of the total absorption, 63.3 percent occurred in the GI tract, 24.2 percent in the nasal passages, and 12.5 percent in the lungs (Sakagami et al., 2003). Another study evaluated oral administration of sodium fluorescein for use in staining part of the eye (the clear vitreous) prior to vitrectomy. No short-term effects were found (Yao et al., 2007).

Studies of uranine provided no evidence for identifying specific long-term health effects that might be associated with exposure during SHAD testing.

VX [active chemical nerve agent]

VX is a chemical warfare agent that is an oily viscous liquid. It is an organophosphate compound⁴ with a chemical formula of C₁₁H₂₆NO₂PS. It exists in several isomers, with CAS registry numbers of 50782-69-9, 51848-47-6, 53800-40-1, and 70938-84-0. Two tests involving releases of VX were reported as part of Project SHAD, one of which involved release over an unmanned barge.

VX is a very potent inhibitor of AChEs, resulting in stimulation of nicotinic, muscarinic, and central nervous system receptors as a result of the buildup of acetylcholine in the synapses of central and peripheral nerves. Acute effects from overstimulation of nicotinic receptors include fatigue, muscle twitching, cramps, and muscle paralysis, including muscles of the respiratory system. Muscarinic effects include miosis, headaches, blurred vision, rhinorrhea, bradycardia, anorexia, nausea, vomiting, diarrhea, sweating, and lacrimation. Acute central nervous system effects are cyanosis, hypotension, generalized weakness, convulsions, loss of consciousness, coma, and death.

The symptoms, severity, and course of toxicity from VX exposure vary by dose and exposure route. When sublethal doses are applied to the skin, hours may elapse before the onset of symptoms. The response to dermal exposure to a small drop of VX may start with localized sweating and muscle twitching, followed by nausea, vomiting, diarrhea, and generalized weakness, typically lasting for several hours. When higher doses of VX are applied to the skin, no symptoms may appear for up to 30 minutes, followed by rapid loss of consciousness, difficulty breathing, convulsions, secretions from nose and mouth, muscle twitching, paralysis,

______________

⁴ See footnote 3 regarding information related to organophosphate pesticides.

and death. Via dermal exposure, VX is considered at least 100 times more toxic than sarin (CRI, 2004m).

Effects from inhalation of VX typically occur within minutes. Symptoms resulting from exposure to low to moderate concentrations include miosis, rhinorrhea, and airway constriction. Relatively short-lived neuropsychiatric effects, such as loss of memory and depression, are also seen following inhalation of VX. In the absence of medical treatment, larger doses result in loss of consciousness, seizures, cessation of cardiac and respiratory activity, and death. Via inhalation, VX is considered twice as lethal as sarin (CRI, 2004m).

Little is known about the long-term toxicity of VX and other nerve agents. Textbooks indicate that effects dissipate within months after exposure, and “VX exposure has not been shown to have delayed or persistent psychological effects or result in any long-term EEG changes” (CRI, 2004m, p. 4). A telephone survey of volunteers who had participated in military testing of chemical agents found greater sleep disturbances reported by those who had been exposed to nerve agents, and fewer attention problems (Page, 2003). Unlike many other organophosphates, VX has not been shown to induce a syndrome called organophosphorus-induced delayed neuropathy (OPIDN). It has also tested negative in assays for mutagenicity and teratogenicity. It is not considered to be a carcinogen (CRI, 2004m).

The literature search update identified many studies related to VX published since the review carried out for the first SHAD study (CRI, 2004). Most of these newer reports focused on refining understanding of animal models and methods for conducting animal tests (e.g., Aurbeck et al., 2006; Nambiar et al., 2006; Rocksen et al., 2008; Wetherell et al., 2008). Some reports were based on testing done in cell culture systems (e.g., Tenn et al., 2012; Thiermann et al., 2010). Among the reports relevant to potentially lasting effects from sub-lethal exposures to VX was evidence from a study in which rats received months of exposure to low doses of VX through osmotic pumps. Changes in the Open Field test⁵ and expression of a certain membrane protein in hippocampal neurons that were evident immediately following termination of exposure had returned to normal after one month (Bloch-Shilderman et al., 2008). Another evaluation of behavioral and biochemical effects in rats of sub-lethal inhalation exposure to VX found only minor performance effects despite substantial biochemical effects (Genovese et al., 2007). A similar experiment with African green monkeys also found that at doses producing substantial inhibition of AChE but no clinical signs, behavioral performance up to 12 weeks after exposure was unaffected (Genovese et al., 2011). In guinea pigs exposed by inhalation to sublethal concentrations of VX, changes in respiratory dynamics returned to normal levels by one month following termination of exposure (Rezk et al., 2007).

Studies of VX provided no evidence for identifying specific long-term health effects that might be associated with exposure during SHAD testing.

Zinc Cadmium Sulfide (ZnCdS) [tracer]

ZnCdS is a compound formed by sintering (combining with heat) zinc sulfide (ZnS) and cadmium sulfide (CdS). It is stable and brightly fluorescent, and it is used in pigments and as a visualization agent. It was used as a tracer for chemical and biological warfare agents in Project SHAD testing.

______________

⁵ The Open Field Test is an experiment used as a measure of a rodent’s movement and willingness to explore, sometimes considered a measure of anxiety (Prut and Belzung, 2003).

ZnCdS was also used as a simulant for biological warfare agents in releases over cities in the United States and the United Kingdom in the 1950s and 1960s. Public concern regarding possible health effects from this testing led to an evaluation by a committee of the National Research Council (NRC, 1997). Although limited information was available on the potential toxicity of ZnCdS, the available data suggested minimal toxicity because the substance is insoluble and unlikely to become bioavailable.

However, the NRC committee carried out a risk assessment using the “worst case” assumption that the ZnCdS broke down into its original components of ZnS and CdS. Under that scenario, CdS is the component of concern because cadmium compounds have been shown to be carcinogenic in humans, with clearest evidence for lung cancer and suggestive evidence for prostate cancer (IARC, 2011). Long-term exposure to cadmium is also harmful to kidney tubules and results in kidney dysfunction. The NRC (1997) risk assessment found that the amount of cadmium to which people might have been exposed in the releases over urban areas was too low to pose a significant health risk. An independent expert assessment carried out on behalf of the United Kingdom came to similar conclusions, noting that “the maximum possible inhaled dose as a result of the Ministry of Defense trials was small relative to background concentrations of inhaled cadmium” (Academy of Medical Sciences, 1999; Elliot et al., 2002, p. 16).

In response to an NRC recommendation for additional research, the Army conducted a study to determine the bioavailability and pulmonary toxicity of ZnCdS in animals (Bergmann et al., 2000). The study found that ZnCdS instilled intratracheally into male Fischer rats at levels 500 to 30,000 times the doses estimated to have been received by residents in the test cities produced insterstitial inflammation and accumulation of foreign material in the lungs and mediastinal lymph nodes. Accumulations of zinc and cadmium in the lungs successively declined at 7 days and 14 weeks after dosing, with indications that the ZnCdS was being cleared from the lungs, mostly within 24 hours of dosing, and was not breaking into elemental components. Small amounts of zinc and cadmium were found in the kidney.

Only one publication that examined potential long-term health effects from ZnCdS exposure was identified as having appeared since the CRI (2004n) review. As one of two case studies used to demonstrate a tool for spatial epidemiological analysis integrating health and environmental data, researchers analyzed the geographic variation in risk of esophageal cancer in relation to ZnCdS exposure in Norwich, United Kingdom (Beale et al., 2010). The standardized risks of esophageal cancer in the county in question were lower than those of England and Wales as a whole, and geographic patterns of rates differed in males and females, suggesting no common geographically determined exposure was likely.

Based on the evidence available regarding potential long-term health effects associated with exposure to ZnCdS, the committee tested the hypotheses that participation in SHAD tests that used this compound may be associated with increased risk for the following conditions:

• Lung cancer
• Kidney disease

REFERENCES

Academy of Medical Sciences. 1999. Zinc cadmium sulphide dispersion trials. London, UK: The Academy of Medical Sciences.

Alshukairi, A. N., M. G. Morshed, and N. E. Reiner. 2006. Q fever presenting as recurrent, culture-negative endocarditis with aortic prosthetic valve failure: A case report and review of the literature. The Canadian Journal of Infectious Diseases & Medical Microbiology 17(6):341-344.

Andersson, E., A. Knutsson, S. Hagberg, T. Nilsson, B. Karlsson, L. Alfredsson, and K. Toren. 2006. Incidence of asthma among workers exposed to sulphur dioxide and other irritant gases. European Respiratory Journal 27(4):720-725.

Angelakis, E., and D. Raoult. 2010. Q fever. Veterinary Microbiology 140(3-4):297-309.

ATSDR (Agency for Toxic Substances and Disease Registry). 2008. Toxicological profile for phenol. Atlanta, GA: Agency for Toxic Substances and Disease Registry, Public Health Service, U.S. Department of Health and Human Services.

ATSDR. 2011. Calcium hypochlorite/sodium hypochlorite. http://www.atsdr.cdc.gov/substances/toxsubstance.asp?toxid=192 (accessed December 7, 2015).

Aurbek, N., H. Thiermann, L. Szinicz, P. Eyer, and F. Worek. 2006. Analysis of inhibition, reactivation and aging kinetics of highly toxic organophosphorus compounds with human and pig acetylcholinesterase. Toxicology 224(1-2):91-99.

Bacci, S., S. Villumsen, P. Valentiner-Branth, B. Smith, K. A. Krogfelt, and K. Molbak. 2012. Epidemiology and clinical features of human infection with Coxiella burnetii in Denmark during 2006-07. Zoonoses and Public Health 59(1):61-68.

Bachmeyer, C., M. Sanguina, Y. Turc, G. Reynaert, and L. Blum. 2004. Necrotizing fasciitis due to Serratia marcescens. Clinical and Experimental Dermatology 29(6):673-674.

Baggish, A. L., and H. Nadiminti. 2007. Intracranial abscess from embolic Serratia marcescens endocarditis. Lancet Infectious Diseases 7(9):630.

Beale, L., S. Hodgson, J. J. Abellan, S. Lefevre, and L. Jarup. 2010. Evaluation of spatial relationships between health and the environment: The rapid inquiry facility. Environmental Health Perspectives 118(9):1306-1312.

Bearelly, S., S. Rao, and S. Fekrat. 2009. Anaphylaxis following intravenous fluorescein angiography in a vitreoretinal clinic: Report of 4 cases. Canadian Journal of Ophthalmology 44(4):444-445.

Berger, J., M. Diab-Elschahawi, A. Blacky, E. Pernicka, V. Spertini, O. Assadian, W. Koller, and K. J. Aichberger. 2010. A matched prospective cohort study on Staphylococcus aureus and Escherichia coli bloodstream infections: Extended perspectives beyond resistance. American Journal of Infection Control 38(10):839-845.

Bergmann, J. D., L. W. Metker, W. C. McCain, P. A. Beall, M. W. Michie, and R. B. Lee. 2000. Intratracheal instillation of zinc-cadmium sulfide (ZnCdS) in Fischer 344 rats. Inhalation Toxicology 12(4):331-346.

Bloch-Shilderman, E., I. Rabinovitz, I. Egoz, L. Raveh, N. Allon, E. Grauer, E. Gilat, and B. A. Weissman. 2008. Subchronic exposure to low-doses of the nerve agent VX: Physiological, behavioral, histopathological and neurochemical studies. Toxicology and Applied Pharmacology 231(1):17-23.

Bruce, W., M. E. Meek, and R. Newhook. 2001. Phenol: Hazard characterization and exposure-response analysis. Journal of Environmental Science and Health, Part C: Environmental Carcinogenesis and Ecotoxicology Reviews 19(1):305-324.

CCRIS (Chemical Carcinogenesis Research Information System). 2010. Methyl acetoacetate. http://toxnet.nlm.nih.gov/newtoxnet/ccris.htm (accessed December 7, 2015).

CDC (Centers for Disease Control and Prevention). 2011. Q fever. http://www.cdc.gov/qfever (accessed December 7, 2015).

CDC. 2012. Statistics and epidemiology: Annual cases of Q fever in the United States. http://www.cdc.gov/qfever/stats/index.html (accessed December 7, 2015).

CIDRAP (Center for Infectious Disease Research and Policy). 2010. Tularemia. http://www.cidrap.umn.edu/cidrap/content/bt/tularemia/biofacts/tularemiafactsheet.html#_Overview_1+CIDRAP (accessed December 7, 2015).

Clark Burton, N., A. Adhikari, S. A. Grinshpun, R. Hornung, and T. Reponen. 2005. The effect of filter material on bioaerosol collection of Bacillus subtilis spores used as a Bacillus anthracis simulant. Journal of Environmental Monitoring 7(5):475-480.

CRI (Center for Research Information). 2004a. Health effects of Project SHAD biological agent: Bacillus globigii. Silver Spring, MD: Center for Research Information, Inc.

CRI. 2004b. Health effects of Project SHAD biological agent: Coxiella burnetii. Silver Spring, MD: Center for Research Information, Inc.

CRI. 2004c. Health effects of Project SHAD biological agent: Pasteurella [Francisella] tularensis. Silver Spring, MD: Center for Research Information, Inc.

CRI. 2004d. Health effects of Project SHAD biological agent: Serratia marcescens. Silver Spring, MD: Center for Research Information, Inc.

CRI. 2004e. Health effects of Project SHAD biological agent: Staphylococal enterotoxin type B. Silver Spring, MD: Center for Research Information, Inc.

CRI. 2004f. Health effects of Project SHAD chemical agent: Betapropiolactone. Silver Spring, MD: Center for Research Information, Inc.

CRI. 2004g. Health effects of Project SHAD chemical agent: Calcofluor. Silver Spring, MD: Center for Research Information, Inc.

CRI. 2004h. Health effects of Project SHAD chemical agent: Diethylphthalate. Silver Spring, MD: Center for Research Information, Inc.

CRI. 2004i. Health effects of Project SHAD chemical agent: Methyl acetoacetate. Silver Spring, MD: Center for Research Information, Inc.

CRI. 2004j. Health effects of Project SHAD chemical agent: Sarin nerve agent. Silver Spring, MD: Center for Research Information, Inc.

CRI. 2004k. Health effects of Project SHAD chemical agent: Sulfur dioxide. Silver Spring, MD: Center for Research Information, Inc.

CRI. 2004l. Health effects of Project SHAD chemical agent: Trioctyl phosphate. Silver Spring, MD: Center for Research Information, Inc.

CRI. 2004m. Health effects of Project SHAD chemical agent: VX nerve agent. Silver Spring, MD: Center for Research Information, Inc.

CRI. 2004n. Health effects of Project SHAD chemical agent: Zinc cadmium sulfide. Silver Spring, MD: Center for Research Information, Inc.

Cullu, E., I. Ozkan, N. Culhaci, and B. Alparslan. 2005. A comparison of the effect of doxorubicin and phenol on the skeletal muscle. May doxorubicin be a new alternative treatment agent for spasticity? Journal of Pediatric Orthopaedics, Part B 14(2):134-138.

Dennis, D. T., T. V. Inglesby, D. A. Henderson, J. G. Bartlett, M. S. Ascher, E. Eitzen, A. D. Fine, A. M. Friedlander, J. Hauer, M. Layton, S. R. Lillibridge, J. E. McDade, M. T. Osterholm, T. O’Toole, G. Parker, T. M. Perl, P. K. Russell, and K. Tonat. 2001. Tularemia as a biological weapon–Medical and public health management. Journal of the American Medical Association 285(21):2763-2773.

DoD (Department of Defense). 2002. Fact sheet: DTC test 68-50. http://www.health.mil/ReferenceCenter/Fact-Sheets/2002/05/23/DTC-Test-6850 (accessed December 7, 2015).

Dokic, M., M. Milanovic, V. Begovic, A. Ristic-Andelkov, and B. Tomanovic. 2004. Infective endocarditis of a rare etiology (Serratia marcescens). [Croatian]. Vojnosanitetski Pregled. Military-Medical and Pharmaceutical Review 61(6):689-694.

DTC (Deseret Test Center). 1968. DTC test 66-13 (Half Note). Fort Douglas, UT: Deseret Test Center.

Duncan, E. J. S., B. Kournikakis, J. Ho, and I. Hill. 2009. Pulmonary deposition of aerosolized Bacillus atrophaeus in a Swine model due to exposure from a simulated anthrax letter incident. Inhalation Toxicology 21(2):141-152.

Elliott, P. J., C. J. C. Phillips, B. Clayton, and P. J. Lachmann. 2002. The risk to the United Kingdom population of zinc cadmium sulfide dispersion by the Ministry of Defence during the “cold war.” Occupational and Environmental Medicine 59(1):13-17.

Ermis, H., M. Gokirmak, Z. Yildirim, S. Yologlu, and H. Ankarali. 2010. Exposure to SO2 does not have a chronic effect on pulmonary functions of apricot workers. Inhalation Toxicology 22(3):219-223.

EurActiv. 2004. EU ministers agree to ban chemicals in toys. http://www.euractiv.com/health/eu-ministers-agree-ban-chemicals-news-212475 (accessed December 7, 2015).

Fraser, J. D. 2011. Clarifying the mechanism of superantigen toxicity. PLoS Biology 9(9):e1001145. doi:10.1371/journal.pbio.1001145.

Friedman, N. D., N. B. Peterson, W. T. Sumner, and B. D. Alexander. 2003. Spontaneous dermal abscesses and ulcers as a result of Serratia marcescens. Journal of the American Academy of Dermatology 49(2 Suppl Case Reports):S193-S194.

Friend, J. C., D. M. Hilligoss, M. Marquesen, J. Ulrick, T. Estwick, M. L. Turner, E. W. Cowen, V. Anderson, S. M. Holland, and H. L. Malech. 2009. Skin ulcers and disseminated abscesses are characteristic of Serratia marcescens infection in older patients with chronic granulomatous disease. Journal of Allergy and Clinical Immunology 124(1):164-166.

Geier, D. A., S. K. Jordan, and M. R. Geier. 2010. The relative toxicity of compounds used as preservatives in vaccines and biologics. Medical Science Monitor 16(5):SR21-SR27.

Genovese, R. F., B. J. Benton, E. H. Lee, S. J. Shippee, and E. M. Jakubowski. 2007. Behavioral and biochemical evaluation of sub-lethal inhalation exposure to VX in rats. Toxicology 232(1-2):109-118.

Genovese, R. F., B. J. Benton, J. L. Oubre, C. E. Byers, E. M. Jakubowski, R. J. Mioduszewski, T. J. Settle, and T. J. Steinbach. 2011. Determination of threshold adverse effect doses of percutaneous VX exposure in African green monkeys. Toxicology 279(1-3):65-72.

Goktepe, S., M. Kilic, S. Gunduz, R. Alaca, and T. A. Kalyon. 2002. The effect of botulinum toxin and phenol injections on lower extremity spasticity in spinal cord injury. Journal of Rheumatology and Medical Rehabilitation 13(2):113-117.

Gray, L. E., Jr., J. Ostby, J. Furr, M. Price, D. N. Veeramachaneni, and L. Parks. 2000. Perinatal exposure to the phthalates DEHP, BBP, and DINP, but not DEP, DMP, or DOTP, alters sexual differentiation of the male rat. Toxicological Sciences 58(2):350-365.

Hartzell, J. D., R. N. Wood-Morris, L. J. Martinez, and R. F. Trottta. 2008. Q fever: Epidemiology, diagnosis, and treatment. Mayo Clinic Proceedings 83(5):574-579.

Healy, B., H. van Woerden, D. Raoult, S. Graves, J. Pitman, G. Lloyd, N. Brown, and M. Llewelyn. 2011. Chronic Q fever: Different serological results in three countries—Results of a follow-up study 6 years after a point source outbreak. Clinical Infectious Diseases 52(8):1013-1019.

Henderson, R. F., E. B. Barr, W. B. Blackwell, C. R. Clark, C. A. Conn, R. Kalra, T. H. March, M. L. Sopori, Y. Tesfaigzi, M. G. Menache, and D. C. Mash. 2002. Response of rats to low levels of sarin. Toxicology and Applied Pharmacology 184(2):67-76.

HSDB (Hazardous Substances Data Bank). 2003a. Phenol. http://toxnet.nlm.nih.gov/cgibin/sis/search2/f?./temp/~sB4HnY:1 (accessed December 7, 2015).

HSDB. 2003b. Trioctyl phosphate. http://toxnet.nlm.nih.gov/cgi-bin/sis/search2/f?./temp/~3CRU19:1 (accessed December 7, 2015).

HSDB. 2005. Methyl acetoacetate. http://toxnet.nlm.nih.gov/cgi-bin/sis/search2/f?./temp/~atmJKb:1 (accessed December 7, 2015).

Huang, C. R., C. H. Lu, C. C. Chien, and W. N. Chang. 2001. Protean infectious types and frequent association with neurosurgical procedures in adult Serratia marcescens CNS infections: Report of two cases and review of the literature. Clinical Neurology and Neurosurgery 103(3):171-174.

Hume, E. B. H., and M. D. P. Willcox. 2004. Emergence of Serratia marcescens as an ocular surface pathogen. Archivos de la Sociedad Espanola de Oftalmologia 79(10):475-477.

IARC (International Agency for Research on Cancer). 1992. Occupational exposures to mists and vapours from strong inorganic acids; and other industrial chemicals. IARC Monographs Vol. 54. Lyon, France: World Health Organization. Pp. 131-188.

IARC. 1997. Chlorinated drinking-water; chlorination by-products; some other halogenated compounds; cobalt and cobalt compounds. IARC Monographs Vol. 52. Lyon, France: World Health Organization. Pp. 7-10.

IARC. 1999a. Re-evaluation of some organic chemicals, hydrazine and hydrogen peroxide: βpropiolactone. IARC Monographs Vol. 71. Lyon, France: World Health Organization. Pp. 1103-1119.

IARC. 1999b. Re-evaluation of some organic chemicals, hydrazine and hydrogen peroxide: Phenol. IARC Monographs Vol. 71. Lyon, France: World Health Organization. Pp. 749-768.

IARC. 2011. Cadmium and cadmium compounds. IARC Monographs Vol. 100C. Lyon, France: World Health Organization. Pp. 121-145.

Iglesias, M. E. L., J. V. De Cabo, J. T. Traspaderne, J. A. Franco, M. B. Alonso, and R. B. De Bengoa Vallejo. 2008. Safety of phenol vapor inhalation during performance of chemical matrixectomy to treat ingrown toenails. Dermatologic Surgery 34(11):1515-1519.

IOM (Institute of Medicine). 2000. Gulf war and health, volume one: Depleted uranium, sarin, pyridostigmine bromide, and vaccines. Washington, DC: National Academy Press.

IOM. 2003. Gulf war and health, volume two: Insecticides and solvents. Washington, DC: The National Academies Press.

IOM. 2004. Gulf war and health: Updated literature review of sarin. Washington, DC: The National Academies Press.

IOM. 2007a. Gulf War and health, volume five: Infectious diseases. Washington, DC: The National Academies Press.

IOM. 2007b. Long-term health effects of participation in Project SHAD (Shipboard Hazard and Defense). Washington, DC: The National Academies Press.

Jarrett, L., P. Nandi, and A. J. Thompson. 2002. Managing severe lower limb spasticity in multiple sclerosis: Does intrathecal phenol have a role? Journal of Neurology, Neurosurgery and Psychiatry 73(6):705-709.

Kaminaka, C., Y. Yamamoto, N. Yonei, and F. Furukawa. 2009a. Phenol application to angiosarcomas: Implications and histologic studies. International Journal of Dermatology 48(5):470-475.

Kaminaka, C., Y. Yamamoto, N. Yonei, A. Kishioka, T. Kondo, and F. Furukawa. 2009b. Phenol peels as a novel therapeutic approach for actinic keratosis and bowen disease: Prospective pilot trial with assessment of clinical, histologic, and immunohistochemical correlations. Journal of the American Academy of Dermatology 60(4):615-625.

Kampschreur, L. M., S. Dekker, J. Hagenaars, P. J. Lestrade, N. H. M. Renders, M. G. L. de Jager-Leclercq, M. H. A. Hermans, C. A. R. Groot, R. H. H. Groenwold, A. I. M. Hoepelman, P. C. Wever, and J. J. Oosterheert. 2012. Identification of risk factors for chronic Q fever, the Netherlands. Emerging Infectious Diseases 18(4):563-570.

Kaufman, F. L., A. N. Kim, M. A. Campbell, K. L. Wu, and J. M. Donald. 2011. Sulfur dioxide-evidence of reproductive and developmental toxicity. Birth Defects Research Part A—Clinical and Molecular Teratology Conference: 51st Annual Meeting of the Teratology Society—24th International Conference of the Organization of Teratology Information Specialists, OTIS and the 35th Annual Meeting of the Neurobehavioral Teratology Society, NBTS Coronado, CA. Conference Publication: (var. pagings) 91(5):378.

Kawada, T., M. Katsumata, H. Suzuki, Q. Li, H. Inagaki, A. Nakadai, T. Shimizu, K. Hirata, and Y. Hirata. 2005. Insomnia as a sequela of sarin toxicity several years after exposure in Tokyo subway trains. Perceptual and Motor Skills 100(3 Pt 2):1121-1126.

Kelly, A. R., F. W. Hartman, and C. E. Rupe. 1957. The toxicology of beta-propiolactone. In Hepatitis Frontiers, edited by F. W. Hartman, G. A. LoGrippo, J. G. Mateer, and J. Barron. Boston, MA: Little, Brown and Company. Pp. 387-406.

Kimber, I., and R. J. Dearman. 2010. An assessment of the ability of phthalates to influence immune and allergic responses. Toxicology 271 (3):73-82.

Kimmerle, G. 1958. [Softener tri-2-ethylhexylphosphate (TOF).] Unpublished report No. 1764 (in German). Leverkusen, Germany: Bayer AG, Laboratory of Toxicology and Pathology.

Kolaski, K., S. J. Ajizian, L. Passmore, N. Pasutharnchat, L. A. Koman, and B. P. Smith. 2008. Safety profile of multilevel chemical denervation procedures using phenol or botulinum toxin or both in a pediatric population. American Journal of Physical Medicine and Rehabilitation 87(7):556-566.

Kwack, S. J., K. B. Kim, H. S. Kim, and B. M. Lee. 2009. Comparative toxicological evaluation of phthalate diesters and metabolites in Sprague-Dawley male rats for risk assessment. Journal of Toxicology and Environmental Health Part A: Current Issues 72(21-22):1446-1454.

Langrock, M. L., H. J. Linde, M. Landthaler, and S. Karrer. 2008. Leg ulcers and abscesses caused by Serratia marcescens. European Journal of Dermatology 18(6):705-707.

Lee, J. H., Y. T. Lin, Y. H. Yang, L. C. Wang, and B. L. Chiang. 2005. Increased levels of serum-specific immunoglobulin e to staphylococcal enterotoxin A and B in patients with allergic rhinitis and bronchial asthma. International Archives of Allergy and Immunology 138(4):305-311.

Lee, L. R., D. P. Hainsworth, C. W. Hamm, and R. W. Madsen. 2001. Temperature effect on nausea during fluorescein angiography. Ophthalmology 108(7):1193-1195.

Lee, W. J., K. Teschke, T. Kauppinen, A. Andersen, P. Jappinen, I. Szadkowska-Stanczyk, N. Pearce, B. Persson, A. Bergeret, L. A. Facchini, R. Kishi, D. Kielkowski, B. A. Rix, P. Henneberger, J. Sunyer, D. Colin, M. Kogevinas, and P. Boffetta. 2002. Mortality from lung cancer in workers exposed to sulfur dioxide in the pulp and paper industry. Environmental Health Perspectives 110(10):991-995.

Li, R., and Z. Meng. 2007. Effects of SO₂ derivatives on expressions of MUC5AC and IL-13 in human bronchial epithelial cells. Archives of Toxicology 81(12):867-874.

Li, R., Z. Meng, and J. Xie. 2007a. Effects of sulfur dioxide derivatives on four asthma-related gene expressions in human bronchial epithelial cells. Toxicology Letters 175(1-3):71-81.

Li, R., Z. Meng, and J. Xie. 2007b. Effects of sulfur dioxide on the expressions of MUC5AC and ICAM1 in airway of asthmatic rats. Regulatory Toxicology and Pharmacology 48(3):284-291.

Li, R., Z. Meng, and J. Xie. 2008. Effects of sulfur dioxide on the expressions of EGF, EGFR, and COX-2 in airway of asthmatic rats. Archives of Environmental Contamination and Toxicology 54(4):748-757.

Liangpunsakul, S., and K. Pursell. 2001. Community-acquired necrotizing fasciitis caused by Serratia marcescens: Case report and review. European Journal of Clinical Microbiology and Infectious Diseases 20(7):509-510.

Liu, T., B. Q. Wang, and P. C. Yang. 2006a. A possible link between sinusitis and lower airway hypersensitivity: The role of staphylococcal enterotoxin B. Clinical and Molecular Allergy 4:7.

Liu, T., B.-Q. Wang, P.-Y. Zheng, S.-H. He, and P.-C. Yang. 2006b. Rhinosinusitis derived staphylococcal enterotoxin B plays a possible role in pathogenesis of food allergy. BMC Gastroenterology 6:24.

LoGrippo, G. A. 1964. A ten year clinical study of plasma treated with betaprone and combined bataprone plus ultraviolet irradiation. Pacific Medicine and Surgery 72:298-302.

MacFarland, H. N., and C. L. Punte, Jr. 1966. Toxicological studies on tri-(2-ethylhexyl)-phosphate. Archives of Environmental Health 13(1):13-20.

Mah-Sadorra, J. H., D. M. Najjar, C. J. Rapuano, P. R. Laibson, and E. J. Cohen. 2005. Serratia corneal ulcers: A retrospective clinical study. Cornea 24(7):793-800.

Mahajan, R., A. Blair, C. F. Lynch, P. Schroeder, J. A. Hoppin, D. P. Sandler, and M. C. Alavanja. 2006. Fonofos exposure and cancer incidence in the Agricultural Health Study. Environmental Health Perspectives 114(2):1838-1842.

Mahlen, S. D. 2011. Serratia infections: From military experiments to current practice. Clinical Microbiology Reviews 24(4):755-791.

Meng, Z., and B. Zhang. 2002. Induction effects of sulfur dioxide inhalation on chromosomal aberrations in mouse bone marrow cells. Mutagenesis 17(3):215-217.

Meng, Z., G. Qin, B. Zhang, H. Geng, Q. Bai, W. Bai, and C. Liu. 2003. Oxidative damage of sulfur dioxide inhalation on lungs and hearts of mice. Environmental Research 93(3):285-292.

Meng, Z., G. Qin, B. Zhang, and J. Bai. 2004. DNA damaging effects of sulfur dioxide derivatives in cells from various organs of mice. Mutagenesis 19(6):465-468.

Meng, Z., G. Qin, and B. Zhang. 2005. DNA damage in mice treated with sulfur dioxide by inhalation. Environmental and Molecular Mutagenesis 46(3):150-155.

Mills, P. K., and R. Yang. 2003. Prostate cancer risk in California farm workers. Journal of Occupational and Environmental Medicine 45(3):249-258.

Miyaki, K., Y. Nishiwaki, K. Maekawa, Y. Ogawa, N. Asukai, K. Yoshimura, N. Etoh, Y. Matsumoto, Y. Kikuchi, N. Kumagai, and K. Omae. 2005. Effects of sarin on the nervous system of subway workers seven years after the Tokyo subway sarin attack. Journal of Occupational Health 47(4):299-304.

Munro, N. B., K. R. Ambrose, and A. P. Watson. 1994. Toxicity of the organophosphate chemical warfare agents GA, GB, and VX: Implications for public protection. Environmental Health Perspectives 102:18-38.

Nambiar, M. P., B. S. Wright, P. E. Rezk, K. B. Smith, R. K. Gordon, T. S. Moran, S. M. Richards, and A. M. Sciuto. 2006. Development of a microinstillation model of inhalation exposure to assess lung injury following exposure to toxic chemicals and nerve agents in guinea pigs. Toxicology Mechanisms and Methods 16(6):295-306.

NIOSH (National Institute for Occupational Safety and Health). 2011. NIOSH skin notation (SK) profiles: Phenol. Publication No. 2011-136. Atlanta, GA: National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, U.S. Department of Health and Human Services.

NRC (National Research Council). 1997. Toxicologic assessment of the Army’s zinc cadmium sulfide dispersion tests. Washington, DC: National Academy Press.

NTP (National Toxicology Program). 1984. NTP toxicology and carcinogenesis studies of tris(2ethylhexyl)phosphate (CAS No. 78-42-2) in F344/N rats and B6C3F1 mice (gavage studies). National Toxicology Program Technical Report Series 274. Triangle Park, NC: U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program.

NTP. 2011. Report on carcinogens, Twelfth ed. Research Triangle Park, NC: U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program. Pp. 366-367.

OEHHA (California Office of Environmental Health Hazard Assessment). 2011. Sulfur dioxide listed to cause reproductive toxicity. http://oehha.ca.gov/prop65/prop65_list/072911list2.html (accessed December 7, 2015).

O’Goshi, K., and J. Serup. 2006. Safety of sodium fluorescein for in vivo study of skin. Skin Research and Technology 12(3):155-161.

Pereira, C., K. Mapuskar, and C. V. Rao. 2006. Chronic toxicity of diethyl phthalate in male Wistar rats—A dose-response study. Regulatory Toxicology and Pharmacology 45(2):169-177.

Pereira, C., K. Mapuskar, and C. V. Rao. 2007. Chronic toxicity of diethyl phthalate—A three generation lactational and gestational exposure study on male Wistar rats. Environmental Toxicology and Pharmacology 23(3):319-327.

Pikhart, H., M. Bobak, P. Gorynski, B. Wojtyniak, J. Danova, M. A. Celko, B. Kriz, D. Briggs, and P. Elliott. 2001. Outdoor sulphur dioxide and respiratory symptoms in Czech and Polish school children: A small-area study (SAVIAH). Small-area variation in air pollution and health. International Archives of Occupational and Environmental Health 74(8):574-578.

Pinder, C., B. Bhakta, and K. Kodavali. 2008. Intrathecal phenol: An old treatment revisited. Disability and Rehabilitation 30(5):381-386.

Probst, A., R. Facius, R. Wirth, and C. Moissl-Eichinger. 2010. Validation of a nylon-flocked-swab protocol for efficient recovery of bacterial spores from smooth and rough surfaces. Applied and Environmental Microbiology 76(15):5148-5158.

Prut, L., and C. Belzung. 2003. The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: A review. European Journal of Pharmacology 463(1-3):3-33.

Rajagopalan, G., M. M. Sen, M. Singh, N. S. Murali, K. A. Nath, K. Iijima, H. Kita, A. A. Leontovich, U. Gopinathan, R. Patel, and C. S. David. 2006a. Intranasal exposure to staphylococcal enterotoxin B elicits an acute systemic inflammatory response. Shock 25(6):647-656.

Rajagopalan, G., M. K. Smart, R. Patel, and C. S. David. 2006b. Acute systemic immune activation following conjunctival exposure to staphylococcal enterotoxin B. Infection and Immunity 74(10):6016-6019.

Raoult, D. , H. Tissot-Dupont, C. Foucault, J. Gouvernet, P. E. Fournier, E. Bernit, A. Stein, M. Nesri, J. R. Harle, and P. J. Weiller. 2000. Q fever 1985-1998: Clinical and epidemiologic features of 1,383 infections. Medicine 79(2):109-123.

Raoult, D., T. Marrie, and J. Mege. 2005. Natural history and pathophysiology of Q fever. The Lancet Infectious Diseases 5(4):219-226.

Rezk, P. E., J. R. Graham, T. S. Moran, R. K. Gordon, A. M. Sciuto, B. P. Doctor, and M. P. Nambiar. 2007. Acute toxic effects of nerve agent VX on respiratory dynamics and functions following microinsillation inhalation exposure in guinea pigs. Inhalation Toxicology 19(3):291-302.

Rocksen, D., D. Elfsmark, V. Heldestad, K. Wallgren, G. Cassel, and A. Goransson Nyberg. 2008. An animal model to study health effects during continuous low-dose exposure to the nerve agent VX. Toxicology 250(1):32-38.

Rusnak, J. M., M. Kortepeter, R. Ulrich, M. Poli, and E. Boudreau. 2004. Laboratory exposures to staphylococcal enterotoxin B. Emerging Infectious Diseases 10(9):1544-1549.

Sakagami, M., W. Kinoshita, and Y. Makino. 2003. Fractional contribution of lung, nasal and gastrointestinal absorption to the systemic level following nose-only aerosol exposure in rats: A case study of 3.7-micro m fluorescein aerosols. Archives of Toxicology 77(6):321-329.

Sang, N., L. Hou, Y. Yun, and G. Li. 2009. SO(2) inhalation induces protein oxidation, DNA-protein crosslinks and apoptosis in rat hippocampus. Ecotoxicology and Environmental Safety 72(3):879-884.

Sang, N., Y. Yun, H. Li, L. Hou, M. Han, and G. Li. 2010. SO₂ inhalation contributes to the development and progression of ischemic stroke in the brain. Toxicological Sciences 114(2):226-236.

Sang, N., Y. Yun, G. Y. Yao, H. Y. Li, L. Guo, and G. K. Li. 2011. SO₂-induced neurotoxicity is mediated by cyclooxygenases-2-derived prostaglandin e-2 and its downstream signaling pathway in rat hippocampal neurons. Toxicological Sciences 124(2):400-413.

Sanz-Garcia, M., A. Fernandez-Cruz, M. Rodriguez-Creixems, E. Cercenado, M. Marin, P. Munoz, and E. Bouza. 2009. Recurrent Escherichia coli bloodstream infections: Epidemiology and risk factors. Medicine 88(2):77-82.

Smith, J. L., and D. Bayles. 2007. Postinfectious irritable bowel syndrome: A long-term consequence of bacterial gastroenteritis. Journal of Food Protection 70(7):1762-1769.

Soria, X., I. Bielsa, M. Ribera, M. J. Herrero, H. Domingo, J. M. Carrascosa, and C. Ferrandiz. 2008. Acute dermal abscesses caused by Serratia marcescens. Journal of the American Academy of Dermatology 58(5):891-893.

Tenn, C. C., M. T. Weiss, C. Beaup, A. Peinnequin, Y. Wang, and F. Dorandeu. 2012. Cyclooxygenase-2 contributes to VX-induced cell death in cultured cortical neurons. Toxicology Letters 210(1):71-77.

Thiermann, H., T. Seeger, S. Gonder, N. Herkert, B. Antkowiak, T. Zilker, F. Eyer, and F. Worek. 2010. Assessment of neuromuscular dysfunction during poisoning by organophosphorus compounds. Chemico-Biological Interactions 187(1-3):265-269.

Tomi, N. S., B. Kranke, and E. Aberer. 2005. Staphylococcal toxins in patients with psoriasis, atopic dermatitis, and erythroderma, and in healthy control subjects. Journal of the American Academy of Dermatology 53(1):67-72.

van der Hoek, W., P. M. Schneeberger, T. Oomen, M. C. Wegdam-Blans, F. Dijkstra, D. W. Notermans, H. A. Bijlmer, K. Groeneveld, C. J. Wijkmans, A. Rietveld, L. M. Kampschreur, and Y. van Duynhoven. 2012. Shifting priorities in the aftermath of a Q fever epidemic in 2007 to 2009 in the Netherlands: From acute to chronic infection. Eurosurveillance 17(3):16-20

Wallace, M. B., A. Meining, M. I. Canto, P. Fockens, S. Miehlke, T. Roesch, C. J. Lightdale, H. Pohl, D. Carr-Locke, M. Lohr, E. Coron, B. Filoche, M. Giovannini, J. Moreau, C. Schmidt, and R. Kiesslich. 2010. The safety of intravenous fluorescein for confocal laser endomicroscopy in the gastrointestinal tract. Alimentary Pharmacology and Therapeutics 31(5):548-552.

Wen, Y. K. 2012. Necrotizing fasciitis caused by Serratia marcescens: A fatal complication of nephrotic syndrome. Renal Failure 34(5):649-652.

Wetherell, J. R., S. J. Armstrong, R. W. Read, and G. F. Clough. 2008. VX penetration following percutaneous poisoning: A dermal microdialysis study in the guinea pig. Toxicology Mechanisms and Methods 18(4):313-321.

WHO (World Health Organization). 2000. Environmental health criteria 218: Flame retardants: Tris(2butoxyethyl)phosphate, tris(2-ethylhexyl)phosphate and tetrakis(hydroxymethyl)phosphonium salts. Geneva, Switzerland: United Nations Environment Programme, the International Labour Organisation, and the World Health Organization.

WHO. 2003. Concise international chemical assessment document, 52: Diethyl phthalate. Geneva, Switzerland: United Nations Environment Programme, the International Labour Organization, and the World Health Organization.

Yamasue, H., O. Abe, K. Kasai, M. Suga, A. Iwanami, H. Yamada, M. Tochigi, T. Ohtani, M. A. Rogers, T. Sasaki, S. Aoki, T. Kato, and N. Kato. 2007. Human brain structural change related to acute single exposure to sarin. Annals of Neurology 61(1):37-46.

Yanagisawa, N., H. Morita, and T. Nakajima. 2006. Sarin experiences in Japan: Acute toxicity and long-term effects. Journal of the Neurological Sciences 249(1):76-85.

Yao, Y., Z.-J. Wang, S. H. Wei, Y. F. Huang, and M. N. Zhang. 2007. Oral sodium fluorescein to improve visualization of clear vitreous during vitrectomy for proliferative diabetic retinopathy. Clinical and Experimental Ophthalmology 35(9):824-827.

Yoshida, R., Y. Takae, Y. Fujio, M. Tanaka, and M. Ohyama. 2009. Cutaneous Serratia marcescens infection on the face of a healthy female. Journal of the European Academy of Dermatology and Venereology 23(10):1213-1215.

Yoshihiro, Y., Y. Soejima, K. Taniguchi, K. Makino, and S. Naito. 2010. A case of Serratia granuloma in the soft tissue around the left kidney: A role of PTHrP in the formation of Serratia granuloma. Journal of Infection and Chemotherapy 16(2):126-130.

Zhang, J., C. Liang, J. Ma, B. Zhou, and J. Wang. 2006a. Changes in testis protein and metabolic enzyme activities in rats induced by sodium fluoride and sulfur dioxide. Fluoride 39(3):179-184.

Zhang, J., C. Liang, J. Ma, B. Zhou, and J. Wang. 2006b. Effects of sodium fluoride and sulfur dioxide on oxidative stress and antioxidant defenses in rat testes. Fluoride 39(3):185-190.

Ziemann, C., T. Hansen, G. Pohlmann, D. Farrar, C. Pohlenz-Michel, and I. Mangelsdorf. 2009. Absence of genotoxicity of sulfur dioxide (SO₂) in a bone marrow micronucleus test with NMRI mice, complemented with several hematological endpoints. Toxicology Letters Conference: 46th Congress of the European Societies of Toxicology, EUROTOX 2009 Dresden Germany. Conference Publication: (var. pagings) 189:S258.