Case Study-1

Individuals working in a chemical plant in a developing country become sick after the plant begins production with a new chemical process. Symptoms of those affected include develop shortness of breath, fatigue, confusion, nausea and swelling in the ankles. Within a few days, several of the older workers exhibit more severe symptoms and are hospitalized. Clinical examination of the hospitalized indicate normal respiratory function and normal levels of aspartate transaminase, alanine transaminase and alkaline phosphatase in the blood. The blood urea nitrogen levels were elevated in all the hospitalized workers. A team of US environmental toxicology and occupational safety analysts visit the plant and eventually identify compound X (shown below) as the cause of the acute toxicology observed.

Given the information above, answer the following questions about this occupational health incident. Note: Each question can be answered with a single paragraph (~ 10 sentences max)

A. Provide a plausible mechanism for the observed toxicity of compound X. What organ(s) are affected to yield the clinical symptoms and what is the chemical doing to the organ(s) to cause the symptoms?

B. Given the structure of the compound, what are likely routes of absorption and where this chemical is likely to accumulate in the body? Justify your response based how the physiochemical properties of a xenobiotic affect absorption.

C. This compound has been profiled by the EPA in acute oral dose animal studies and dose/response curves are shown in the graph above. Estimate the LD50s for both rat and dog and provide a plausible explanation for the differences in LD50 values between the two species.

D. Use the data above to calculate the Reference Dose for compound X using the standard uncertainty factors (Show your calculation for partial credit). Explain in your own words what this reference dose means and how it can be used to assess the risk of Compound X and enable the chemical plant to modify procedures to protect workers.

Case Study -2

A Phase III clinical drug trial was conducted for an antibacterial drug used to treat a number of severe bacterial infections. In the trial, 800 patients were treated with the drug shown below. Three patients in the trial that were given the drug developed fever, a severe rash and after a few days became jaundiced and eventually developed acute liver failure. In the patients with the severe reaction, the nitroso form of the drug was present at high concentrations in the bile as a glutathione conjugate, but at much lower levels in unaffected individuals.

Answer the following questions based on the information provided above. Each question can be answered with a short paragraph (8-10 sentences max)

A. Given the structure of the compound and the data provided above, provide a plausible mechanism for why this compound exhibits liver toxicity? What type of liver injury is observed? Justify your answer. Suggest a molecular mechanism.

B. Explain why only a very small number of patients who take the drug develop hepatotoxicity. Why might this not show up in preclinical animal studies?

Although hepatotoxicity was observed in only a few participants taking the drug, ~ 5% of individuals taking the drug developed a severe skin rash.

C. Explain how the drug above might have caused the skin rash. How would you confirm your hypothesis with a simple blood test?

Case Study -3

A luxury Manhattan apartment building popular with young couples exhibits an unusual phenomena. More than 75% of the babies born to women living in the apartment are female. In addition, there are an unusually high number of women in the building developing breast cancer. An environmental and toxicology team investigated this apartment and found unusually high levels of the compound below in the drinking water of the building.

Answer the following questions based on the information provided above. Each question can be answered with a short paragraph (8-10 sentences max)

A. Propose a mechanism and biological pathway affected by this compound could increase the ratio of female/male babies?

B. Describe a validated cell-based assay you could utilize to validate your proposed mechanism. How would this assay predict the effects of the compound?

C. Identify a standard animal study you could use to further validate your proposed mechanism. Explain how this toxicity tests works and would provide further verification of your hypothesis.

D. Explain the biological mechanism by which this compound may also be carcinogenic. Describe an in vitro test you could perform that would demonstrate the carcinogenicity of this compound.

Case Study -4

In a neighborhood within 3-5 miles of a former garbage dump, plastics and battery recycling plant site that has been shut down for just over a year, 56 children have become unexpectedly ill all exhibiting the same or similar overlapping symptoms. The symptoms include moderate to severe headaches, acute abdominal pain, low red blood cell counts, and in some patients, severe cases have exhibited seizures and kidney failure. Upon looking into the patient backgrounds of children of age to attend elementary school or higher, it was found that these children over the last 3-5 month period have been uncharacteristically irritable in school and at home and have had significant drops in their grades in school. More than half of the parents report their children have been acting more uncoordinated during this last 3-5 month window. All 56 patients were from that same neighborhood, living in households with well water provided by simple ground water in houses that range from anywhere between 6-48 years old. The households shop at various supermarkets in the area and are made up of a variety of demographics (17% Hispanic, 36% White, 28% African American, 19% other/not specified). The adults in these households have suffered from occasional mild headaches during the last 3-5 months, but display no consistent moderate to severe symptomology. Since you are the head of the hospital unit dealing with these patients,

it is up to you to make the proper diagnosis and begin treatments (if there are appropriate treatments to administer).

Write a short essay (limit 1000 words) that incorporates answers to the following questions

1) What could the contaminant/toxicant/pollutant be?

2) From where could the contaminant likely have originated? How?

3) Explain how all the information provided in the case study backs up your diagnosis.

4) Describe any additional tests you might run to confirm your diagnosis. Based on your diagnosis, describe the appropriate treatment(s) which should be administered.

Case Study- 5

Anytown transformed itself from a 1950's small, poor town with a high unemployment rate to a 1970's industrial town known for its plumbing supplies, including some of the largest manufacturing facilities of PVC (polyvinyl chloride) pipe in the nation. These industrial sites and factories were thought to be a godsend to this small town, offering jobs, a boost to the local economy, a reputation as a true, hard- working, blue collar town, and a bit of esteem and recognition as the place to go if one were in need of plumbing supplies, clothing, upholstery, electrical cable insulation, inflatable products, and more.

During this short 20 year period, more and more Industrial workers in Anytown, USA were becoming ill. In retrospect, individual cases involving the mentioned symptoms began to arise in just months after the industrial park factories opened, increasing in number as time went on, raising the suspicions of doctors in the area. Doctors began to investigate by calling workers (both symptomatic and asymptomatic) to come in for health evaluations. During these physical exams and a battery of tests individuals were found to have portal hypertension related to sinusoidal endothelial damage, angiosarcoma of the liver, and potential cases of hepatocarcinoma. Doctors found elevated gamma-glutamyltransferase (GGT) concentrations in workers. Though elevated GGT levels did not fit, alcoholism, a primary cause of liver disease, was thought at first to be an obvious culprit. However, alcoholism was eliminated as a primary effector since the majority of individuals truthfully conveyed they did not partake in alcohol consumption of any significant amount either currently or in the past. Likewise, viral causes of liver disease and liver cancers, such as Hepatitis C, were eliminated as well, since most patients tested negative for Hepatitis C exposure. Doctors were puzzled.

Eventually the thinking shifted to consider toxic byproducts and routes of exposure to toxic compounds. As investigations continued, and it did seem that there was some correlation to the industrial renaissance and this onset of corresponding symptomology. Individuals in the town were polled. Investigators focused on those individuals who lived or worked in close proximity to the factories. Studies showed that though there were a significant number of cases among individuals in very close proximity (less than 1 mile) of the Industrial park/factory sites, many individuals living more than 5 miles away were also showing symptoms. It was also found that of those individuals with symptoms outside of the 5 mile radius of the industrial park, 97% of them worked in the factories themselves on a daily basis. This suggested the factories as a source of the toxicant. However, symptomatic individuals had jobs that ranged from being "floor" workers with direct contact to product to administrative assistants housed in the same facilities, but with no direct physical contact to the products. Officials began to suspect that they may be dealing with an airborne carcinogen or toxin. They attempted to determine if there were any odors that could be detected in proximity to the factories, finding that no significant odors existed. However, with physical contact eliminated as a source of exposure to a toxin, very few routes of exposure remained, including the respiratory route. Upon further investigation Doctor's found something in the air that was the likely culprit.

Regulatory measures put in place in the 1970's after this investigation produced a marked reduction of new cases of this disease. However, those individuals exposed to the agent prior to the regulations demonstrated that inhalation absorption of the substance was not only quite rapid, but data from volunteers exposed to low concentrations of the substance also showed that they retained more than 40% of the inhaled amount.

Write a ~ 1000 word essay that incorporates answers to the following questions:

1. What could this toxic agent be? Justify your answer citing information in the above case report.

2. Where might it have come from (be as specific as you can)?

3. How might you explain the facts in the case above (proximity effects on towns people living close versus far from industrial sites, liver symptomology, etc.) to support your argument?

4. Do you think modern day EPA and Federal regulations (if they were similarly in place in the early 1950's) would have been effective in countering this "unknown" problem before it started to effect individuals, or do you think that even with regulation in place this threat might have occurred the same way? Why? Justify your answer.