Gulf War and Health: Updated Literature Review of Depleted Uranium (2008)

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6 Clinical End Points of Interest T his chapter identifies the health outcomes on the basis of which the commit- tee draws conclusions about the long-term human health effects associated with exposure to natural and depleted uranium (the committee’s conclusions are presented in Chapter 8). It also provides background information, including incidence and prevalence rates and known risk factors, on each health outcome. Cancer Outcomes Cancer is a group of diseases characterized by uncontrolled growth and spread of abnormal cells (WHO, 2003; ACS, 2007b). Cancer can affect almost any tissue. It is caused by external factors (such as tobacco, chemicals, radia- tion, and infectious agents) and internal factors (such as inherited mutations, hormones, immune conditions, and mutations that result from metabolism). Such factors may act together or in combination to initiate or promote carcinogenesis (ACS, 2007b). In adults, a latent period of 10 years or more may elapse between exposure or mutation and the detection of cancer. Worldwide, among the member states of the World Health Organization, cancer is the third-leading cause of death after heart disease and infectious and parasitic diseases (WHO, 2003). Each year, cancer leads to 12% of deaths, or about 6 million people (WHO, 2003). In men, lung and stomach cancers are the most common worldwide; in women, breast, cervical, and lung cancers are the most common (WHO, 2003). In the United States, cancer is the second-leading cause of death, exceeded only by heart disease. An estimated 565,650 Americans are expected to die from cancer in 2008, accounting for about one-fourth of all 105 

106 updated literature review of depleted uranium deaths (ACS, 2007b). Lung cancer remains the leading cause of cancer deaths in both men and women; prostatic cancer is the most frequently diagnosed cancer in men, and breast cancer in women (ACS, 2007b). Although several of the studies reviewed cancer at all sites, the committee chose to focus on selected sites, specifically leukemias, lymphomas, and lung, bone, renal, bladder, stomach, brain and other parts of the central nervous system, prostatic, and testicular cancer. Most of those may be found on the basis of the route of exposure (generally inhalation or ingestion) and the mechanism of clear- ance of radiologic and chemical toxicants. Testicular cancer, being the most com- mon cancer among young men, is of special interest to Gulf War veterans, and some studies of veterans suggested a higher but nonsignificantly increased risk in them than in their nondeployed counterparts (IOM, 2006b). Prostatic cancer is the most frequently diagnosed cancer in men in the United States, and any slight increase in risk could result in large numbers of cases or deaths. Lung Cancer (ICD-10 C34) Lung cancer is the leading cause of cancer death in the United States and the second-most common cancer in both American men and women. An estimated 213,380 new cases of and 160,390 deaths from lung cancer were expected in 2007 in the United States, accounting for about 14.8% of all cancer diagnoses and 28.7% of all cancer deaths. Lung-cancer incidence in men has been declin- ing substantially from a peak of 102 cases per 100,000 men in 1984; in women, the incidence is reaching a plateau after decades of increase (ACS, 2007b). In 2004 (the most recent year with available published incidence data), there were 60.0 new cases of lung cancer per 100,000 people in the United States (73.6 in men and 50.2 in women) and 53.3 deaths per 100,000 (70.3 in men and 40.9 in women) (Ries et al., 2007). Lung cancer is classified into two main types based on the appearance of its cells. Non–small-cell lung cancer accounts for about 87% of all lung cancers and is divided into three subtypes based on size, shape, and chemical makeup: squamous-cell carcinoma (25-30% of all lung cancers) is linked to smoking and commonly found near a bronchus, adenocarcinoma (40% of all lung cancers) appears in the outer regions of the lungs, and large-cell undifferentiated carci- noma (10-15% of all lung cancers) is found in all areas and tends to metastasize quickly. The second main type, small-cell lung cancer, also known as oat-cell carcinoma, accounts for the remaining 10-15% and is almost always linked to smoking. Small-cell lung cancer originates primarily in the bronchi and tends to metastasize quickly throughout the body fairly early in the disease process. Tobacco-smoking is the predominant risk factor and is thought to account for about 87% of lung-cancer deaths. Other risk factors include exposures to such   ICD-10 is the 10th edition of the International Classification of Diseases. 

clinical end points of interest 107 carcinogens as radon, asbestos, beryllium, silica, arsenic, and secondhand smoke; family history; and diet (ACS, 2007g). Leukemias (ICD-10 C91-95) Leukemias are malignant diseases that arise from precursor cells of white blood cells. An estimated 44,240 new cases of and 21,790 deaths from leukemia were expected in 2007 in the United States, accounting for about 3.1% of all cancer diagnoses and 3.9% of all cancer deaths (ACS, 2007b). In 2004, there were 12.0 new cases of leukemia per 100,000 people in the United States (15.4 in men and 9.5 in women) and 7.2 deaths per 100,000 (9.7 in men and 5.5 in women) (Ries et al., 2007). Although all leukemias originate in the bone marrow, there are four main types, classified by the type and developmental stage of the cells involved. Leu- kemias can be acute—in which case the cells grow rapidly and are not able to mature—or chronic—in which case the cells grow and accumulate slowly and look mature. And leukemias can affect different types of cells: lymphocytic leu- kemias affect the lymphocytes, white blood cells that make up lymphoid tissue, and myeloid leukemias affect granulocytes or monocytes, white blood cells that circulate and protect the body against infection (ACS, 2007k). Acute lympho- cytic leukemia affects children more frequently than adults, whereas chronic lymphocytic leukemia affects only adults, mostly over the age of 40 years (ACS, 2007d,f). Acute myeloid leukemia, also called acute nonlymphocytic leukemia, is the most common leukemia and usually affects adults, particularly men, although it can occur in children (ACS, 2007e). Chronic myeloid leukemia affects mostly adults and is rare in children (ACS, 2007a). The four types of leukemias can be divided into subtypes based on progression and cell subtypes. Characterizing leukemia cases gathered retrospectively for epidemiologic studies and integrating the results of studies conducted over several decades are particularly challenging because successive diagnostic criteria, with correspond- ing groupings and nomenclature, have been used. Individual leukemias may have unique etiologic factors (for example, T-cell leukemia is caused by the retrovirus HTLV-I), but the recognized risk factors for leukemias in general include expo- sure to ionizing radiation or some chemicals (such as occupational exposure to benzene or chemotherapy with alkylating agents), some genetic conditions (such as some chromosomal abnormalities, including Down syndrome), and particular acquired blood diseases (for example, myelodysplastic syndromes may develop into acute myeloid leukemia) (NCI, 2003). Lymphomas (ICD-10 C81-85) This section discusses two types of lymphomas: Hodgkin’s disease (HD; also called Hodgkin lymphoma) (ICD-10 C81) and non-Hodgkin lymphoma (NHL) 

108 updated literature review of depleted uranium (ICD-10 C82-85). The lymph nodes are sites of particular concern because ura- nium is known to accumulate in them. HD is a very rare cancer that originates in lymphatic tissue (ACS, 2007i). An estimated 8,190 new cases of and 1,070 deaths from HD were expected in 2007 in the United States, accounting for about 0.6% of all cancer diagnoses and 0.2% of all cancer deaths (ACS, 2007b). In 2004, there were 2.9 new cases of HD per 100,000 people in the United States (2.9 in men and 2.8 in women) and 0.4 death per 100,000 (0.5 in men and 0.3 in women) (Ries et al., 2007). HD is a B-cell lymphoma characterized by microscopically identifiable Reed-Sternberg cells; all other cancers of the lymphatic tissues are NHL. The only known risk factors for HD are infectious mononucleosis (caused by the Epstein-Barr virus) and low immunity. HD has not been associated with family history, diet, or environmental exposure, including exposure to uranium. An estimated 63,190 new cases of and 18,660 deaths from NHL were expected in 2007 in the United States, accounting for about 4.4% of all cancer diagnoses and 3.3% of all cancer deaths (ACS, 2007b). In 2004, there were 20.4 new cases of NHL per 100,000 people in the United States (24.7 in men and 17.1 in women) and 7.0 deaths per 100,000 (8.8 in men and 5.7 in women) (Ries et al., 2007). NHL originates in the B cells or, less frequently, the T cells of the lymphatic tissue (ACS, 2007i). It encompasses the many types of lymphoma that remain after the exclusion of HD (B-cell lymphoma). In the evolving classification systems for lymphohematopoietic cancers overall, there have been a series of systems just for NHL. In ICD-10 coding, NHL is divided among ICD-10 C82-85. Characterizing NHL cases gathered retrospectively for epidemiologic studies and integrating the results of studies conducted over several decades are particularly challenging because of the nonconstancy in the terminology and coding for reporting diagnoses of or deaths from this family of diseases. Many risk factors have been identified for NHL: genetic or acquired severely compromised immune system; infection by HIV, related T-cell viruses, or Epstein-Barr virus or by some bacteria (such as Helicobacter pylori in the case of gastric lymphoma); aging; obesity, the only recognized “lifestyle” factor; radiation; chemotherapy drugs; and possibly some chemicals, with benzene, herbicides, and insecticides most often implicated. Bone Cancer (ICD-10 C40-41) An estimated 2,370 new cases of and 1,330 deaths from bone and joint can- cer were expected in 2007 in the United States, accounting for about 0.2% of all cancer diagnoses and all cancer deaths (ACS, 2007b). During 2000-2004, there was 0.9 new case of bone and joint cancer per 100,000 people in the United States (1.0 in men and 0.8 in women) and 0.4 death per 100,000 (0.5 in men and 0.3 in women) (Ries et al., 2007). 

clinical end points of interest 109 Of the several forms of primary bone and joint cancer, osteosarcoma is the most common primary bone cancer, accounting for about 35% of all cases. Occurring more frequently in males, osteosarcoma is found mostly in people 10-30 years old and rarely during middle age. About 10% of cases develop in people 60 years old and older. Other rare forms of primary bone cancer include chondrosarcoma (cancer of cartilage cells), Ewing tumor (cancer of the bone cav- ity), chordoma (cancer of the skull base and spinal bones), and malignant fibrous histiocytoma and fibrosarcoma (cancer of the connective tissues). The 5-year survival rate can be as high as 80%, but the prognosis for people with primary bone cancer varies greatly, depending on the specific type of cancer and the stage at which it is diagnosed (NCI, 2002a; ACS, 2006b). Risk factors for bone cancer are exposure to ionizing radiation, particularly at an early age or at high doses; a history of bone disorders, such as Paget disease; and the presence of multiple exostoses (overgrowths of bone tissue), multiple osteochondromas (benign bone tumors formed by bone and cartilage), multiple enchondromas (benign cartilage tumors), and some genetic factors (such as muta- tion of the p53 tumor-suppressor gene) (NCI, 2002a; ACS, 2006b). Renal Cancer (ICD-10 C64-66) An estimated 51,190 new cases of and 12,890 deaths from cancer of the kid- ney and renal pelvis were expected in 2007 in the United States, accounting for about 3.5% of all cancer diagnoses and 2.3% of all cancer deaths (ACS, 2007b). In 2004, there were 13.1 new cases of renal and renal pelvis cancer per 100,000 people in the United States (17.8 in men and 9.2 in women) and 4.1 deaths per 100,000 (5.9 in men and 2.7 in women) (Ries et al., 2007). Over 90% of renal cancers in adults are renal-cell carcinomas (RCCs) or ade- nocarcinomas (ACS, 2007j). Most other malignant renal tumors are ­transitional- cell carcinomas that arise in the renal pelvis, ureter, or urethra; these are jointly referred to as urothelial carcinomas or cancers of the renal pelvis. Smoking and obesity are the major risk factors for renal cancer. Others are diet, increasing age, male sex, some hereditary conditions (such as Von Hippel- Lindau disease and hereditary papillary renal-cell carcinoma), and dialysis treat- ment for renal disease. Such medications as phenacetin and diuretics (or the high blood pressure that they are used to treat) have also been associated with RCC, as has occupational exposure to asbestos, cadmium, and some organic solvents (ACS, 2007c). Bladder Cancer (ICD-10 C67) An estimated 67,160 new cases of and 13,750 deaths from urinary bladder cancer were expected in 2007 in the United States, accounting for about 4.6% of all cancer diagnoses and 2.5% of all cancer deaths (ACS, 2007b). In 2004, there 

110 updated literature review of depleted uranium were 20.6 new cases of urinary bladder cancer per 100,000 people in the United States (36.3 in men and 9.1 in women) and 4.4 deaths per 100,000 (7.6 in men and 2.2 in women) (Ries et al., 2007). The bladder is lined with transitional and squamous cells. More than 90% of bladder cancers arise in transitional cells, and squamous-cell carcinomas make up only about 8% of bladder cancers (NCI, 2002b). Although cells that line the renal pelvis and ureter are histologically similar to bladder epithelial cells, tumors of the renal pelvis, ureters, and urethra are considered urothelial-cell tumors and are traditionally grouped with renal cancer. This section, however, addresses only bladder cancer. The major risk factor for bladder cancer is smoking. Demographic factors that have some influence on the occurrence of bladder cancer are race (the inci- dence is highest in whites and lowest in Asians), increasing age, sex (males are at higher risk), and family history. Chronic bladder inflammation due to infections, bladder or kidney stones, and parasites has been associated with bladder cancer. Known occupational risk factors include use of the drug cyclophosphamide and exposure to aromatic amines, arsenic, and organic chemicals associated with manufacture of rubber, leather, textiles, and paint (ACS, 2006a). Brain and Other Nervous System Cancers (ICD-10 C71-72) An estimated 20,500 new cases of and 12,740 deaths from brain and other nervous system cancers were expected in 2007 in the United States, account- ing for about 1.4% of all cancer diagnoses and 2.3% of all cancer deaths (ACS, 2007b). In 2004, there were 6.5 new cases of brain and other nervous system cancers per 100,000 people in the United States (7.6 in men and 5.5 in women) and 4.3 deaths per 100,000 (5.2 in men and 3.5 in women) (Ries et al., 2007). Most nervous system tumors, including brain tumors, are not associated with known risk factors. The few known risk factors associated with these cancers are radiation, immune system disorders, and family history. Stomach Cancer (ICD-10 C16) Gastric cancer (commonly known as stomach cancer) was once a leading cause of cancer deaths in the United States; it is now more common in other countries. An estimated 21,260 new cases of and 11,210 deaths from stomach cancer were expected in 2007 in the United States, accounting for about 1.5% of all cancer diagnoses and 2.0% of all cancer deaths (ACS, 2007b). In 2004, there were 7.6 new cases of stomach cancer per 100,000 people in the United States (10.9 in men and 5.1 in women) and 4.0 deaths per 100,000 (5.5 in men and 2.8 in women) (Ries et al., 2007). Helicobacter pylori infection is a major cause of stomach cancer. Other risk factors include sex, age, ethnicity, diet, tobacco use, family history, and occupation (ACS, 2007m). 

clinical end points of interest 111 Male Genital Cancers (ICD-10 C61-62) An estimated 218,890 new cases of and 27,050 deaths from prostatic cancer were expected in 2007 in the United States, accounting for about 28.5% of all cancer diagnoses and 9.3% of all cancer deaths in American men (ACS, 2007b). An estimated 7,920 new cases of and 380 deaths from cancer of the testis were expected, accounting for about 1% of all cancer diagnoses and 0.1% of all deaths in men. In 2004, there were 159.5 new cases of prostatic cancer per 100,000 men in the United States and 25.4 deaths per 100,000, and there were 5.7 new cases of testicular cancer per 100,000 and 0.2 death per 100,000 (Ries et al., 2007). Factors that increase the risk of prostatic cancer include increasing age, race, and family history (ACS, 2007l). Testicular cancer is uncommon but highly treatable. Known or suspected risk factors include cryptorchidism, family history, some occupational exposures, multiple atypical nevi, HIV infection, race and eth- nicity, body size, and maternal hormone use during pregnancy (ACS, 2007h). Noncancer Outcomes Nonmalignant health outcomes selected by the committee for evaluation include renal disease, respiratory disease, neurologic effects, and reproductive effects. In addition to information on disease prevalence and risk factors, a dis- cussion of clinical tests used to evaluate organ or organ-system function for renal and respiratory disease is included. Nonmalignant Renal Disease (ICD-10 N18) Chronic kidney disease (CKD), also known as chronic renal insufficiency, is the permanent loss of renal function (NIDDK, 2008). According to data from the National Health and Nutrition Examination Survey for 1994-2004, the prevalence of CKD in US adults 20 years old or older was 16.8% (NHANES, 2007). Dia- betes and hypertension are leading risk factors for CKD, and many other factors have also been implicated, such as obesity, family history, ethnicity, race, and cardiovascular disease. Stages of renal function are assigned according to the estimated glomerular filtration rate (GFR), a measure of the kidneys’ capacity to filter toxins from the blood, and the presence of protein in the urine (proteinuria). Renal function is evaluated with numerous tests that broadly provide an indication of the GFR, the level of proteinuria, or how well the tubular portions of the kidneys’ cellular structures are able to modify the fluid filtered from the blood as it is processed into urine (for example, on the basis of urinary pH, urinary glucose, and tubular protein markers). Abnormalities of the GFR and proteinuria are highly predic- tive not only of progressive kidney disease but of cardiovascular morbidity and mortality. 

112 updated literature review of depleted uranium The GFR is most accurately measured with a clinical test in which an exog- enous marker (for example, inulin, iohexol, or iothalamate) is injected into the body and then measured in carefully timed specimens of blood and urine as it is filtered and excreted by the kidneys. This type of testing is used principally in research settings because of the time and effort it demands. In the clinical setting, the attributes of the endogenous substance creatinine are often exploited to provide an indication of the GFR. Creatinine is a product of normal muscle metabolism and is principally excreted from the body by the kidneys through the process of filtration. Because creatinine production is typically constant (relative to a person’s muscle mass) over short to medium periods, increases in blood creatinine concentration often indicate diminished GFR and therefore a loss of renal function. A more accurate way of using the creatinine concentration as a measure of renal function is to relate blood creatinine concentration to the quan- tity of creatinine excreted in the urine over a specified period (typically measured with a 24-hour urine collection). The quotient of urinary creatinine divided by plasma creatinine is known as the creatinine clearance. This value is a good proxy for the GFR measured with exogenous markers. Finally, to obviate the timed collection of urine, which can be inconvenient and difficult in the clinical setting, mathematical equations have been developed to estimate the GFR. The most commonly used equation is derived from the Modification of Diet in Renal Disease Study and incorporates age, race, sex, and serum creatinine to provide an estimate of GFR (eGFR). This metric appears to work reasonably well when the true GFR is 60 mL/min per 1.73 m2 or lower, but it substantially underestimates the GFR in people who have more preserved renal function. Normally, there is essentially no plasma protein in urine. The filtering struc- tures in the kidneys (glomeruli) should permit only the aqueous portion of plasma and none of its protein to enter the urine. When the filtering structures become diseased, plasma protein can pass into the urine, a phenomenon that may or may not be accompanied by a decrease in the GFR. This form of glomerular protein- uria is predictive of poor clinical outcomes. Measures of the function of the renal tubular structures are less commonly used in the clinical setting. Some, such as measures of tubular protein, have an uncertain relationship to clinical renal disease, and they do not clearly provide prognostic information with respect to the clinically important measures of GFR or glomerular proteinuria. Finally, many other specialized tests can be used to assess specific aspects of the kidneys’ ability to modify the filtered plasma as it is transformed into urine. They include measures of the electrolyte composition of the urine (for example, phosphate, calcium, sodium, and potassium), of the acidifying capabilities of the kidneys (for example, urinary pH), and of the kidneys’ ability to appropriately reclaim small molecules, such as glucose, that are filtered but are not excreted in the urine of healthy people. 

clinical end points of interest 113 Nonmalignant Respiratory Disease (ICD-10 J43-46) The category of nonmalignant respiratory disease includes several condi- tions. Chronic obstructive pulmonary disease (COPD), pneumonia, pneumoconi- osis, and asthma are described here because they are common and an association between them and exposure to uranium is biologically plausible. COPD includes two frequently coexisting conditions: chronic bronchitis and emphysema. Chronic bronchitis is characterized by symptoms of cough and sputum production, which may be associated with poorly reversible pathologic changes in the airways. Emphysema is characterized by the progressive destruction of alveoli and per- manent changes in the airways. COPD causes airflow obstruction that interferes with normal breathing. In 2005, an estimated 11.6 million adults in the United States had COPD; in 2004, 118,171 adults in the United States died from it (CDC, 2006). The primary risk factor for COPD is smoking; other risk factors include occupational exposure, sex, childhood history of respiratory infections, and fam- ily history (ALA, 2007a). Pneumonia is an infection or inflammation of the lungs. It can affect a section or lobe of a lung (lobar pneumonia) or patches throughout both lungs (broncho- pneumonia). Risk factors for pneumococcal pneumonia include chronic illness, recent recovery from severe illness, such specific environments as chronic-care facilities, and age. In 2004, deaths in the United States attributed to pneumonia numbered 58,564 (19.9 deaths per 100,000 people) (CDC, 2007c). Pneumoconiosis is caused by exposure to inorganic dust. It may be function- ally important, representing interstitial fibrosis, or have little or no functional impact. Asthma is a chronic inflammatory condition in which acute exacerbations are caused by airway obstruction and inflammation; it is classified as a reversible obstructive lung disease caused by increased reaction of the airways to stimuli. Asthma interferes with breathing when the airways are narrowed because of swelling of the lining, tightening of the muscle, and increased mucus secretion. Its symptoms are coughing, wheezing, and shortness of breath, and they are trig- gered by such stimuli as respiratory infections, environmental pollutants, tem- perature change, and exercise (ALA, 2007b). In 2004, an estimated 15.7 million adults in the United States had asthma, and deaths in the United States attributed to asthma numbered 3,816 (1.3 deaths per 100,000 people) (CDC, 2007b). Nonmalignant respiratory effects may be ascertained by several methods, including the following: • Mortality: Deaths ascribed to such causes may be identified on the basis of death-certificate data. • Physician diagnosis: Medical diagnosis of a nonmalignant respiratory disease may be determined from medical records or from patient reporting of the presence of a physician diagnosis. 

114 updated literature review of depleted uranium • Symptoms: Symptoms consistent with a nonmalignant respiratory dis- order may be identified by using standardized self-administered or interview- administered questionnaires. • Pulmonary-function testing: Pulmonary-function testing, particularly spi- rometry, is commonly used to evaluate respiratory function clinically and in epidemiologic studies. Major measures include forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1:FVC ratio. The latter is indicative of COPD and asthma. A statistical association between a pulmonary- function test result and a measured exposure suggests that the exposure agent has the potential to produce disease in people who are sufficiently exposed. • Radiographic (imaging) studies: “Chest x-ray” testing is particularly useful for diagnosing interstitial lung diseases, such as pneumoconiosis. Such methods are widely used in studies of occupational cohorts exposed to agents other than uranium but have had only limited application to uranium-exposed workers. Neurologic Effects (ICD-10 G00-G99) and Neurobehavioral and Neurocognitive Effects (ICD-10 F00-99) There are numerous diseases of the nervous system, and, as described in Chapters 7 and 8, the epidemiologic studies of uranium-exposed populations do not specify individual neurologic diseases in their analyses. Prevalence, inci- dence, and risk factors vary among nervous system diseases. Several studies have suggested an increased risk of amyotrophic lateral sclerosis in Gulf War veterans (IOM, 2006a), but no risk factor has been identified. Neurocognitive and neu- robehavioral outcomes have been assessed in a group of Gulf War veterans who were exposed to depleted uranium. Birth Defects and Other Adverse Reproductive Outcomes (ICD-10 O00-Q99) Birth defects occur in about one in 33 live births in the United States (CDC, 2007a). The numerous types of birth defects—several thousand have been identified—include structural defects, chromosomal abnormalities, and birth- defect syndromes (California Birth Defects Monitoring Program, 2006; March of Dimes, 2006). The most common birth defects in the United States are cleft palate, cleft lip, and Down syndrome (March of Dimes, 2006). Birth defects are caused by genetic and environmental factors (for example, chemicals and infec- tious agents) or a combination of such factors. The causes of most cases of birth defects are unknown (CDC, 2007a). In addition to birth defects, adverse outcomes of pregnancy include early pregnancy loss (before 8 weeks), spontaneous abortion (8-20 weeks), ectopic pregnancy, and late fetal death and stillbirth. Such outcomes, especially early 

clinical end points of interest 115 pregnancy loss and spontaneous abortion, are often not reported, so it is difficult to estimate their frequencies precisely. However, about 20-30% of implantations end in early pregnancy loss, and about 10-20% of clinically recognized pregnan- cies result in spontaneous abortion (NRC, 2000). Adverse reproductive outcomes include abnormal male and female hormone profiles, altered menstrual and ovarian cycles, longer than normal time to preg- nancy, abnormal semen characteristics, gynecologic and urologic disorders, and premature reproductive senescence (NRC, 2001). Information on the number of people affected by reproductive disorders is sparse. References ACS (American Cancer Society). 2006a. Detailed guide: Bladder cancer—what is bladder cancer? http://www.cancer.org/docroot/CRI/CRI_2_3x.asp?dt=44 (accessed March 4, 2008). ———. 2006b. Detailed guide: Bone cancer. http://www.cancer.org/docroot/lrn/lrn_0.asp (accessed March 4, 2008). ———. 2007a. All about leukemia—chronic myeloid (CML). http://www.cancer.org/docroot/CRI/ CRI_2x.asp?sitearea=&dt=83 (accessed March 4, 2008). ———. 2007b. Cancer facts and figures. Atlanta, GA: American Cancer Society. ———. 2007c. Detailed guide: Kidney cancer—what is kidney cancer (renal cell carcinoma)? http:// www.cancer.org/docroot/CRI/content/CRI_2_4_1X_What_is_kidney_cancer_22.asp?sitearea= (accessed March 4, 2008). ———. 2007d. Detailed guide: Leukemia—acute lymphocytic (ALL). http://www.cancer.org/docroot/ CRI/CRI_2_3x.asp?dt=57 (accessed March 3, 2008). ———. 2007e. Detailed guide: Leukemia—acute myeloid (AML). http://www.cancer.org/docroot/ CRI/CRI_2_3x.asp?dt=82 (accessed March 3, 2008). ———. 2007f. Detailed guide: Leukemia—chronic lymphocytic (CLL). http://www.cancer.org/ docroot/CRI/CRI_2_3x.asp?dt=62 (accessed March 3, 2008). ———. 2007g. Detailed guide: Lung cancer—small cell. What is small cell lung cancer? http://www. cancer.org/docroot/CRI/content/CRI_2_4_1X_What_is_small_cell_lung_cancer.asp?sitearea= (accessed February 27, 2008). ———. 2007h. Detailed guide: Testicular cancer. http://www.cancer.org/docroot/CRI/CRI_2_ 3x.asp?dt=41 (accessed March 4, 2008). ———. 2007i. Hodgkin’s disease detailed guide. http://www.cancer.org/docroot/CRI/content/CRI_ 2_4_7x_CRC_Hodgkin_Disease_PDF.asp (accessed March 4, 2008). ———. 2007j. Overview: Kidney cancer—what is kidney cancer? http://www.cancer.org/docroot/CRI/ content/CRI_2_2_1X_What_is_kidney_cancer_22.asp?sitearea= (accessed March 4, 2008). ———. 2007k. Overview: Leukemia—acute myeloid (AML). The different types of leukemia. http:// www.cancer.org/docroot/CRI/content/CRI_2_2_1x_The_Different_Types_of_Leukemia_AML. asp?sitearea= (accessed March 3, 2008). ———. 2007l. Overview: Prostate cancer—what is prostate cancer? http://www.cancer.org/docroot/ CRI/content/CRI_2_2_1X_What_is_prostate_cancer_36.asp (accessed March 4, 2008). ———. 2007m. Overview: Stomach cancer—what causes stomach cancer? http://www.cancer.org/ docroot/CRI/content/CRI_2_2_2X_What_causes_stomach_cancer_40.asp?sitearea= (accessed February 27, 2008). ALA (American Lung Association). 2007a. Chronic obstructive pulmonary disease (COPD) fact sheet. http://www.lungusa.org/site/apps/nl/content3.asp?c=dvLUK9O0E&b=2058829& content_id=EE451F66-996B-4C23-874D-BF66586196FF&notoc=1#5 (accessed February 27, 2008). 

116 updated literature review of depleted uranium ———. 2007b. Diseases A to Z. http://www.lungusa.org/site/pp.asp?c=dvLUK9O0E&b=33316#p (accessed March 4, 2008). California Birth Defects Monitoring Program. 2006. Discoveries and data center. http://www.cbdmp. org/bd_intro.htm (accessed March 4, 2008). CDC (Centers for Disease Control and Prevention). 2006. Summary health statistics for U.S. Adults: National health interview survey, 2005. Hyattsville, MD: U.S. Department of Health and Hu- man Services. ———. 2007a. Birth defects: Frequently asked questions (FAQs). http://www.cdc.gov/ncbddd/bd/ faq1.htm (accessed March 4, 2008). ———. 2007b. National Center for Health Statistics: Asthma. http://www.cdc.gov/nchs/fastats/ asthma.htm (accessed February 27, 2008). ———. 2007c. National Center for Health Statistics: Pneumonia. http://www.cdc.gov/nchs/fastats/ pneumonia.htm (accessed February 27, 2008). IOM (Institute of Medicine). 2006a. Amyotrophic lateral sclerosis in veterans: Review of the scientific literature. Washington, DC: The National Academies Press. ———. 2006b. Gulf War and health, volume 4: Health effects of serving in the Gulf War. Washington, DC: The National Academies Press. March of Dimes. 2006. Quick references and fact sheets: Birth defects. http://www.marchofdimes. com/professionals/14332.asp (accessed March 4, 2008). NCI (National Cancer Institute). 2002a. Bone cancer: Questions and answers. http://www.cancer. gov/cancertopics/factsheet/Sites-Types/bone (accessed March 4, 2008). ———. 2002b. What you need to know about bladder cancer. http://www.cancer.gov/cancertopics/ wyntk/bladder (accessed March 4, 2008). ———. 2003. What you need to know about leukemia. http://www.cancer.gov/cancertopics/wyntk/ leukemia/page3 (accessed March 4, 2008). NHANES (National Health and Nutrition Examination Survey). 2007. Prevalence of chronic kidney disease and associated risk factors—United States, 1999-2004. Morbidity and Mortality Weekly Report 56(8):161-165. NIDDK (National Institute of Diabetes and Digestive and Kidney Diseases). 2008. Health information for the public. http://www2.niddk.nih.gov/ (accessed March 4, 2008). NRC (National Research Council). 2000. Scientific frontiers in developmental toxicology and risk assessment. Washington, DC: National Academy Press. ———. 2001. Evaluating chemical and other agent exposures for reproductive and developmental toxicity. Washington, DC: National Academy Press. Ries, L. G., D. Melbert, M. Krapcho, B. A. Miller, E. J. Freuer, L. Clegg, M. J. Horner, N. Howlader, M. P. Eisner, M. Reichman, and B. K. Edwards. 2007. SEER cancer statistics review, 1975-2004. http://seer.cancer.gov/csr/1975_2004/ (accessed March 3, 2008). WHO (World Health Organization). 2003. World health report 2003—shaping the future. http://www. who.int/whr/2003/en/ (accessed February 28, 2007).