WEBVTT 1 00:00:00.720 --> 00:00:01.740 Hi, all. 2 00:00:01.740 --> 00:00:02.573 In this lecture, 3 00:00:02.573 --> 00:00:05.010 we'll be discussing the epidemiology of kidney cancer. 4 00:00:05.940 --> 00:00:07.050 The goals of this lecture 5 00:00:07.050 --> 00:00:09.540 are to review the anatomy and function of the kidney. 6 00:00:09.540 --> 00:00:12.360 to describe the global burden of kidney cancer, 7 00:00:12.360 --> 00:00:15.240 and look at trends and differences in mortality rates. 8 00:00:15.240 --> 00:00:17.520 We'll also define renal cell carcinoma 9 00:00:17.520 --> 00:00:20.193 and describe risk factors for renal cell carcinoma. 10 00:00:21.090 --> 00:00:24.302 So to begin with, to give an overview of the kidney, 11 00:00:24.302 --> 00:00:26.640 the human kidneys are paired organs 12 00:00:26.640 --> 00:00:29.040 that excrete waste products and metabolism, 13 00:00:29.040 --> 00:00:31.770 regulate the body's concentration of water and salt, 14 00:00:31.770 --> 00:00:34.350 maintain the acid-base balance of the blood, 15 00:00:34.350 --> 00:00:36.960 regulate blood pressure, and secrete important hormones, 16 00:00:36.960 --> 00:00:41.820 including erythropoietin, renin, and prostaglandins. 17 00:00:41.820 --> 00:00:43.260 Urea is the most abundant 18 00:00:43.260 --> 00:00:45.090 of the nitrogen-containing waste products 19 00:00:45.090 --> 00:00:46.830 created by the kidneys. 20 00:00:46.830 --> 00:00:49.470 Urea is formed for ammonia or ammonia acids 21 00:00:49.470 --> 00:00:52.140 by a series of reactions known as the urea cycle, 22 00:00:52.140 --> 00:00:54.780 which occurs primarily in the liver. 23 00:00:54.780 --> 00:00:58.320 The basic functional unit of the kidney is the nephron. 24 00:00:58.320 --> 00:01:00.690 Each kidney contains up to 1 million nephrons 25 00:01:00.690 --> 00:01:03.390 that carry out the essential functions of the kidney. 26 00:01:03.390 --> 00:01:05.370 Each nephron receives unfiltered blood 27 00:01:05.370 --> 00:01:09.120 from an afferent or arterial, 28 00:01:09.120 --> 00:01:12.290 which divides into capillaries of the glomerulus. 29 00:01:13.480 --> 00:01:16.590 The glomerulus filters urea and other waste products 30 00:01:16.590 --> 00:01:17.463 from the blood. 31 00:01:18.930 --> 00:01:23.930 In 2012, 337,860 new cases were detected, 32 00:01:24.420 --> 00:01:29.400 and 143,369 deaths were attributed to kidney cancer. 33 00:01:29.400 --> 00:01:30.480 The incidence and mortality 34 00:01:30.480 --> 00:01:33.150 have increased steadily in the past two decades. 35 00:01:33.150 --> 00:01:34.890 And while the arising incidence rates 36 00:01:34.890 --> 00:01:36.990 may be partly attributable to improvements 37 00:01:36.990 --> 00:01:38.872 in imaging tech techniques, 38 00:01:38.872 --> 00:01:40.920 better detection does not explain 39 00:01:40.920 --> 00:01:42.753 the worldwide increase in mortality. 40 00:01:44.220 --> 00:01:47.580 During 2012, the annual incidence rates in populations 41 00:01:47.580 --> 00:01:51.930 of developed nations, 10 per 100,000 for men 42 00:01:51.930 --> 00:01:55.290 and five per 100,000 for women were five-fold higher 43 00:01:55.290 --> 00:01:58.650 than corresponding rates in low and middle income countries, 44 00:01:58.650 --> 00:02:00.480 which were two per 100,000 for men 45 00:02:00.480 --> 00:02:03.180 and one per 100,000 for women. 46 00:02:03.180 --> 00:02:05.670 Mortality rate shows similar pattern. 47 00:02:05.670 --> 00:02:08.310 Such differences are largely attributable to under-reporting 48 00:02:08.310 --> 00:02:10.950 due to lack of diagnostic imaging and detection 49 00:02:10.950 --> 00:02:13.170 in low- and middle-income countries. 50 00:02:13.170 --> 00:02:14.850 Differential effects of lifestyle 51 00:02:14.850 --> 00:02:17.733 and environmental exposures may also be contributing. 52 00:02:18.960 --> 00:02:21.780 Historically, the cross triad of clinical signs, 53 00:02:21.780 --> 00:02:25.440 flank pain, hematuria, and palpable mass in a patient 54 00:02:25.440 --> 00:02:27.660 usually led to the detection of a large tumor of the kidney 55 00:02:27.660 --> 00:02:29.670 at a late stage of development. 56 00:02:29.670 --> 00:02:33.270 Such tumors have often metastasized to other anatomic sites 57 00:02:33.270 --> 00:02:34.770 by the time they were diagnosed, 58 00:02:34.770 --> 00:02:37.143 making treatment difficult and prognosis poor. 59 00:02:38.070 --> 00:02:39.810 In the current practice of medicine, 60 00:02:39.810 --> 00:02:41.910 kidney tumors are often detected incidentally 61 00:02:41.910 --> 00:02:43.680 at a relatively early stage of development 62 00:02:43.680 --> 00:02:47.190 during imaging studies of the abdomen for other conditions. 63 00:02:47.190 --> 00:02:48.660 As with all forms of cancer, 64 00:02:48.660 --> 00:02:50.520 early detection of kidney cancer is essential 65 00:02:50.520 --> 00:02:53.970 for successful therapy and prolonged patient survival. 66 00:02:53.970 --> 00:02:56.040 Kidney tumors detected in an early stage 67 00:02:56.040 --> 00:02:57.960 often respond well to treatment, 68 00:02:57.960 --> 00:03:00.570 and as a consequence, survival rates have improved 69 00:03:00.570 --> 00:03:02.550 and mortality rates have stabilized or declined 70 00:03:02.550 --> 00:03:05.190 in many developed nations of the world. 71 00:03:05.190 --> 00:03:07.170 Nevertheless, in less developed nations 72 00:03:07.170 --> 00:03:09.690 without sophisticated methods of early detection, 73 00:03:09.690 --> 00:03:12.750 the upward trend in mortality is continuing. 74 00:03:12.750 --> 00:03:14.910 In 2020, there was an age-standardized incidence 75 00:03:14.910 --> 00:03:18.840 of 4.6 per 100,000 people overall. 76 00:03:18.840 --> 00:03:21.660 In men, that incidence was 1.8 per 100,000. 77 00:03:21.660 --> 00:03:24.810 While in women it was 3.2 per 100,000. 78 00:03:24.810 --> 00:03:28.110 The overall mortality rate was 1.8 per 100,000. 79 00:03:28.110 --> 00:03:31.000 While in men, that rate was 2.5 per 100,000, 80 00:03:31.000 --> 00:03:34.503 and 1.2 per 100,000 in women. 81 00:03:35.700 --> 00:03:38.190 There's several different kinds of kidney cancer. 82 00:03:38.190 --> 00:03:41.100 Renal cell carcinoma arises from epithelial cells 83 00:03:41.100 --> 00:03:42.480 that line the renal tubules, 84 00:03:42.480 --> 00:03:45.420 and is the most common type of kidney cancer, 85 00:03:45.420 --> 00:03:48.120 accounting for approximately 85 to 90% 86 00:03:48.120 --> 00:03:50.490 of all malignant kidney tumors. 87 00:03:50.490 --> 00:03:52.170 These cells normally secrete a variety 88 00:03:52.170 --> 00:03:54.663 of vasoactive and regulatory hormones. 89 00:03:56.497 --> 00:04:00.240 Wilms' tumor, named after the German surgeon, Max Wilms, 90 00:04:00.240 --> 00:04:01.200 who first described it, 91 00:04:01.200 --> 00:04:03.873 counts for about 5% of malignant kidney tumors. 92 00:04:04.710 --> 00:04:06.810 This tumor occurs almost exclusively in children 93 00:04:06.810 --> 00:04:09.930 under the age of 10 years, usually before the age of five. 94 00:04:09.930 --> 00:04:11.730 And Wilms' tumor are comprised 95 00:04:11.730 --> 00:04:13.590 of mixed stromal and epithelial cells 96 00:04:13.590 --> 00:04:14.850 with a board of configurations 97 00:04:14.850 --> 00:04:17.763 of renal, glomeruli, and tubules. 98 00:04:21.300 --> 00:04:24.240 Transitional cell carcinomas arising from epithelial cells 99 00:04:24.240 --> 00:04:26.970 of the junction of the renal pelvis and the ureter 100 00:04:26.970 --> 00:04:30.270 constitute 5 to 10% of malignant kidney tumors. 101 00:04:30.270 --> 00:04:32.490 Microscopically, transitional cell carcinomas 102 00:04:32.490 --> 00:04:36.030 of the renal pelvis are similar to urothelial carcinomas 103 00:04:36.030 --> 00:04:37.353 of the urinary bladder. 104 00:04:38.460 --> 00:04:42.360 These transitional epithelial cells are intermediate 105 00:04:42.360 --> 00:04:45.363 between flat squamous cells and tall columnar cells. 106 00:04:48.420 --> 00:04:52.740 There's a number of risk factors for renal cell carcinoma. 107 00:04:52.740 --> 00:04:54.660 Epidemiologic studies have clearly established 108 00:04:54.660 --> 00:04:55.620 that each of these factors 109 00:04:55.620 --> 00:04:58.830 has an etiologic link with renal cell carcinoma. 110 00:04:58.830 --> 00:05:00.210 Specific dietary factors 111 00:05:00.210 --> 00:05:01.710 and certain other environmental factors 112 00:05:01.710 --> 00:05:04.980 have also so shown effects in some studies. 113 00:05:04.980 --> 00:05:06.840 A notable finding for molecular analysis 114 00:05:06.840 --> 00:05:09.630 of renal cell tumors or a clear cell subtype 115 00:05:09.630 --> 00:05:11.550 is the frequent presence of abnormalities 116 00:05:11.550 --> 00:05:13.170 in the von Hippel Lindau gene, 117 00:05:13.170 --> 00:05:15.600 a tumor suppressor gene with pleiotropic 118 00:05:15.600 --> 00:05:19.020 are multiple effects on tumor growth and development. 119 00:05:19.020 --> 00:05:21.810 Renal cell carcinoma occurs in a male to female ratio 120 00:05:21.810 --> 00:05:25.113 of approximately 1.6:1 in most populations studied. 121 00:05:27.029 --> 00:05:30.240 Recent analysis of the U.S. Surveillance, Epidemiology, 122 00:05:30.240 --> 00:05:33.570 and End Results, or SEER database shows that men present 123 00:05:33.570 --> 00:05:35.850 with significantly higher and higher grade 124 00:05:35.850 --> 00:05:38.760 are larger and higher grade tumors than women. 125 00:05:38.760 --> 00:05:39.750 Women have a slightly higher 126 00:05:39.750 --> 00:05:41.826 five-year survival rate than men. 127 00:05:41.826 --> 00:05:44.400 And men have higher levels of exposure to tobacco 128 00:05:44.400 --> 00:05:47.040 and other toxic compounds than women. 129 00:05:47.040 --> 00:05:50.163 Women are also traditionally more health conscious than men. 130 00:05:53.280 --> 00:05:55.860 The association of smoking in renal cell carcinoma 131 00:05:55.860 --> 00:05:57.390 was examined in a meta-analysis 132 00:05:57.390 --> 00:06:00.030 of 24 epidemiologic investigations, 133 00:06:00.030 --> 00:06:03.750 19 case control studies, and five cohort studies. 134 00:06:03.750 --> 00:06:06.660 Combined estimates of relative risk forever smokers 135 00:06:06.660 --> 00:06:11.310 compared to never smokers were 1.38 for all subjects, 136 00:06:11.310 --> 00:06:16.260 1.54 for men, and 1.22 for women. 137 00:06:16.260 --> 00:06:19.290 There were significant dose responses and the risk 138 00:06:19.290 --> 00:06:20.760 with increasing intensity of smoking 139 00:06:20.760 --> 00:06:23.640 in both men and women, and significant risk reductions 140 00:06:23.640 --> 00:06:26.040 were evident in former smokers. 141 00:06:26.040 --> 00:06:27.750 Two case control studies found evidence 142 00:06:27.750 --> 00:06:29.280 that exposure to environmental smoke 143 00:06:29.280 --> 00:06:31.290 significantly increase the risk 144 00:06:31.290 --> 00:06:33.450 of developing renal cell carcinoma, 145 00:06:33.450 --> 00:06:35.070 but further studies will be needed 146 00:06:35.070 --> 00:06:36.873 to confirm this association. 147 00:06:38.670 --> 00:06:39.780 Regulation of blood pressure 148 00:06:39.780 --> 00:06:41.100 is an important kidney function. 149 00:06:41.100 --> 00:06:44.070 And as such, hypertension has been extensively studied 150 00:06:44.070 --> 00:06:44.940 as a risk factor 151 00:06:44.940 --> 00:06:47.730 for the development of renal cell carcinoma. 152 00:06:47.730 --> 00:06:49.917 Several recent epidemiologic studies of hypertension 153 00:06:49.917 --> 00:06:52.650 and renal cell carcinoma in different populations 154 00:06:52.650 --> 00:06:56.100 show reasonable consistency in revealing an association. 155 00:06:56.100 --> 00:06:58.290 Nevertheless, whether hypertension is a cause 156 00:06:58.290 --> 00:07:00.150 or an effect of this malignancy 157 00:07:00.150 --> 00:07:02.103 remains a topic of high controversy. 158 00:07:04.260 --> 00:07:06.720 A study in 2000 examined the health records 159 00:07:06.720 --> 00:07:10.290 of 363,992 Swedish men 160 00:07:10.290 --> 00:07:14.370 who underwent at least one fiscal exam during 1971 to 1992, 161 00:07:14.370 --> 00:07:15.600 and were followed until death 162 00:07:15.600 --> 00:07:17.553 or the end of the study in 1995. 163 00:07:18.387 --> 00:07:20.430 In this study, cases of kidney cancer 164 00:07:20.430 --> 00:07:22.290 were identified through cross linkage of data 165 00:07:22.290 --> 00:07:24.510 within nationwide Swiss Cancer Registry, 166 00:07:24.510 --> 00:07:26.910 or Swedish Cancer Registry. 167 00:07:26.910 --> 00:07:28.890 Results revealed that obesity and hypertension 168 00:07:28.890 --> 00:07:30.330 independently increased the risk 169 00:07:30.330 --> 00:07:32.310 of developing renal cell carcinoma, 170 00:07:32.310 --> 00:07:35.310 but not transitional cell carcinoma, 171 00:07:35.310 --> 00:07:37.200 whereas smoking was a risk factor 172 00:07:37.200 --> 00:07:39.423 for both forms of kidney cancer. 173 00:07:41.940 --> 00:07:43.800 Another study published in 2005 174 00:07:43.800 --> 00:07:46.290 examined the association between death from kidney cancer 175 00:07:46.290 --> 00:07:49.590 and baseline hypertension in a large cohort of Korean men 176 00:07:49.590 --> 00:07:52.620 who were studied from 1992 to 2001. 177 00:07:52.620 --> 00:07:53.453 In this study, 178 00:07:53.453 --> 00:07:55.650 hypertension was found to significantly increased the risk, 179 00:07:55.650 --> 00:07:58.623 and the risk was particularly high among cigarette smokers. 180 00:07:59.520 --> 00:08:01.740 Finally, in a 2005 study, 181 00:08:01.740 --> 00:08:03.660 hypertension was examined 182 00:08:03.660 --> 00:08:06.330 in relation with thiazide use, body mass index, 183 00:08:06.330 --> 00:08:07.713 weight change, and smoking. 184 00:08:09.090 --> 00:08:10.800 Those all were considered as risk factors 185 00:08:10.800 --> 00:08:13.773 for renal cell carcinoma in prospective cohorts in the U.S. 186 00:08:16.380 --> 00:08:18.360 After adjusting for other variables, 187 00:08:18.360 --> 00:08:20.100 hypertension significantly increased the risk 188 00:08:20.100 --> 00:08:23.100 of cancer development in both women and men. 189 00:08:23.100 --> 00:08:24.630 Risk increases were also noted 190 00:08:24.630 --> 00:08:25.980 for obesity and chronic smoking, 191 00:08:25.980 --> 00:08:29.313 but there was no increase with thiazide use. 192 00:08:34.035 --> 00:08:37.290 What's clear from these numerous studies 193 00:08:37.290 --> 00:08:39.510 is that hypertension is independently associated 194 00:08:39.510 --> 00:08:41.310 with a significant increase 195 00:08:41.310 --> 00:08:43.500 in the risk of developing renal cell carcinoma 196 00:08:43.500 --> 00:08:45.360 in both men and women. 197 00:08:45.360 --> 00:08:48.840 What is not yet clear is the sequence of pathogenesis. 198 00:08:48.840 --> 00:08:51.540 Does malignant transformation induced changes 199 00:08:51.540 --> 00:08:55.050 in renin and other vasoactive substances in the kidney 200 00:08:55.050 --> 00:08:56.220 that increase blood pressure? 201 00:08:56.220 --> 00:08:58.680 Or does an increase in blood pressure 202 00:08:58.680 --> 00:09:00.363 cause malignant transformation? 203 00:09:05.670 --> 00:09:07.950 Since type 2 diabetes is ideologically linked 204 00:09:07.950 --> 00:09:09.420 to chronic diseases of the kidney, 205 00:09:09.420 --> 00:09:11.190 like nephrosis and nephritis, 206 00:09:11.190 --> 00:09:12.990 it's logical to examine the association 207 00:09:12.990 --> 00:09:15.720 between diabetes and kidney cancer. 208 00:09:15.720 --> 00:09:18.840 Across numerous studies, individuals with diabetes 209 00:09:18.840 --> 00:09:20.940 were at increased risk for the development of kidney cancer 210 00:09:20.940 --> 00:09:23.160 compared to those without diabetes. 211 00:09:23.160 --> 00:09:26.280 However, there was statistically significant heterogeneity 212 00:09:26.280 --> 00:09:28.860 among studies and the association with diabetes 213 00:09:28.860 --> 00:09:31.140 was stronger in women than men. 214 00:09:31.140 --> 00:09:33.690 Additional studies designed to assess the time interval 215 00:09:33.690 --> 00:09:35.160 both between the onset of diabetes 216 00:09:35.160 --> 00:09:37.893 and the development of kidney cancer are necessary. 217 00:09:40.170 --> 00:09:43.380 Renal cell carcinomas occasionally occur 218 00:09:43.380 --> 00:09:44.460 in a familial setting 219 00:09:44.460 --> 00:09:46.680 in association with certain genetic abnormalities. 220 00:09:46.680 --> 00:09:50.460 However, only a small fraction of cases, or about 4%, 221 00:09:50.460 --> 00:09:53.490 report a positive family history of kidney cancer. 222 00:09:53.490 --> 00:09:55.860 Familial cases often develop multifocal 223 00:09:55.860 --> 00:09:59.190 and or bilateral tumors at a relatively early age. 224 00:09:59.190 --> 00:10:00.930 Among the heritable cancer syndromes, 225 00:10:00.930 --> 00:10:03.600 the most important are the von Hippel Lindau syndrome 226 00:10:03.600 --> 00:10:06.510 and the Birt-Hogg-Dube syndrome. 227 00:10:06.510 --> 00:10:08.822 The von Hippel Lindau syndrome 228 00:10:08.822 --> 00:10:10.890 is a rare autosomal dominant cancer syndrome, 229 00:10:10.890 --> 00:10:14.520 with a prevalence rate of about one in 36,000 individuals. 230 00:10:14.520 --> 00:10:16.920 The syndrome is caused by a mutant tumor suppressor gene 231 00:10:16.920 --> 00:10:20.370 called the von Hippel Lindau gene, or the VHL gene. 232 00:10:20.370 --> 00:10:23.310 Approximately 1/3 of patients who carry a mutant VHL gene 233 00:10:23.310 --> 00:10:26.703 develop clear cell renal carcinoma. 234 00:10:29.550 --> 00:10:31.260 Birt-Hogg-Dube syndrome is a rare 235 00:10:31.260 --> 00:10:33.270 autosomal dominant syndrome that has been identified 236 00:10:33.270 --> 00:10:35.640 in about 50 families worldwide. 237 00:10:35.640 --> 00:10:37.890 This syndrome is characterized by renal cancer. 238 00:10:37.890 --> 00:10:39.090 renal and pulmonary cysts, 239 00:10:39.090 --> 00:10:41.730 and benign tumors of the hair follicles. 240 00:10:41.730 --> 00:10:45.090 It's caused by mutations in the folliculin gene, 241 00:10:45.090 --> 00:10:47.700 or the FLCN, a tumor suppressor gene 242 00:10:47.700 --> 00:10:50.193 located in the short arm of chromosome 17. 243 00:10:52.050 --> 00:10:54.120 Occupational exposures can also play a role 244 00:10:54.120 --> 00:10:56.295 in the development of renal cell carcinoma, 245 00:10:56.295 --> 00:10:58.680 and we see here that asbestos, cadmium, 246 00:10:58.680 --> 00:11:00.960 and petroleum products, and dry cleaning solvents 247 00:11:00.960 --> 00:11:05.960 all have an elevated risk of development of RCC. 248 00:11:07.560 --> 00:11:09.210 We also see that there's synergism 249 00:11:09.210 --> 00:11:12.603 involving environmental exposures in some studies. 250 00:11:14.940 --> 00:11:16.620 A combination of cadmium exposure 251 00:11:16.620 --> 00:11:18.540 and cigarette smoking, for example, 252 00:11:18.540 --> 00:11:21.120 increase the risk of renal cell carcinoma 253 00:11:21.120 --> 00:11:22.413 more than four-fold. 254 00:11:24.570 --> 00:11:26.580 Results of studies of renal cell carcinoma 255 00:11:26.580 --> 00:11:30.210 and heavier long-term use of analgesics are inconsistent. 256 00:11:30.210 --> 00:11:34.650 One study looked at 440 cases of renal cell carcinoma, 257 00:11:34.650 --> 00:11:39.330 spouses of 151 cases, and 691 control subjects. 258 00:11:39.330 --> 00:11:41.700 This study found there was no significant excess risk 259 00:11:41.700 --> 00:11:43.860 observed with regular use of aspirin, acetaminophen, 260 00:11:43.860 --> 00:11:46.173 or combinations of these agents. 261 00:11:47.970 --> 00:11:49.440 Acquired cystic kidney disease 262 00:11:49.440 --> 00:11:51.600 develops in approximately 50% of patients 263 00:11:51.600 --> 00:11:54.060 who are maintained on chronic hemodialysis 264 00:11:54.060 --> 00:11:57.570 and peritoneal dialysis for kidney failure. 265 00:11:57.570 --> 00:11:59.250 A major complication of this condition 266 00:11:59.250 --> 00:12:01.770 is the development of renal cell carcinoma. 267 00:12:01.770 --> 00:12:03.000 Follow up studies of patients 268 00:12:03.000 --> 00:12:04.680 with acquired cystic kidney disease 269 00:12:04.680 --> 00:12:07.080 suggests that their risk of developing renal cell carcinoma 270 00:12:07.080 --> 00:12:11.070 is 50-fold higher than in the general population. 271 00:12:11.070 --> 00:12:13.230 Careful surveillance of dialysis patients 272 00:12:13.230 --> 00:12:16.050 by periodic ultrasonography and computerized tomography 273 00:12:16.050 --> 00:12:18.750 is recommended for the early detection of such tumors. 274 00:12:20.430 --> 00:12:22.380 Finally, the profile of risk factors 275 00:12:22.380 --> 00:12:23.430 associated with the development 276 00:12:23.430 --> 00:12:25.710 of transitional cell carcinomas of the renal pelvis 277 00:12:25.710 --> 00:12:28.290 is essentially the same as for transitional cell carcinomas 278 00:12:28.290 --> 00:12:30.210 of the urinary bladder. 279 00:12:30.210 --> 00:12:31.440 The dominant risk factors, 280 00:12:31.440 --> 00:12:34.020 chronic exposure to tobacco smoke, 281 00:12:34.020 --> 00:12:35.340 which has been found to elevate the risk 282 00:12:35.340 --> 00:12:38.250 two- to three-fold compared to non-smokers. 283 00:12:38.250 --> 00:12:40.080 Carcinogenesis associated with smoking 284 00:12:40.080 --> 00:12:43.320 is primarily the result of aromatic amines and oral amines 285 00:12:43.320 --> 00:12:45.600 present in cigarette smoke. 286 00:12:45.600 --> 00:12:47.910 A number of environmental and occupational factors 287 00:12:47.910 --> 00:12:48.810 increase the risk, 288 00:12:48.810 --> 00:12:51.280 including occupational exposure to aerial amines 289 00:12:52.440 --> 00:12:54.360 and other compounds in intermediates 290 00:12:54.360 --> 00:12:56.580 in the synthesis of azo dyes and pigments 291 00:12:56.580 --> 00:12:58.560 used in the textiles, printing, plastic, rubber, 292 00:12:58.560 --> 00:12:59.643 and cable industries. 293 00:13:00.870 --> 00:13:02.550 Long-term exposure to these compounds 294 00:13:02.550 --> 00:13:04.260 among workers in the industries 295 00:13:04.260 --> 00:13:06.833 increase the risk by about 50%.