Environmental & Occupational Risk Factors for Bladder Cancer

Environmental & Occupational Risk Factors for Bladder Cancer Part I: What Do We Know? July 24, 2018 Presented by: Dr. Debra Key Silverman is the Chief of the Occupational and Environmental Epidemiology Branch at the National Cancer Institute. She received her Doctorate in Epidemiology from the TH Chan Harvard School of Public Health, and her Master's degree in Biostatistics from Johns Hopkins Bloomberg School of Hygiene and Public Health. She joined the NCI as a biostatistician in 1972, and has served as a cancer epidemiologist since 1983. Dr. Silverman's research focused on better understanding three areas of cancer epidemiology; the carcinogenicity of diesel exhaust, the etiology of cancers of the bladder and the pancreas.

Dr. Silverman: My presentation today will include four parts. I'll start off by giving some descriptive factors regarding bladder cancer, and then I'll talk about the occupational and environmental risk factors for the disease, and what we can do about it. There are over 1.3 million patients living with bladder cancer in the world today, and over 600,000 of them are American. Bladder cancer, as you probably are aware, has a favorable survival, however, it does have a high recurrence rate, which leads to lifelong surveillance and care, and makes bladder cancer one of the most expensive cancers in terms of the cost per patient. This year, it's estimated that there will be over 81,000 new cases and more than 17,000 deaths from bladder cancer in the US. This slide shows the bladder cancer mortality rates in the United States. For whites, we have for both men and women, two time periods, 1950 to 1979, and 1980 to 2004. What you can see is that bladder cancer is elevated in the northeastern United States, this elevation is apparent in men and in women, and it has spanned these two large time periods. The elevation is especially pronounced in the Northern part of New England, as well as New Jersey and New York. I'm going to talk more about this excess in a few minutes. You'll also note that rates are elevated in parts of the Midwest, and the far western states,

Environmental & Occupational Risk Factors for Bladder Cancer Dr. Debra Silverman, Lynn Thorp & Dr. Polly Hoppin

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and this is in contrast to the south, where rates are particularly low except for, perhaps, Louisiana and Florida. Here, we have the trends in bladder cancer incidence in the US from 1975 to 2015. By incidence, I mean the new cases diagnosed. Among men, those are the lines with the black symbols. There is a slight decline in incidence, which as occurred since 2005, and it's apparent in all racial groups except black. Among women, incidence is also declining, but the declines are more substantial in black and Hispanic women. These observed declines in the past decade may be partly due to the declines in smoking in the US population. Here, we have the age specific year, bladder cancer incident rates by gender, and race. The striking thing is that incidence rates rise sharply with age, and they plateau at the high, oldest ages and the sharp increase is apparent for both men and women. More than 2/3 of cases are diagnosed at age 65 or older. Because the incidence rates rise sharply with age, as the US population ages, the burden of bladder cancer in the US will continue to grow. Now, onto the accepted risk factors. Bladder cancer is mainly a disease of older, white men. Now, as I mentioned, age is a profound risk factor. The median age at diagnosis is 73. Race is also a risk factor. Incidence rates among white Hispanics and black men are about half of those of white non-Hispanic. Men have a much higher risk than women. There are three or four male cases diagnosed for every female case. Finally, cigarette smoking is the most established risk factor for bladder cancer. What proportion of bladder cancer is attributable to smoking? It's about half of all cases in men and women. This has actually changed over the past 30 years. It used to be that the percent in women was 40%, but as women increased their smoking habits, women have now caught up to men. What are the risks for smokers? Regular smokers have two to three times the risk of nonsmokers. Occasional smokers have nearly twice the risk of nonsmokers. Former smokers have twice the risk of nonsmokers, and current smokers have four to five times the risk of nonsmokers. This risk has increased in recent years.


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This slide shows the variation over time in the risks for current smokers in US studies. In the 1960's, current smokers had about three times the risk of nonsmokers. By the 1990's, it's gone up to four to five times the risk of nonsmokers. On to the occupational risk factors. After smoking, occupational exposures are the other major risk factor for bladder cancer. In men, occupational exposures account for 20 to 30% of cases. In women, it's quite a bit less, about 10 to 17% of cases are caused by occupational exposure. Since the mid-20th century, scores of studies have suggested about 40 potentially high risk occupations for bladder cancer; however, many of the reported associations have not been consistently observed, and strong evidence of increased risk is actually apparent for very few occupational groups, and they're shown on the slide. Workers in the aluminum products industry, such as dye manufacturing, rubber product manufacturing, truck drivers, metalworkers and machinists, hairdressers, painters, textile workers, leather workers, people in dry cleaning, some chemical workers, and printers all are at increased risk of bladder cancer. Now, this slide shows the known or suspected high risk of occupational exposure. Several aromatic amines cause bladder cancer. Aromatic amines are used in dye production, in the manufacturing of synthetic rubber, as a curing agent in epoxy resin systems, and in the polyurethane manufacturing industry. In addition, metalworking fluids are used as cutting oils and coolants; metalworkers and machinists are exposed to them and straight metalworking fluids, in particular, are highly suspect as bladder carcinogens. So is perchloroethylene, or known as perch, which is the primary solvent used in the dry cleaning industry in this country. Diesel engine exhaust is also suspect. Long haul truck drivers and many others are exposed to diesel engine exhaust. Polycyclic aromatic hydrocarbons, or PAHs, and combustion have been linked to bladder cancer as well, and so has combustion and pyrolysis products from natural gas that gas workers are exposed to. Even some pesticides have now been linked to bladder cancer, including Agent Orange as being suspect. Lastly, coal-tar pitch, such as those who work in aluminum smelters, also causes increased risk of bladder cancer.


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Now, environmental exposure. Arsenic is a natural occurring heavy metal. High levels of arsenic in drinking water cause bladder cancer. This has been observed in several countries, including Taiwan, Chile, and Argentina. However, arsenic levels in those countries is several hundredfold higher than what we see here in the United States. Effective ingesting, low to moderate levels of arsenic in water is not well established. Low to moderate levels of arsenic, however, are prevalent in the well water in many parts of the United States, and particularly in northern New England, and may be responsible for the New England bladder cancer excess. As I mentioned earlier, bladder cancer mortality maps show excess mortality from bladder cancer is about a 20% excess that's spanned at least five decades in both men and women, suggesting that it's environmental in origin. We conducted a special study to identify the factors that might be contributing to this high mortality and incidence from bladder cancer in northern New England. It was an epidemiologic study known as a case-control study. We compared patients and non-patients with respect to various exposures of interest. The study included all newly diagnosed bladder cancer patients from 2001 to 2004 who were residents of the states of Maine, New Hampshire, and Vermont, ages 30 to 79. It was a large study and included almost 1200 cases and 1400 control. This slide shows the arsenic concentration in the private well water in the current homes of the controls in our study. It's apparent that low to moderate levels of arsenic are prevalent in the well water in northern New England. You can see this by the red and the orange dots on the slide. A unique characteristic of the New England population is that 45% of the population used private wells as their primary source of drinking water. This compares to about 15% in the total US and in contrast to public supplies, private wells are not regulated. Now, here we have bladder cancer risks by average arsenic concentration, and I'd like to explain a few things. OR stands for odds ratio, which is an estimate of the relevant risk, and what it does is just a measure that gives us the risk of bladder cancer at each level of exposure, relative to the lowest level, which in this case, is less than or equal to .4 micrograms per liter. I'd also like you to know that all the odds ratios I'll be presenting today have been adjusted for smoking, and other bladder cancer risk factors. Overall, we're really not seeing much in effect for average arsenic concentration. There is a slight elevation at the highest level, 1.5 is equivalent to a 50% excess. It's not significant, and the trend is not


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significant. This shows the risk of accumulative arsenic intake, which incorporates a person's individual water intake into the exposure metric. For cumulative arsenic intake, we observed a significant trend in risk, with a doubling of risk at the high end of exposure, which is significant, and a significant trend. The contrast in the findings between the cumulative and average arsenic concentration underscores the importance of incorporating the amount of water consumed by an individual in estimating their arsenic exposure when you're in a low to moderately high population, such as in northern New England. Here we have the risk with just simple water intake, where we see a significant trend in risk with increasing water intake, again, a doubling of risk at the high end of exposure. Because of the region's high prevalence of private well use, we examined the water intake risk association by the type of well people use. Was it a dug, shallow well? This would be defined as less than 150 feet deep, compared to a well that's drilled deep into the bedrock. We also looked at when in time the well was used to gain insight into the region's bladder cancer excess. Here we have the water intake effect amongst those who ever used a private well. We see a significant trend in risk with increasing water intake, nearly a doubling of risk at the high end. When we look at those who never used a private well, the odds ratios really don't look all that different between the two groups, however, this trend is not significant, and this points to an estimate of risk which is not significant. We looked at water intake by type of well used. We see a significant trend in risk with increasing water with exclusive use of dug wells. These people never drank from a drilled well. They have a fourfold risk at the high end of water intake. We don't see the same effect among those who were exclusive users of drilled wells. The trend is not significant.


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Now, we are seeing a marginally significant increased risk here at the high ends of exposure, and it's important to note that drilled wells can have arsenic. Then, we looked at the prevalence of well use by well type over time. Dug wells, that's the blue line, they were dominant type of well, actually, in the US, until about 1960. At that point, after 1960, drilled wells, the red dotted line, became the dominant type of well. This slide shows the heavy use as far as chemical pesticides, that's the red dotted line, in agriculture. In the first half of the 20th century, at the same time that the dug wells were prevalent, that's the blue line. Arsenical pesticides were used on many crops, including those that were very prevalent in northern New England, the blueberries, apples, and potatoes in particular. The dug wells were potentially vulnerable to contamination from arsenic leaching from the treated soils, because they were shallow. This slide shows the water intake effect with timing of the dug well use. Among users of dug wells before 1960, heavy consumption of water was associated with a doubling of risk and a significant trend. However, dug well use after 1960 was not associated with a significant trend. This led us to conclude that the historic consumption of water from private wells, particularly the shallow dug wells in an era when arsenical pesticides were widely used, was associated with increased risk and may have contributed to the New England excess. Our findings are also important because they support an association between exposure to low-to-moderate levels of arsenic in drinking water and bladder cancer in New England. The study was published in 2016 and when it came out, it received quite a bit of press attention, particularly in New England. As the picture suggests, it encouraged New Englanders to get their well water tested for arsenic. In addition to arsenic, a second important question regarding water contaminants in bladder cancer risk, is what the drinking water with high levels of disinfection byproducts, we'll call them DBPs, whether that increases risk. DBPs are formed when chlorine or other disinfectants react with the constituents in source water. Elevated


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levels are found in the public water supplies, which is in contrast to arsenic, which is found mainly in the private wells. There are more than 600 species of DBPs, many of them are genotoxic and mutagenic. It's not clear which ones are the most relevant for bladder cancer. Some evidence suggests that brominated compounds may be important, and in addition to ingestion, other exposure routes include dermal exposure and inhalation from bathing, showering, and swimming. Here, we have the bladder cancer risks, their odds ratio is plotted, for average daily intake of trihalomethanes or THMs. THMs are a leading group of DBPs and they appear in much of the bladder cancer epidemiologic studies, for total THM exposure, we see only an increased risk at the top level of exposure. It's true for the chlorinated THMs and the brominated THM. The trend for the brominated THMs is significant, as is the odds ratio of almost two for the high level of brominated THM ingestion. Here we see the risk from THMs from showering and bathing. There doesn't seem to be an association overall with THM exposure, however, there is a suggestion of an increased risk at the higher levels for the brominated compounds, the trend is not significant. Here, we have the bladder cancer risk by hours of swimming pool use. Basically, we're seeing no association with increased swimming pool use, which should be good news for the swimmers this summer. In conclusion regarding ingestion, increased risk is suggested only at the highest levels of total THMs in this study. However, the overall levels of THMs in New England tends to be lower than that which we see in other studies, and you can see that on this slide. This is New England, and the highest level of exposure, the 95th percentile is 46 micrograms per liter. When you look at the previous studies, this is a pooled analysis, that level is about the 75th percentile, and shows a significant 50% elevation in risk at that level of exposure, with a significant trend. For showering and bathing, overall we're seeing no association, but there is a suggestion of an increased risk with the brominated compounds. It may be the trihalomethanes is not the perfect surrogate for the bladder carcinogens and DBPs, and that's why the effects are not coming out that strong. As far as swimming pool use, we're seeing no association. We don't know everything there is to know about environmental bladder cancer, unfortunately, and there are challenges to identifying bladder carcinogens in the environment.


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Environmental exposures to bladder carcinogens are typically low. The expected risks are low also, which requires large studies with good exposure assessment. Bladder cancer generally has a very long latency. It can be decades, which require us to do exposure assessments in the distant past, which is often difficult in an epidemiologic study. As in all epidemiologic studies, there is misclassification of exposure, which can cause an attenuation of risk, making it difficult to estimate smaller risks in the environment. What can we do? First and foremost, stop smoking cigarettes and remove the known bladder carcinogens from the workplace. The workplace is OSHA's job, and the environment, that's EPA's work. If you have a private well, have your water tested for arsenic. You can install special water filters in homes to reduce elevated arsenic levels and also, elevated DBPs. To get information on water testing, you should be able to obtain that from your state department of health and environmental health services.

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