Trihalomethanes in global drinking water: Distributions, risk assessments, and attributable disease burden of bladder cancer.

This study aimed to assess the global spatiotemporal variations of trihalomethanes (THMs) in drinking water, evaluate their cancer and non-cancer risks, and THM-attributable bladder cancer burden. THM concentrations in drinking water around fifty years on a global scale were integrated. Health risks were assessed using Monte Carlo simulations and attributable bladder cancer burden was estimated by comparative risk assessment methodology. The results showed that global mean THM concentrations in drinking water significantly decreased from 78.37 µg/L (1973-1983) to 51.99 µg/L (1984-2004) and to 21.90 µg/L (after 2004). The lifestage-integrative cancer risk and hazard index of THMs through all exposure pathways were acceptable with the average level of 6.45 × 10-5 and 7.63 × 10-2, respectively. The global attributable disability adjusted of life years (DALYs) and the age-standardized DALYs rate (ASDR) dropped by 16% and 56% from 1990-1994 to 2015-2019, respectively. A big decline in the attributable ASDR was observed in the United Kingdom (62%) and the United States (27%), while China experienced a nearly 3-fold increase due to the expanded water supply coverage and increased life expectancy. However, China also benefited from the spread of chlorination, which helped reduce nearly 90% of unsafe-water-caused mortality from 1998 to 2018.

Sodium-Glucose Cotransporter 2 Inhibitors and the Short-term Risk of Bladder Cancer: An International Multisite Cohort Study.

OBJECTIVE: To determine whether sodium-glucose cotransporter 2 (SGLT2) inhibitors, compared with glucagon-like peptide 1 receptor agonists (GLP-1RAs) or dipeptidyl peptidase 4 (DPP-4) inhibitors, are associated with an increased risk of early bladder cancer events. RESEARCH DESIGN AND METHODS: We conducted a multisite, population-based, new-user, active comparator cohort study using the U.K. Clinical Practice Research Datalink, Medicare fee-for-service, Optum's de-identifed Clinformatics Data Mart Database (CDM), and MarketScan Health databases from January 2013 through December 2020. We assembled two cohorts of adults with type 2 diabetes initiating 1) SGLT2 inhibitors or GLP-1RAs and 2) SGLT2 inhibitors or DPP-4 inhibitors. Cox proportional hazards models were fit to estimate hazard ratios (HRs) and 95% CIs of incident bladder cancer. The models were weighted using propensity score fine stratification. Site-specific HRs were pooled using random-effects models. RESULTS: SGLT2 inhibitor (n = 453,560) and GLP-1RA (n = 375,997) users had a median follow-up ranging from 1.5 to 2.2 years. Overall, SGLT2 inhibitors were not associated with an increased risk of bladder cancer compared with GLP-1RAs (HR 0.90, 95% CI 0.81-1.00). Similarly, when compared with DPP-4 inhibitors (n = 853,186), SGLT2 inhibitors (n = 347,059) were not associated with an increased risk of bladder cancer (HR 0.99, 95% CI 0.91-1.09) over a median follow-up ranging from 1.6 to 2.6 years. Results were consistent across sensitivity analyses. CONCLUSIONS: Contrary to previous randomized controlled trials, these findings indicate that the use of SGLT2 inhibitors is not associated with an increased risk of bladder cancer compared with GLP-1RAs or DPP-4 inhibitors. This should provide reassurance on the short-term effects of SGLT2 inhibitors on bladder cancer incidence.

Risk assessment for o-toluidine and bladder cancer incidence.

BACKGROUND: Elevated bladder cancer incidence has been reported in a cohort of 1875 workers manufacturing chemicals used in the rubber industry and employed any time during 1946-2006. o-Toluidine (OT), an aromatic amine, was the prime suspect agent. Using the available environmental data and process characterization, previous investigators assigned ranks to volatile chemical air concentrations across time in departments and jobs, reflecting probabilities of exposure and use of personal protective equipment for airborne and dermal exposures. Aniline, another aromatic amine, was present at comparable concentrations and is known to be an animal carcinogen but produced lower levels in post-shift urine and of hemoglobin adducts than OT in a group of workers. METHODS: A quantitative risk assessment was performed based on this same population. In this study, cumulative OT exposures were estimated (a) based on previously assigned ranks of exposure intensity and reported actual exposures in jobs with the highest assigned rank, and (b) directly from the historical environmental sampling for OT. Models of bladder cancer incidence were evaluated taking into account possible healthy worker survivor effects. RESULTS: Under various assumptions regarding workforce turnover, the excess lifetime risk of bladder cancer from OT exposure at 1 ppb was estimated to be in the range 1-7 per thousand. CONCLUSIONS: The current ACGIH TLV and OSHA standards for OT are 2 and 5 ppm, respectively, 1000-fold higher than the exposure estimated here for 1-7 per thousand excess lifetime risk.

Ongoing risk of bladder cancer among former workers at the last benzidine manufacturing facility in the USA.

OBJECTIVE: To determine whether there is an ongoing risk of developing bladder cancer in a previously studied cohort of workers exposed to both benzidine and dichlorobenzidine or dichlorobenzidine only in the last benzidine manufacturing plant in the USA. METHODS: Workers (n=488) were identified from the quarterly 941 forms the employer was required to submit to the Social Security Administration from 1960 to 1977. Exposures were assigned based on dates worked and known benzidine/dichlorobenzidine production schedules. Incidence, vital status and cause of death were determined through 2014. Analyses were restricted to white men. RESULTS: Bladder cancer incidence and mortality were significantly increased (25 incident cases, standardised incidence ratio (SIR) 2.19, 95% CI 1.42 to 3.23, and 5 deaths, standardised mortality ratio (SMR) 3.79, 95% CI 1.23 to 8.84). There were significant increases in incidence and mortality in those exposed to both benzidine and dichlorobenzidine (SIR 3.11, 95% CI 1.97 to 4.67, SMR 4.10, 95% CI 1.12 to 10.50), but not among workers exposed to dichlorobenzidine only (two incident cases, SIR 0.89, 95% CI 0.11 to 3.23 and one death, SMR 2.90, 95% CI 0.07 to 16.15). Bladder cancer incidence and mortality were increased in individuals with >20 years since last exposure with >5 years worked (six observed, SIR 5.94, 95% CI 2.18 to 12.92 and two deaths, SMR 7.93, 95% CI 0.96 to 28.65). CONCLUSIONS: Incidence and mortality due to bladder cancer increased among workers exposed to benzidine but not among workers exposed only to dichlorobenzidine. The risk of incidence and death from bladder cancer remain elevated more than 20 years after last exposure to benzidine in those who worked >5 years.

Multiple metal(loid)s bioaccessibility from cooked seafood and health risk assessment.

Seafood has been generally considered to be the main diet exposure source of metal(loid)s. We evaluated health risk of mercury (Hg), arsenic (As), cadmium (Cd), lead (Pb), chromium (Cr), nickel (Ni), copper (Cu), and zinc (Zn) through consumption of cooked seafood based on bioaccessibility, which was obtained by physiologically based extraction test method. Results showed that cooking practices could decrease metal(loid)s concentration from seafood (by 6.0-45.7%). Metal(loid)s release from seafood in this study followed the descending order of Hg > Zn > Ni > Cd > Pb > As > Cu > Cr. On average, cooking lowered the bioaccessibility of As, Hg, Cd, Pb, Ni, Cr, Cu, and Zn by 15.2, 26.1, 30.9, 30.7, 25.7, 31.2, 17.6, and 22.4%, respectively. Health risk calculation results showed that Cr, Ni, and Zn in seafood species in this study were within the human health benefits range. Hg, Cd, Pb, and Cu exposure from cooked seafood was within the safe dose. However, we found that there is a potential of having cancer (especially bladder and lung cancer) for people exposure to iAs from seafood based on bioaccessible contents the first time.

Study design choices for evaluating the comparative safety of diabetes medications: An evaluation of pioglitazone use and risk of bladder cancer in older US adults with type-2 diabetes.

AIM: The aim of the study was to empirically demonstrate the effect of varying study designs when evaluating the safety of pioglitazone in treating bladder cancer. METHODS: We identified Medicare beneficiaries above 65 years of age with diabetes between 2008 and 2015 and with classified exposure (at least two claims within 180 days) to glucose-lowering drugs (GLD), pioglitazone or another drug. The effects of varying the following study design parameters on bladder cancer risk were assessed: use of a new vs existing drug, choice of referent (all non-users and users of GLDs, non-insulin GLDs and DPP-4s) and whether or not censoring accounted for treatment change. We used the Cox proportional hazards model to obtain adjusted HRs and 95% CIs. RESULTS: We included 1,510,212 patients classified as pioglitazone users (N = 135,188) or non-users (N = 1,375,024). Users had more diabetic complications than non-users, but fewer than insulin users. The HR ranged from 1.10 (1.01-1.20) to 1.13 (0.99-1.29) when censoring ignored treatment change, suggesting a weak association or none between pioglitazone and bladder cancer, probably under-estimating risk. However, the HR was 1.20 (1.01-1.42) when cohorts were restricted to new users, censored upon treatment change, and when DPP-4 was used as the referent, suggesting an increased risk of bladder cancer associated with pioglitazone. CONCLUSIONS: The continued demand for new GLDs indicates the need for more robust observational methods to improve the value of generating real-world evidence in equipping clinicians to make informed prescribing decisions. Although there is no one-size-fits-all approach, we recommend active comparator new user study designs that compare therapeutically equivalent drugs and account for treatment changes during follow-up to present the least biased comparative safety estimates.

Development of a Cryptosporidium-arsenic multi-risk assessment model for infant formula prepared with tap water in France.

Tap water is used in France to reconstitute powder infant formula, although it is not sterile and possibly contaminated by microbiological and chemical hazards. The present study aims to quantify risks of using tap water in France for the preparation of infant formula, during the first six months of life. Cryptosporidium and arsenic were selected as hazards of greatest concern in microbiology and chemistry, respectively. A probabilistic model was developed using French (when available) and European (alternatively) data. Second order Monte Carlo simulation was used to separate uncertainty and variability of inputs. Outputs were expressed at the individual level as probability of illness and at the population level, using a common metric, the DALY (Disability Adjusted Life Year). Two scenarios of milk preparation were considered: with un-boiled or boiled tap water. Consuming infant formula rehydrated with un-boiled tap water during the first six months of life led to a total of 2250 DALYs per 100,000 infants (90% uncertainty interval [960; 7650]) for Cryptosporidium due to diarrhea, and 1 DALY [0.4; 2] for arsenic due to expected lifetime risk of lung and bladder cancer as a result of early exposure in life. For the entire population, boiling water would suppress the risk from Cryptosporidium. In contrast, the incremental cancer risk was low at the population level but elevated for 5% of the population exposed to high levels of arsenic. A stringent monitoring of tap water supply points should be continued. This multi-risk assessment model could help public health authorities and managers in evaluating both microbiological and chemical safety issues associated with using infant formula prepared with tap water.

Comparative safety of pioglitazone versus clinically meaningful treatment alternatives concerning the risk of bladder cancer in older US adults with type 2 diabetes.

AIMS: To compare bladder cancer incidence between patients initiating pioglitazone treatment and patients initiating treatment with dipeptidyl-peptidase-4 inhibitors [DPP-4s] or sulfonylureas. METHODS: We identified Medicare beneficiaries aged >65 years who initiated treatment with pioglitazone (N = 38 700), DPP-4s (N = 82 552) or sulfonylureas (N = 126 104) between 2007 and 2014 after at least 6 months without prescriptions for these drug classes. Patients were followed from second prescription until bladder cancer outcome (2 claims within 60 days) using a 6-month induction/latency period, censoring for treatment change, death or end of 2014. We used propensity score-weighted Cox proportional-hazards models to obtain adjusted hazard ratios (aHR) and their 95% confidence intervals. RESULTS: Overall mean age of participants was 75 years and 41% were men. Over a median of 1.2 treatment years, 727 beneficiaries developed bladder cancer. Pioglitazone initiators had an increased incidence of bladder cancer (308 vs 204 [DPP-4s] or 231 [sulfonylureas] per 100 000 person-years; aHR, 1.57 [1.23-2.00] vs DPP-4s and 1.32 [1.02-1.70] vs sulfonylureas). The increased risk emerged within the first 2 years of treatment (aHR, 1.63 [1.22-2.17] vs DPP-4s and 1.32 [0.98-1.78] vs sulfonylureas). If treatment was discontinued within the first 2 years, the risk after 2 years post initiation was attenuated (aHR, 0.89 [0.61-1.28]) compared with patients treated for more than 2 years (aHR, 1.45 [0.93-2.26]) both vs DPP-4s. Findings were consistent across secondary and sensitivity analyses. CONCLUSIONS: Pioglitazone was associated with an elevated risk of bladder cancer compared with DPP-4s and sulfonylureas. The elevated risk emerged within the first 2 years of treatment and was attenuated after discontinuing. Pioglitazone's relative effectiveness should be weighed against a small absolute increase in risk of bladder cancer.

Quantitative assessment of lung and bladder cancer risk and oral exposure to inorganic arsenic: Meta-regression analyses of epidemiological data.

Inorganic arsenic (iAs) in drinking water varies geographically and is prevalent worldwide. While exposures in the US are generally low, there are some areas with higher levels of naturally occurring iAs (potentially >100µg/L) where residents rely on unregulated drinking water wells. Much of the evidence on the association between iAs and cancer comes from epidemiological studies conducted in South American and Asian populations. These populations have generally been exposed to much higher levels of iAs and have differing underlying characteristics, both of which make comparing them to Western populations difficult. A key question is whether and how one should extrapolate from these high exposure studies to estimate cancer risk at lower exposures. We conducted an independent analysis to determine the most appropriate cancer endpoints, studies, and models to support an oral carcinogenicity assessment of iAs, taking into consideration factors that affect the apparent potency of iAs across geographically and culturally distinct populations. We identified bladder and lung cancer as high-priority endpoints and used meta-regression to pool data across studies from different regions of the world to derive oral cancer slope factors (CSFs) and unit risks (excess risk per µg/L) for iAs based on the background risks of bladder and lung cancer in the US. We also calculated concentrations of iAs in water that are not likely to result in cancer risk above what is considered acceptable by the United States Environmental Protection Agency (US EPA). While we derived these factors assuming a linear, no-threshold relationship between iAs and cancer risk, we also evaluated the shape of the dose-response curves and assessed the evidence for overall nonlinearity. Overall, we found that the incremental risks of bladder and lung cancer associated with iAs were relatively low. The sensitivity analyses we conducted suggested that populations with relatively high iAs exposures appeared to drive the pooled cancer risk estimates, but many of our other tested assumptions did not substantially alter these estimates. Finally, we found that the mode of action evidence supports there being a threshold, but making a robust quantitative demonstration of a threshold using epidemiological data is difficult. When considered in the context of typical exposure levels in the US, our potency estimates indicate that iAs-induced cancer risk is much lower than observed bladder and lung cancer incidences. This suggests that the low iAs levels to which much of the general US population is exposed likely do not result in substantial additional cancer risk.

Pioglitazone (Actos) and bladder cancer: Legal system triumphs over the evidence.

In preclinical studies, pioglitazone was associated with bladder cancer in male rats (but not in female rats, mice dogs or monkeys). Because of this association, the Federal Drug Administration requested a large 10year epidemiological study to evaluate whether there was an association between bladder cancer and exposure to pioglitazone in patients. A 5-year interim report published in 2011 showed no significant association between ever vs never exposure to the drug but a significant association in patients exposed to pioglitazone for >2years. Importantly, the final 10year report did not confirm the 5year interim report finding no association between bladder cancer and pioglitazone, even after >4years of exposure to the drug. However, as would be expected, following the 5-year interim report, many epidemiological studies were carried out and civil litigation lawsuits began to be filed. Of the 23 epidemiological studies that have been published to date, 18 showed no association between bladder cancer and pioglitazone (5 with a combination of rosiglitazone and pioglitazone). Of the five that did show a significant association with pioglitazone, three could not be confirmed in the same population and in one of them there were significantly more risk factors for bladder cancer in the patients exposed to pioglitazone. In the fourth one, a significant association became non-significant when patients >79years were included. In the fifth one, detection bias was a major flaw. Currently, >11,000 legal cases have been filed, many of which claim emotional distress due to the fear of bladder cancer. To limit their legal costs, the pharmaceutical company has established a 2.4 billion dollar settlement pool. So much for evidence-based medicine.

Effects of safety warnings and risk management plan for Thiazolidinediones in Taiwan.

PURPOSE: To evaluate changes in thiazolidinedione use and quality of prescription following safety warnings for thiazolidinediones and cardiac risk in 2007, Risk Management Plan (RMP) policy for rosiglitazone in 2010, and warning for pioglitazone and bladder cancer risk in 2010 in Taiwan. METHODS: We obtained 2003-2011 claims data from Taiwan's National Health Insurance Research Database. Using an interrupted time series design and segmented regression, we estimated changes in monthly prescribing rates for thiazolidinediones among all and prevalent diabetes patients with and without cardiovascular disease history (CV history). We also compared time to prescription of thiazolidinediones among new diabetes patients with CV history before and after each regulatory action using survival analysis. RESULTS: Among prevalent patients with and without CV history, the prescribing rates of rosiglitazone decreased 36.88% and 28.92% after safety warnings in 2007 respectively. Pioglitazone prescriptions increased 13% among patients with CV history, but no changes were detected among patients without CV history. After rosiglitazone's RMP policy in 2010, large reductions in prescriptions were observed in patients with CV history (-101.67%) and those without CV history (-88.04%). Among new diabetes patients with CV history, cardiac safety warnings in 2007 significantly delayed the prescription of rosiglitazone, but no significant change was found for pioglitazone. CONCLUSIONS: The Taiwan FDA regulatory actions for thiazolidinediones communicated possible risks of cardiac events and bladder cancer. Different safety regulatory actions had differential impacts on the use of rosiglitazone and pioglitazone and the quality use of these drugs among the high-risk patients.

Low-dose risk assessment for arsenic: a meta-analysis approach.

We conducted a meta-analysis to explore dose-response relationships for bladder and lung cancers when people are chronically exposed to low doses of arsenic. We searched electronic databases for articles published through 2010. Ten studies on bladder cancer and ingested arsenic exposure and five studies on lung cancer and ingested arsenic exposure fit our selection criteria. We also investigate the sensitivity of the absolute risk of lung and bladder cancer under different underlying prevalence measures. Males have a higher risk of bladder cancer than do females at all maximum contamination levels. The absolute risk of bladder cancer and lung cancer from ingested arsenic correlates highly with smoking rates. For a maximum contamination level of 10 µg/L, we estimate that there are about 2.91 additional bladder cancer cases per 100,000 people and, considering studies since 2000, we estimate that there are about 4.51 additional lung cancer cases per 100,000 people.

Use of mode of action data to inform a dose-response assessment for bladder cancer following exposure to inorganic arsenic.

In the recent National Research Council report on conducting a dose-response assessment for inorganic arsenic, the committee remarked that mode of action data should be used, to the extent possible, to extrapolate below the observed range for epidemiological studies to inform the shape of the dose-response curve. Recent in vitro mode of action studies focused on understanding the development of bladder cancer following exposure to inorganic arsenic provide data to inform the dose-response curve. These in vitro data, combined with results of bladder cancer epidemiology studies, inform the dose-response curve in the low-dose region, and include values for both pharmacokinetic and pharmacodynamic variability. Integration of these data provides evidence of a range of concentrations of arsenic for which no effect on the bladder would be expected. Specifically, integration of these results suggest that arsenic exposures in the range of 7-43 ppb in drinking water are exceedingly unlikely to elicit changes leading to key events in the development of cancer or noncancer effects in bladder tissue. These findings are consistent with the lack of evidence for bladder cancer following chronic ingestion of arsenic water concentrations <100 ppb in epidemiological studies.

The global burden of disease for skin, lung, and bladder cancer caused by arsenic in food.

BACKGROUND: Arsenic is a ubiquitous, naturally occurring metalloid that poses a significant human cancer risk. While water consumption provides the majority of human exposure, millions of individuals worldwide are significantly exposed to arsenic through naturally occurring levels of arsenic in grains, vegetables, meats and fish, as well as through food processed with water containing arsenic. Thus, we estimated the global burdens of disease for bladder, lung, and skin cancers attributable to inorganic arsenic in food. METHODS: To determine foodborne inorganic arsenic exposures worldwide, we used World Health Organization estimates of food consumption in thirteen country clusters, in conjunction with reported measurements of total and inorganic arsenic in different foods. We estimated slope factors for arsenic-related bladder and lung cancers, and used the U.S. Environmental Protection Agency skin cancer slope factor, to calculate the annual risk of the cancer incidence in males and females within each country cluster. RESULTS: We estimated that each year 9,129 to 119,176 additional cases of bladder cancer, 11,844 to 121,442 of lung cancer, and 10,729 to 110,015 of skin cancer worldwide are attributable to inorganic arsenic in food. CONCLUSIONS: These estimates indicate that foodborne arsenic exposure causes a significant global burden of human disease. IMPACT: Estimating the global cancer burden caused by arsenic exposure in food will support policies that reduce exposure to disease-promoting environmental hazards.

Arsenic exposure and bladder cancer: quantitative assessment of studies in human populations to detect risks at low doses.

While exposures to high levels of arsenic in drinking water are associated with excess cancer risk (e.g., skin, bladder, and lung), exposures at lower levels (e.g., <100-200 µg/L) generally are not. Lack of significant associations may result from methodological issues (e.g., inadequate statistical power, exposure misclassification), or a different dose-response relationship at low exposures, possibly associated with a toxicological mode of action that requires a sufficient dose for increased tumor formation. The extent to which bladder cancer risk for low-level arsenic exposure can be statistically measured by epidemiological studies was examined using an updated meta-analysis of bladder cancer risk with data from two new publications. The summary relative risk estimate (SRRE) for all nine studies was elevated slightly, but not significantly (1.07; 95% confidence interval [CI]: 0.95-1.21, p-Heterogeneity [p-H]=0.543). The SRRE among never smokers was 0.85 (95% CI: 0.66-1.08, p-H=0.915), whereas the SRRE was positive and more heterogeneous among ever smokers (1.18; 95% CI: 0.97-1.44, p-H=0.034). The SRRE was statistically significantly lower than relative risks predicted for never smokers in the United States based on linear extrapolation of risks from higher doses in southwest Taiwan to arsenic water exposures >10 µg/L for more than one-third of a lifetime. By contrast, for all study subjects, relative risks predicted for one-half of lifetime exposure to 50 µg/L were just above the upper 95% CI on the SRRE. Thus, results from low-exposure studies, particularly for never smokers, were statistically inconsistent with predicted risk based on high-dose extrapolation. Additional studies that better characterize tobacco use and stratify analyses of arsenic and bladder cancer by smoking status are necessary to further examine risks of arsenic exposure for smokers.

Exposure to o-toluidine, aniline, and nitrobenzene in a rubber chemical manufacturing plant: a retrospective exposure assessment update.

The National Institute for Occupational Safety and Health previously conducted a retrospective cancer incidence and mortality study of workers employed at a rubber chemical manufacturing plant. Compared with New York State incidence, the bladder cancer risk was 6.5 times higher for workers considered to have definite exposure to ortho-toluidine and aniline, and 4 times higher for workers with possible exposure. Exposure characterization in the original study utilized a surrogate measure based only on departments in which each worker was ever employed. As part of an update of that study, some departments in the three original exposure groups were reclassified based on a follow-up site visit; interviews with employees, management, and union representatives; and review of records including exposure data. An additional evaluation of department-job combinations, rather than only departments, was used to stratify exposure into four categories. An approximate rank of "relative" exposure level for each department-job-year combination was also assigned using a ranking scale of 0 to 10. The ranks were supported by quantitative exposure levels and by professional judgment. The numerical ranking scale was applied to each worker by multiplying the exposure rank by duration for each job held based on comprehensive individual work histories. The cumulative rank scores for this cohort ranged from 0 to 300 unit-years. The medians of the cumulative rank scores for the exposure categories showed very good agreement with increasing exposure classifications (e.g., 0.72, 4.6, 11, 14 unit-years for the four exposure categories). Workers' breathing zone air sampling data collected at this plant from 1976-2004 were well below published occupational exposure limits for these chemicals, but additional cases of bladder cancer have been reported. The exposure assessment revisions and rank estimates will be used to analyze the updated bladder cancer incidence data.

[Procedures for determining occupational diseases in cases of urological disorders]. / Das Berufskrankheitenverfahren bei urologischen Erkrankungen.

According to section sign 202 of the German Social Security Code VII, individuals diagnosed with bladder cancer or renal cell cancer who had been occupationally exposed to carcinogens known to induce cancer in these human tissues must be reported to the statutory accident insurance. In this paper, the course of the administrative procedure, particularly considering the reporting procedure and screening for occupational risk factors by a CD-based tool, developed by the authors, is described.