Disinfection by-products (DBPs) are formed when disinfectants (chlorine, ozone, chlorine dioxide, or chloramines) react with naturally occurring organic matter, anthropogenic contaminants, bromide, and iodide during the production of drinking water. Here we review 30 years of research on the occurrence, genotoxicity, and carcinogenicity of 85 DBPs, 11 of which are currently regulated by the U.S., and 74 of which are considered emerging DBPs due to their moderate occurrence levels and/or toxicological properties. These 74 include halonitromethanes, iodo-acids and other unregulated halo-acids, iodo-trihalomethanes (THMs), and other unregulated halomethanes, halofuranones (MX [3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone] and brominated MX DBPs), haloamides, haloacetonitriles, tribromopyrrole, aldehydes, and N-nitrosodimethylamine (NDMA) and other nitrosamines. Alternative disinfection practices result in drinking water from which extracted organic material is less mutagenic than extracts of chlorinated water. However, the levels of many emerging DBPs are increased by alternative disinfectants (primarily ozone or chloramines) compared to chlorination, and many emerging DBPs are more genotoxic than some of the regulated DBPs. Our analysis identified three categories of DBPs of particular interest. Category 1 contains eight DBPs with some or all of the toxicologic characteristics of human carcinogens: four regulated (bromodichloromethane, dichloroacetic acid, dibromoacetic acid, and bromate) and four unregulated DBPs (formaldehyde, acetaldehyde, MX, and NDMA). Categories 2 and 3 contain 43 emerging DBPs that are present at moderate levels (sub- to low-mug/L): category 2 contains 29 of these that are genotoxic (including chloral hydrate and chloroacetaldehyde, which are also a rodent carcinogens); category 3 contains the remaining 14 for which little or no toxicological data are available. In general, the brominated DBPs are both more genotoxic and carcinogenic than are chlorinated compounds, and iodinated DBPs were the most genotoxic of all but have not been tested for carcinogenicity. There were toxicological data gaps for even some of the 11 regulated DBPs, as well as for most of the 74 emerging DBPs. A systematic assessment of DBPs for genotoxicity has been performed for approximately 60 DBPs for DNA damage in mammalian cells and 16 for mutagenicity in Salmonella. A recent epidemiologic study found that much of the risk for bladder cancer associated with drinking water was associated with three factors: THM levels, showering/bathing/swimming (i.e., dermal/inhalation exposure), and genotype (having the GSTT1-1 gene). This finding, along with mechanistic studies, highlights the emerging importance of dermal/inhalation exposure to the THMs, or possibly other DBPs, and the role of genotype for risk for drinking-water-associated bladder cancer. More than 50% of the total organic halogen (TOX) formed by chlorination and more than 50% of the assimilable organic carbon (AOC) formed by ozonation has not been identified chemically. The potential interactions among the 600 identified DBPs in the complex mixture of drinking water to which we are exposed by various routes is not reflected in any of the toxicology studies of individual DBPs. The categories of DBPs described here, the identified data gaps, and the emerging role of dermal/inhalation exposure provide guidance for drinking water and public health research.

Occurrence, genotoxicity, and carcinogenicity of regulated and emerging disinfection by-products in drinking water: a review and roadmap for research.

https://www.europeanurology.com/article/S0302-2838(12)00878-0/pdf/epidemiology-and-risk-factors-of-urothelial-bladder-cancer

Epidemiology and risk factors of urothelial bladder cancer

Ductal carcinoma in situ (DCIS) of the breast represents a heterogeneous group of neoplastic lesions in the breast ducts. The goal for management of DCIS is to prevent the development of invasive breast cancer. This manuscript focuses on the NCCN Guidelines Panel recommendations for the workup, primary treatment, risk reduction strategies, and surveillance specific to DCIS.

https://www.unitypoint.org/desmoines/filesimages/Cancer%20Education/Oncology%20Nursing%20Conference/2015/2014%20NCCN%20Clin%20Pract%20Guidelines%20Male%20Sex%20Dysf.pdf

Clinical practice guidelines in oncology

ESMO Consensus Guidelines for management of patients with colon and rectal cancer. A personalized approach to clinical decision making

H. pylori is a common bacterium, and approximately 50 percent of the world's population has been estimated to be infected (198). Humans are the principal reservoir. The prevalence of H. pylori infection varies widely by geographic area, age, race, ethnicity, and SES. Rates appear to be higher in developing than in developed countries, with most of the infections occurring during childhood, and they seem to be decreasing with improvements in hygiene practices. H. pylori causes chronic gastritis and has been associated with several serious diseases of the gastrointestinal tract, including duodenal ulcer and gastric cancer. Since its "discovery" in 1982 by Warren and Marshall (1), H. pylori has been the topic of extensive research. A number of studies have used questionnaire components to investigate factors possibly related to the etiology of H. pylori infection. The majority of recent studies have not found tobacco use or alcohol consumption to be risk factors for H. pylori infection. Adequate nutritional status, especially frequent consumption of fruits and vegetables and of vitamin C, appears to protect against infection with H. pylori. In contrast, food prepared under less than ideal conditions or exposed to contaminated water or soil may increase the risk. Overall, inadequate sanitation practices, low social class, and crowded or high-density living conditions seem to be related to a higher prevalence of H. pylori infection. This finding suggests that poor hygiene and crowded conditions may facilitate transmission of infection among family members and is consistent with data on intrafamilial and institutional clustering of H. pylori infection. Understanding the route of H. pylori transmission is important if public health measures to prevent its spread are to be implemented. Iatrogenic transmission of H. pylori following endoscopy is the only proven mode. For the general population, the most likely mode of transmission is from person to person, by either the oral-oral route (through vomitus or possibly saliva) or perhaps the fecal-oral route. The person-to-person mode of transmission is supported by the higher incidence of infection among institutionalized children and adults and the clustering of H. pylori infection within families. Also lending support to this concept is the detection of H. pylori DNA in vomitus, saliva, dental plaque, gastric juice, and feces. Waterborne transmission, probably due to fecal contamination, may be an important source of infection, especially in parts of the world in which untreated water is common. Recent studies in the United States have linked clinical H. pylori infection with consumption of H. pylori-contaminated well water. This area of research is worthy of further investigation. Although H. pylori has been isolated in domestic cats, additional research has suggested that H. pylori is probably uncommon in domestic cats and thus is probably not a major concern for cat owners. Several studies have suggested sheep as a possible source of H. pylori transmission, a hypothesis that deserves additional investigation. The most recent reservoir suggested for H. pylori transmission is the housefly. However, evidence is lacking that H. pylori can be transmitted to humans from flies that have been in contact with H. pylori-infected feces. Nevertheless, the hypothesis is appealing since flies are known to carry many other infectious diseases. Knowledge of the epidemiology and mode of transmission of H. pylori is important to prevent its spread and may be useful in identifying high-risk populations, especially in areas that have high rates of gastric lymphoma, gastric cancer, and gastric ulcer.

Helicobacter pylori: epidemiology and routes of transmission.

Objective To quantify the association of cancer treatment delay and mortality for each four week increase in delay to inform cancer treatment pathways. Design Systematic review and meta-analysis. Data sources Published studies in Medline from 1 January 2000 to 10 April 2020. Eligibility criteria for selecting studies Curative, neoadjuvant, and adjuvant indications for surgery, systemic treatment, or radiotherapy for cancers of the bladder, breast, colon, rectum, lung, cervix, and head and neck were included. The main outcome measure was the hazard ratio for overall survival for each four week delay for each indication. Delay was measured from diagnosis to first treatment, or from the completion of one treatment to the start of the next. The primary analysis only included high validity studies controlling for major prognostic factors. Hazard ratios were assumed to be log linear in relation to overall survival and were converted to an effect for each four week delay. Pooled effects were estimated using DerSimonian and Laird random effect models. Results The review included 34 studies for 17 indications (n=1 272 681 patients). No high validity data were found for five of the radiotherapy indications or for cervical cancer surgery. The association between delay and increased mortality was significant (P Conclusions Cancer treatment delay is a problem in health systems worldwide. The impact of delay on mortality can now be quantified for prioritisation and modelling. Even a four week delay of cancer treatment is associated with increased mortality across surgical, systemic treatment, and radiotherapy indications for seven cancers. Policies focused on minimising system level delays to cancer treatment initiation could improve population level survival outcomes.

https://www.bmj.com/content/bmj/371/bmj.m4087.full.pdf

Mortality due to cancer treatment delay: systematic review and meta-analysis

Context Adjuvant chemotherapy (AC) improves survival among patients with resected colorectal cancer. However, the optimal timing from surgery to initiation of AC is unknown. Objective To determine the relationship between time to AC and survival outcomes via a systematic review and meta-analysis. Data Sources MEDLINE (1975 through January 2011), EMBASE, the Cochrane Database of Systematic Reviews, and the Cochrane Central Register of Controlled Trials were searched to identify studies that described the relationship between time to AC and survival. Study Selection Studies were only included if the relevant prognostic factors were adequately described and either comparative groups were balanced or results adjusted for these prognostic factors. Data Extraction Hazard ratios (HRs) for overall survival and disease-free survival from each study were converted to a regression coefficient (β) and standard error corresponding to a continuous representation per 4 weeks of time to AC. The adjusted β from individual studies were combined using a fixed-effects model. Inverse variance (1/SE 2 ) was used to weight individual studies. Publication bias was investigated using the trim and fill approach.
 Results We identified 10 eligible studies involving 15 410 patients (7 published articles, 3 abstracts). Nine of the studies were cohort or population based and 1 was a secondary analysis from a randomized trial of chemotherapy. Six studies reported time to AC as a binary variable and 4 as 3 or more categories. Meta-analysis demonstrated that a 4-week increase in time to AC was associated with a significant decrease in both overall survival (HR, 1.14; 95% confidence interval [CI], 1.10-1.17) and disease-free survival (HR, 1.14; 95% CI, 1.10-1.18). There was no significant heterogeneity among included studies. Results remained significant after adjustment for potential publication bias and when the analysis was repeated to exclude studies of largest weight. Conclusion In a meta-analysis of the available literature on time to AC, longer time to AC was associated with worse survival among patients with resected colorectal cancer.

Association between time to initiation of adjuvant chemotherapy and survival in colorectal cancer: a systematic review and meta-analysis.

Background: Exposure to disinfection byproducts in drinking water has been associated with an increased risk of bladder cancer. We pooled the primary data from 6 case-control studies of bladder cancer that used trihalomethanes as a marker of disinfection byproducts. Methods: Two studies were included from the United States and one each from Canada, France, Italy, and Finland. Inclusion criteria were availability of detailed data on trihalomethane exposure and individual water consumption. The analysis included 2806 cases and 5254 controls, all of whom had measures of known exposure for at least 70% of the exposure window of 40 years before the interview. Cumulative exposure to trihalomethanes was estimated by combining individual year-by-year average trihalomethane level and daily tap water consumption. Results: There was an adjusted odds ratio (OR) of 1.24 in men exposed to an average of more than 1 g/L (ppb) trihalomethanes compared with those who had lower or no exposure (95% confidence interval [CI] 1.09 ‐1.41). Estimated relative risks increased with increasing exposure, with an OR of 1.44 (1.20 ‐1.73) for exposure higher than 50 g/L (ppb). Similar results were found with other indices of trihalomethane exposure. Among women, trihalomethane exposure was not associated with bladder cancer risk (0.95; 0.76 ‐1.20). Conclusions: These findings strengthen the hypothesis that the risk of bladder cancer is increased with long-term exposure to disinfection byproducts at levels currently observed in many industrialized countries. (Epidemiology 2004;15: 357‐367)

Disinfection byproducts and bladder cancer: a pooled analysis.

The relationship between waiting time for radiotherapy and clinical outcomes: A systematic review of the literature

Chlorine is by far the most commonly used chemical for the disinfection of water supplies in North America. However, chlorine reacts with organic material in the raw water producing a number of halogenated hydrocarbon by-products. This population-based case-control study in Ontario, Canada examined the relationship between bladder cancer and exposure to chlorination by-products in public water supplies. Residence and water source histories and data from municipal water supplies were used to estimate individual exposure according to water source, chlorination status, and by-product levels (represented by trihalomethane [THM] concentration). Exposures were estimated for the 40-year period prior to the interview, using 696 cases diagnosed with bladder cancer between 1 September 1992 and 1 May 1994 and 1,545 controls with at least 30 years of exposure information. Odds ratios (OR) adjusted for potential confounders were used to estimate relative risk. Those exposed to chlorinated surface water for 35 or more years had an increased risk of bladder cancer compared with those exposed for less than 10 years (OR = 1.41, 95 percent confidence interval [CI] = 1.10-1.81). Those exposed to an estimated THM level > or = 50 micrograms/liter for 35 or more years had 1.63 times the risk of those exposed for less than 10 years (CI = 1.08-2.46). These results indicate that the risk of bladder cancer increases with both duration and concentration of exposure to chlorination by-products, with population attributable risks of about 14 to 16 percent. Chlorination by-products represent a potentially important risk factor for bladder cancer.

Will D. King

Papers

Mortality due to cancer treatment delay: systematic review and meta-analysis

Association between time to initiation of adjuvant chemotherapy and survival in colorectal cancer: a systematic review and meta-analysis.

Disinfection byproducts and bladder cancer: a pooled analysis.

The relationship between waiting time for radiotherapy and clinical outcomes: A systematic review of the literature

Case-control study of bladder cancer and chlorination by-products in treated water (Ontario, Canada).