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. Author manuscript; available in PMC: 2025 Mar 11.
Published in final edited form as: Environ Mol Mutagen. 2024 Mar 11;65(1-2):47–54. doi: 10.1002/em.22588

Urinary mutagenicity and bladder cancer risk in northern New England

Jason YY Wong 1,2,*, Alexander H Fischer 2,*, Dalsu Baris 2, Laura E Beane-Freeman 2, Margaret R Karagas 3, Molly Schwenn 4, Alison Johnson 5, Peggy P Matthews 6, Adam E Swank 6, G Monawar Hosain 7, Stella Koutros 2, Debra T Silverman 2,§, David M DeMarini 6,§, Nathaniel Rothman 2,§,**
PMCID: PMC11089907  NIHMSID: NIHMS1981005  PMID: 38465801

Abstract

Background:

The etiology of bladder cancer among never smokers without occupational or environmental exposure to established urothelial carcinogens remains unclear. Urinary mutagenicity is an integrative measure that reflects recent exposure to genotoxic agents. Here, we investigated its potential association with bladder cancer in rural northern New England.

Methods:

We analyzed 156 bladder cancer cases and 247 cancer-free controls from a large population-based case-control study conducted in Maine, New Hampshire, and Vermont. Overnight urine samples were deconjugated enzymatically and the extracted organics were assessed for mutagenicity using the plate-incorporation Ames assay with the Salmonella frameshift strain YG1041 +S9. Logistic regression was used to estimate the odds ratios (OR) and 95% confidence intervals (CI) of bladder cancer in relation to having mutagenic versus non-mutagenic urine, adjusted for age, sex, and state, and stratified by smoking status (never, former, and current).

Results:

We found evidence for an association between having mutagenic urine and increased bladder cancer risk among never smokers (OR = 3.8, 95% CI: 1.3–11.2) but not among former or current smokers. Risk could not be estimated among current smokers because nearly all cases and controls had mutagenic urine. Urinary mutagenicity among never-smoking controls could not be explained by recent exposure to established occupational and environmental mutagenic bladder carcinogens evaluated in our study.

Conclusions:

Our findings suggest that among never smokers, urinary mutagenicity potentially reflects genotoxic exposure profiles relevant to bladder carcinogenesis. Future studies are needed to replicate our findings and identify compounds and their sources that influence bladder cancer risk.

Keywords: Urine, Mutagenicity, Bladder, Cancer, Smoking

Introduction

Bladder cancer is a significant health burden in the United States (US), with an estimated 81,180 new cases and 17,100 related deaths in 2022 (NCI 2022). Since 1950, there has been a well-documented excess of bladder cancer in northern New England, a rural region of the US comprised of Maine, New Hampshire, and Vermont (Baris et al. 2016). In these states, incidence rates of bladder cancer were similar in 2001–2004 and were nearly 20% higher compared with the US overall for both men and women (Baris et al. 2016).

Risk factors for bladder cancer include occupational and environmental exposures, smoking, medication, dietary factors, family history of bladder cancer, and genetic susceptibility (Spinelli et al. 1991; Ronneberg et al. 1999; Colt et al. 2011; Wu et al. 2012; Baris et al. 2013; Colt et al. 2014; Figueroa et al. 2014; Baris et al. 2016; Beane Freeman et al. 2017; Cumberbatch et al. 2018; Barry et al. 2020; Sung et al. 2021; Leeming et al. 2022; Weisman et al. 2022; IARC 2023). Among occupational and environmental exposures, known or suspected bladder carcinogens include arsenic, nitrate, diesel engine exhaust, coal-tar pitch volatiles, disinfection by-products, benzidine, beta napthylamine, and coke oven emissions. For most of these agents, genotoxic mechanisms have been identified that are causally related to bladder cancer, including those involving prolonged inflammation and oxidative stress to bladder urothelial cells (IARC 2012b; IARC 2012a; IARC 2012d; IARC 2012c; IARC 2014).

Urinary mutagenicity is an integrative measure that reflects recent exposure to genotoxic agents. It is useful as a biomarker of exposure to complex mixtures of mutagens of known or unknown chemical composition and has been used extensively in biomonitoring studies (Cerna et al. 1997; Andre et al. 2002; Cerna and Pastorkova 2002). A kinetics study in humans found that peak urine mutagenicity occurred 4–5 h after cigarette use, which returned to occasional-smoking baseline levels after 12 h for occasional smokers and after 18 h for heavy smokers (Kado et al. 1985). Besides cigarette smoke (Yamasaki and Ames 1977), urinary mutagenicity is associated with exposure to a variety of carcinogens including benzidine (DeMarini et al. 1997), heterocyclic amines from fried meat (Peters et al. 2004; Shaughnessy et al. 2011), nitrotoluenes (Sabbioni et al. 2006), woodsmoke (Kato et al. 2004; Long et al. 2014), municipal and wildland fires (Keir et al. 2017; Wu et al. 2021), coke oven emissions (De Meo et al. 1987; Clonfero et al. 1995; Simioli et al. 2004), and diesel exhaust and coal combustion emissions (Wong et al. 2021).

The reported evidence for the association between urinary mutagenicity and bladder cancer risk is limited. One case-control “pilot” study in an industrialized part of England found some evidence of an association between urinary mutagenicity and bladder cancer among non-smokers but not smokers (Garner et al. 1982). However, the study design was not provided and there was no reported attempt to exclude sources of known non-tobacco mutagens and bladder carcinogens (Garner et al. 1982). To address this knowledge gap, we measured urinary mutagenicity in the New England Bladder Cancer Study (NEBCS), a population-based case-control study of residents aged 30–79 years in Maine, Vermont, and New Hampshire, which was conducted in 2001–2004 to understand the etiology of bladder cancer (Baris et al. 2009). The NEBCS previously collected and stored urine biospecimens from a large proportion of its participants for future ancillary molecular studies (Fischer et al. 2023), which we now use in our current investigation.

Our primary study aim was to investigate the association between urinary mutagenicity and bladder cancer risk, particularly among participants who never smoked. We focused attention on never smokers because it is likely that their exposure profiles reflected by urinary mutagenicity remained consistent from the etiologic time window relevant for bladder cancer to the time of biospecimen collection. Findings from our study could inform on whether having mutagenic urine reflects exposures and biological processes relevant to bladder carcinogenesis.

Methods

Study design and population

We randomly selected a subset of 490 subjects (~20%) from the NEBCS, a population-based case-control study conducted in Maine, Vermont, and New Hampshire (Baris et al. 2009; Colt et al. 2011). The source study included 1,193 cases with histologically confirmed carcinoma of the urinary bladder. The details of the bladder cancer case ascertainment and control subject selection were previously described in detail (Baris et al. 2009). Briefly, the bladder cancer cases were aged 30–79 years at diagnosis and were diagnosed between September 1, 2001, and October 31, 2004 (Maine and Vermont) or between January 1, 2002, and July 31, 2004 (New Hampshire). A total of 1,418 population-based controls were frequency-matched to cases by state, gender, and age at the date of diagnosis for cases or date of selection for controls (± 5 years).

Collection and preparation of overnight urine samples

Of the 490 study participants, 480 subjects agreed and were physically able to provide overnight urine samples and provided sufficient volume of urine. Subjects selected for overnight urine collection received oral and written information describing the procedures as well as a collection kit that included a cooler with ice packs to store the urine. Overnight urine collection began after the evening meal and continued up to and including the first morning void of the following day. Urine samples were stored in a cooler, retrieved, and stored at −70°C. Subjects completed a questionnaire that included detailed questions about diet, medication, household exposures, and smoking up to 48 h prior to completion of urine collection.

Urine mutagenicity assays

There were 471 subjects (203 cases and 268 controls) with adequate volumes of urine for mutagenicity assays. Urinary mutagenicity was measured as described previously (Kato et al. 2004). Briefly, 50 ml of urine was thawed, filtered through 0.25 μm filters to remove urothelial cells, and de-conjugated enzymatically in 0.2-M (10% v/v) sodium acetate buffer (pH 5.0) (Sigma-Aldrich, St. Louis, MO) containing β-glucuronidase (6 U/ml urine; Cat. No. G-7017, Sigma-Aldrich) and sulfatase (2 U/ml urine; Cat. No. S-9751, Sigma-Aldrich) for 16 h at 37°C. Each urine sample was then poured through a C18 silica-gel column (Waters Sep-Pak WAT04305, Milford, MA), and the organics were eluted with 10 ml of methanol. The organics were then solvent-exchanged into dimethyl sulfoxide (DMSO) to produce an organic concentrate at 150x for the assay. Negative controls consisted of DMSO (100 μl/plate) and C18 resin blanks in which 40 ml of glass-distilled deionized water instead of urine was passed through the columns. The positive control was 2-aminoanthracene (Sigma-Aldrich) at 0.5 μg/plate.

The organic concentrates were assessed for mutagenicity in the standard plate-incorporation assay (Ames test) at 0.3, 0.6, 1.2, 3, 6, and 12 ml-equivalents (ml-eq) per plate (Maron and Ames 1983). The majority (89%) of the concentrates were evaluated at two plates per dose; the remainder were evaluated at one plate per dose due to limited amount of sample. Preliminary studies (data not shown) found that the most sensitive strain was the Salmonella frameshift strain YG1041, which is a derivative of strain TA98 (hisD3052, rfa, ΔuvrB, pKM101) that over-expresses acetyltransferase and nitroreductase (Hagiwara et al. 1993). All experiments used Aroclor-induced, Sprague-Dawley rat liver S9 (Moltox, Boone, NC) in 500 μl of S9 mix per plate to give 2 mg of S9 protein/plate; the S9 mix was prepared as described (Maron and Ames 1983). After 3 days of incubation at 37°C, the revertant (rev) colonies were counted using an automatic colony counter (AccuCount 1000, Manassas, VA).

A urine sample was considered mutagenic if it produced (a) at least a two-fold greater number of rev/ml-eq in at least one replicate plate at a minimum of one dose relative to the average rev/plate of the DMSO control and (b) a positive dose-response that permitted the calculation of a slope over the linear portion of the dose-response curve using Prism (GraphPad, San Diego, CA). Samples that did not meet these criteria were considered non-mutagenic. Samples that exhibited no initial positive dose-response but produced a decrease in the number of rev/ml-eq as the urine concentration increased were considered cytotoxic and were excluded from the final analyses.

All samples were masked to the laboratory personnel and decoded by a data analyst after completing the assays. Mutagenicity assays for the study were divided into 58 batches to avoid exceeding the capacity of the laboratory, which was an average of eight subjects per batch. Urinary mutagenicity among inter-batch masked duplicates showed 71.4% agreement among samples, and inter-batch pooled quality control showed 67.9% agreement among samples.

Definition of variables

A trained interviewer obtained detailed information on demographics, use of tobacco products, and other potential risk factors using a computer-assisted personal interview. Never smokers were defined as subjects who had smoked less than 100 cigarettes over their lifetime. Subjects who had smoked 100 or more cigarettes over their lifetime were classified as: 1) occasional smokers who had smoked more than 100 cigarettes overall but never consumed cigarettes regularly (i.e., at least one cigarette per day for at least 6 months), 2) former smokers who consumed cigarettes regularly but quit smoking 1 year or more before the reference date, and 3) current smokers who consumed cigarettes regularly and were still smoking regularly at the time of their interview or had quit within one year of the reference date. Information on cancer treatment, dietary intake, and environmental exposures in the 48 h prior to the completion of urine collection was obtained via questionnaire at the time of biospecimen retrieval. Current smoking intensity was defined as the number of cigarettes smoked in the 24 h prior to the completion of urine collection.

Statistical Analysis

We excluded subjects who received chemotherapy (n = 21), identified as occasional smokers (n = 9), had unknown smoking status (n = 2), had unknown cigarette consumption in the last 24 h (n = 6), were former smokers who had smoked within the last 24 h (n = 2), and were current smokers who had not smoked in the last 24 h (n = 28). Our final analytic sample included 403 subjects (156 cases and 247 controls). Cytotoxic samples (12 cases and 5 controls) were excluded from the primary analyses. In this group, the urine sample was collected a median of 166 (Range: 60–933) days after diagnosis for cases.

Bivariate analyses were conducted using chi-squared and Fisher exact tests where appropriate. Among never, former, and current smokers, we used multivariable logistic regression to estimate the odds ratios (ORs) and 95% confidence intervals (CI) of bladder cancer in relation to having mutagenic versus non-mutagenic urine, adjusting for age (<55, 55–64, 65–74, and ≥75 years), sex (male or female), and state of residence (Maine, New Hampshire, or Vermont). To test for linear trends, we computed the Wald statistic, treating the median value of each exposure variable category as continuous. To test for multiplicative interaction between two independent variables, we included a cross-product term to the logistic regression model and conducted a likelihood ratio test. Statistical analyses were performed using Stata 14.2 (StataCorp, College Station, TX) unless stated otherwise.

Results

The majority of bladder cancer tumors were non-invasive papillary carcinoma (stage 0a, Ta; 76.2%) and others were stage T1 (13.6%). Only 7 bladder cancer tumors (4.8%) were tumor stage II/III/IV. The distribution of gender, state of residence, ancestry, Hispanic status, and age were similar among bladder cancer cases and controls (Table 1). However, the cases had a significantly higher proportion of current smokers compared with the controls (25.6 vs. 13.0%, P < 0.001). Among current smokers, cases and controls had similar proportions of those who reported smoking >20 cigarettes in the 24 h prior to the completion of overnight urine collection. Notably, the overall distribution of urinary mutagenicity was significantly different between cases and controls (P = 0.04).

Table 1:

Characteristics of Bladder Cancer Cases and Controls with Urinary Mutagenicity Measurements

Cases Controls
n = 156 (%) n = 247 (%) P-value
Gender
 Female 41 (26.3) 67 (27.1)
 Male 115 (73.7) 180 (72.9) 0.85
State of Residence
 Maine 89 (57.1) 137 (55.5)
 Vermont 21 (13.5) 37 (15.0)
 New Hampshire 46 (29.5) 73 (29.6) 0.91
Ancestry
 European 147 (94.2) 234 (94.7)
 Native American/European 8 (5.1) 9 (3.6)
 Other 1 (0.6) 4 (1.6) 0.57
Hispanic
 Yes 4 (2.6) 5 (2.0)
 No 152 (97.4) 241 (97.6)
 Unknown 0 (0.0) 1 (0.4) 0.84
Age (Years)
 <55 29 (18.6) 40 (16.2)
 55–64 44 (28.2) 55 (22.3)
 65–74 55 (35.3) 109 (44.1)
 ≥75 28 (18.0) 43 (17.4) 0.31
Smoking Status
 Never Smoker 23 (14.7) 85 (34.4)
 Former Smoker 93 (59.6) 130 (52.6)
 Current Smoker 40 (25.6) 32 (13.0) <0.001
Current Smoking Intensity by Smoking Statusa
 Among Never Smokers
  0 cigarettes/24 h 23 (100.0) 85 (100.0)
 Among Former smokers
  0 Cigarettes/24 h 93 (100.0) 130 (100.0)
 Among Current Smokers
  1–20 Cigarettes/24 h 23 (57.5) 23 (71.9)
  >20 Cigarettes/24 h 17 (42.5) 9 (28.1) 0.21
Urinary Mutagenicity
 Non-mutagenic 66 (42.3) 128 (51.8) 0.13b
 Mutagenic 81 (51.9) 114 (46.2)
 Cytotoxic 9 (5.8) 5 (2.0)
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a

Current smoking intensity was defined as the number of cigarettes consumed in the 24 h prior to the end of overnight urine collection.

b

Comparing non-mutagenic to mutagenic urine, excluding cytotoxic samples.

We found evidence that having mutagenic urine was associated with increased risk of bladder cancer among never smokers (OR = 3.8; 95% CI: 1.3–11.2; Table 2). However, we did not detect associations between urinary mutagenicity and bladder cancer among former smokers. We could not effectively model associations between urinary mutagenicity and bladder cancer among current smokers because the vast majority of subjects who recently smoked had mutagenic urine (i.e., lack of statistical variation).

Table 2.

Urinary mutagenicity and bladder cancer risk in northern New England by smoking status

Urine Mutagenicity Cases (%) Controls (%) OR (95% CI)*
Never smokers
 Non-mutagenic 8 (36.4) 54 (63.5) 1.0 (Ref)
 Mutagenic 14 (63.6) 31 (36.5) 3.8 (1.3–11.2)
Former smokers
 Non-mutagenic 53 (60.2) 74 (58.7) 1.0 (Ref)
 Mutagenic 35 (39.8) 52 (41.3) 1.0 (0.6–1.8)
Current smokers†
 Non-mutagenic 5 (13.5) 0 (0.0)
 Mutagenic 32 (86.5) 31 (100.0) **
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Cytotoxic samples were excluded from the analysis.

*

Multivariable logistic regression models were adjusted for age (<55, 55–64, 65–74,75+ years), gender (male, female), and state of residence (Maine, Vermont, New Hampshire).

**

Could not be estimated.

†

Current smokers who smoked in the last 24 hours.

Among never-smoking controls, there was evidence of a higher proportion of subjects with mutagenic urine among those who reported using a wood-burning fireplace or stove in the 24 h prior to completion of urine collection (P=0.037; Supplementary Table 1). We did not find an association between urine mutagenicity and current self-reported exposure to environmental tobacco smoke or estimated current occupational exposure to machining fluids or diesel engine exhaust (Supplementary Table 1). Although disinfection byproducts at the highest levels of exposure were previously found to be associated with bladder cancer risk in the source study (Beane Freeman et al. 2017), we did not observe relationships between estimated cumulative and average exposure to disinfection byproducts and urinary mutagenicity among never-smoking controls (Supplementary Table 1).

Discussion

To the best of our knowledge, we conducted the largest population-based epidemiologic study of urinary mutagenicity and bladder cancer risk. Among never smokers, we found evidence that having mutagenic urine was associated with increased risk of bladder cancer compared to having non-mutagenic urine. Associations were not detected among former smokers, and we were unable to effectively estimate associations among current smokers.

We expected to detect associations between urinary mutagenicity and bladder cancer risk among never smokers if they truly exist, but not among former and current smokers. This expectation was based on the assumption that genotoxic exposure profiles reflected by urinary mutagenicity were more likely to remain relatively similar from the etiologic window relevant for bladder carcinogenesis through to the time of biospecimen collection among never smokers. Conversely, we reasoned that current mutagenicity patterns in former smokers are less likely to reflect exposure patterns during the etiologic window, especially when they were smoking. Further, if past tobacco use is responsible for the vast majority of bladder cancer risk among former smokers, it is less likely that recent non-tobacco related exposures reflected by urinary mutagenicity would contribute measurably to bladder carcinogenesis in this subgroup. Among current smokers, the effect of recent tobacco use on urinary mutagenicity is so strong (Kado et al. 1985) that it can potentially hide the contribution of other non-smoking exposures. Indeed, nearly all subjects who recently used tobacco in our analyses had mutagenic urine, which prevented us from effectively modeling effect estimates. As such, never smokers are the most appropriate subgroup to investigate non-tobacco associations reflected by urinary mutagenicity and bladder cancer risk.

We found a higher proportion of never smoking controls with mutagenic urine among those who were recently exposed to indoor woodsmoke, although the majority of controls with mutagenic urines did not have this exposure. This suggestive finding was consistent with results from previous studies (Kato et al. 2004; Wu et al. 2021). The prominent carcinogenic components of biomass combustion emissions include aromatic amines and various species of polycyclic aromatic hydrocarbons (PAHs) (DeMarini and Linak 2022). Although woodsmoke (IARC 2010) has not been established as a bladder carcinogen and has yet to be linked to bladder cancer risk in NEBCS, an IARC working group recently concluded that occupational firefighting causes bladder cancer (IARC 2023). Further, firefighters have been reported to have mutagenic urine (Keir et al. 2017; Wu et al. 2021). Our finding and previous reports suggest that there should be further study of exposure to indoor air pollution from woodburning and bladder cancer risk.

Our study had notable strengths. First, we conducted the largest known study of urinary mutagenicity and bladder cancer risk. Second, we conducted the Ames tests with duplicate measurements for most urine samples, which had good inter-batch agreement, thus improving our confidence in the reliability of our results. Third, we were able to explore relationships between current occupational and environmental exposures and urinary mutagenicity.

Our study had some limitations. First, we were unable to assess mutagenicity in urine samples determined to be cytotoxic. Second, urinary mutagenicity is an integrative measure that reflects recent overall exposure to genotoxic agents and cannot be used to disentangle the contribution of specific exposures. Third, bladder cancer patients potentially had altered behavioral or exposure patterns in the days leading up to biospecimen collection that differentially affected their urinary mutagenicity levels compared with controls. However, we excluded cases who underwent mutagenic chemotherapy to remove this notable source of disease effect bias. In addition, substantial time had elapsed between diagnosis and enrollment of cases. Thus, the vast majority of cases had limited disease making it less likely that the disease, diagnostic procedure, or treatment influenced daily habits and exposures that contributed to urine mutagenicity.

Conclusions

In summary, we found evidence that urinary mutagenicity was associated with increased risk of bladder cancer among never smokers. Further investigation in larger epidemiologic studies of never smokers is needed to confirm our findings and additional analysis of these mutagenic urine samples is needed to identify the specific compounds and their sources that contribute to urinary mutagenicity to extend our understanding of the etiology of bladder cancer in never smokers.

Supplementary Material

1

Acknowledgments

We acknowledge the assistance of L.C. Michael and W. Studabaker at Research Triangle Institute, Research Triangle Park, NC, for performing hydrolyses, organic extractions, and solvent-exchanges of some of the urine samples. We thank Hannah K. Liberatore, Sarah H. Warren, and Lance R. Brooks (U.S. EPA) for their helpful comments.

Funding sources

This research was funded by the intramural research program of the Office of Research and Development, U.S Environmental Protection Agency, Research Triangle Park, NC; as well as by the intramural research program of the National Cancer Institute, National Institutes of Health, Bethesda, MD. This article has been reviewed and approved for publication by the National Cancer Institute (NCI) and the Office of Research and Development (ORD) and the Chemical Characterization and Exposure Division of the U.S. Environmental Protection Agency. Approval does not signify that the contents necessarily reflect the views and policies of the U.S. EPA and/or the NCI, nor does mention of trade names or commercial products constitute endorsement or recommendation of use.

Human subjects institutional review board

The protocol for this study was approved by the National Institutes of Health Institutional Review Board and by the human studies approving officials at the U.S. Environmental Protection Agency.

Abbreviations:

OR

odds ratio

95% CI

95% confidence interval

rev

revertants

Footnotes

CRediT authorship contribution statement

Jason Y.Y. Wong: Analyzed data and wrote subsequent drafts. Alexander H. Fischer: Analyzed data and wrote first draft. Dalsu Baris: Performed the epidemiological study. Debra T. Silverman: Designed and led the epidemiological study. Margaret R. Karagas: Funding acquisition and investigation and supervision of data collection in New Hampshire. Molly Schwenn: Provided study data. Alison Johnson: Provided study data. Richard Waddell: Provided study data. Sai Cherala: Provided study data. Laura E. Beane-Freeman: Analyzed data. Stella Koutros: Provided edits to draft manuscript. Peggy P. Matthews: Prepared media and performed mutagenicity experiments. Adam E. Swank: Performed hydrolyses, organic extractions, and solvent-exchanges of urines. David M. DeMarini: Designed mutagenicity experiments, analyzed the data, and wrote and edited subsequent drafts of the manuscript. Nathaniel Rothman: Conceived and designed the mutagenicity study, directed the analysis, and edited the manuscript.

Declaration of Competing Interest

The authors declare no financial or personal conflicts of interest.

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