Maternal and Paternal Household Pesticide Exposure During Pregnancy and Risk of Childhood Acute Lymphoblastic Leukemia.

OBJECTIVE: The aim of this study was to investigate whether risk estimates for childhood acute lymphoblastic leukemia change when restricting model comparison groups to "nonpesticide exposure" (NPE10) households. METHODS: Cases ( n = 1810) 15 years or younger were identified through Children's Cancer Group institutions between 1989 and 1993 and age-/sex-matched to controls ( n = 1951). Household pesticide use during pregnancy/month prior was collected via telephone. NPE10 comparison group reporting no parental exposure to 10 pesticide classes was identified. RESULTS: Adjusted odds ratios increased from 15% to 49% when limiting the comparison to NPE10. Maternal termite insecticide exposure was associated with greatest risk (adjusted odds ratio, 4.21; 95% confidence interval, 2.00-8.88). There was minimal evidence of interaction by child sex or occupational pesticide exposure, and no monotonic dose-response pattern with frequency of use (times per year). CONCLUSIONS: Elevated risks are consistent with published pooled-/meta-analyses and DNA damage. The consistency and magnitude of these associations warrant product labeling, exposure reduction interventions, or both.

Diagnostic Utility of CDC DPDx for an Atypical Presentation of Infectious Crystalline Keratopathy-Like Infiltrate Secondary to Microsporidia.

PURPOSE: To report a case of atypical infectious crystalline keratopathy-like stromal infection secondary to microsporidia wherein diagnosis of the causative organism was aided by use of the Center for Disease Control (CDC) DPDx program. METHODS: We report the case of a 73-year-old woman who presented with atypical infectious crystalline keratopathy-like corneal infection without previous surgical history. RESULTS: The patient had previously been treated for recalcitrant corneal infection with topical antibiotics and steroids at an outside provider before referral. Further treatment with topical fortified antibiotics failed to improve the infection. Corneal biopsy was performed and sent to the CDC DPDx for diagnostic confirmation for presumptive microsporidia. The patient underwent therapeutic penetrating keratoplasty without recurrence of ocular infection. CONCLUSIONS: Utilization of the DPDx resource may help guide appropriate and timely diagnosis and management strategies in atypical presentations of infectious keratitis.

Coffee intake and trace element blood concentrations in association with renal cell cancer among smokers.

PURPOSE: To determine whether higher coffee intake may reduce the risk of renal cell cancer (RCC) associated with lead (Pb) and other heavy metals with known renal toxicity. METHODS: We conducted a nested case-control study of male smokers (136 RCC cases and 304 controls) within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Cases diagnosed with RCC at 5 or more years following cohort enrollment were matched to controls on age (± 7 years) and whole blood draw date (± 30 days). Conditional logistic regression (using two-sided tests) was used to test for main effects and additive models of effect modification. RESULTS: After a mean follow-up of 16.3 years, coffee consumption was not significantly associated with renal cell cancer risk, when adjusting for blood concentrations of Cd, Hg, and Pb and RCC risk factors (age, smoking, BMI, and systolic blood pressure) (p-trend, 0.134). The association with above median blood Pb and RCC (HR = 1.69, 95% CI 1.06, 2.85) appeared to be modified by coffee consumption, such that RCC risk among individuals with both increased coffee intake and higher blood lead concentration were more than threefold higher RCC risk (HR = 3.40, 95% CI 1.62, 7.13; p-trend, 0.003). CONCLUSION: Contrary to our initial hypothesis, this study suggests that heavy coffee consumption may increase the previously identified association between higher circulating lead (Pb) concentrations and increased RCC risk. Improved assessment of exposure, including potential trace element contaminants in coffee, is needed.

Targeted Deep Sequencing of Bladder Tumors Reveals Novel Associations between Cancer Gene Mutations and Mutational Signatures with Major Risk Factors.

PURPOSE: Exome- and whole-genome sequencing of muscle-invasive bladder cancer has revealed important insights into the molecular landscape; however, there are few studies of non-muscle-invasive bladder cancer with detailed risk factor information. EXPERIMENTAL DESIGN: We examined the relationship between smoking and other bladder cancer risk factors and somatic mutations and mutational signatures in bladder tumors. Targeted sequencing of frequently mutated genes in bladder cancer was conducted in 322 formalin-fixed paraffin-embedded bladder tumors from a population-based case-control study. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI), evaluating mutations and risk factors. We used SignatureEstimation to extract four known single base substitution mutational signatures and Poisson regression to calculate risk ratios (RR) and 95% CIs, evaluating signatures and risk factors. RESULTS: Non-silent KDM6A mutations were more common in females than males (OR = 1.83; 95% CI, 1.05-3.19). There was striking heterogeneity in the relationship between smoking status and established single base substitution signatures: current smoking status was associated with greater ERCC2-Signature mutations compared with former (P = 0.024) and never smoking (RR = 1.40; 95% CI, 1.09-1.80; P = 0.008), former smoking was associated with greater APOBEC-Signature13 mutations (P = 0.05), and never smoking was associated with greater APOBEC-Signature2 mutations (RR = 1.54; 95% CI, 1.17-2.01; P = 0.002). There was evidence that smoking duration (the component most strongly associated with bladder cancer risk) was associated with ERCC2-Signature mutations and APOBEC-Signature13 mutations among current (P trend = 0.005) and former smokers (P = 0.0004), respectively. CONCLUSIONS: These data quantify the contribution of bladder cancer risk factors to mutational burden and suggest different signature enrichments among never, former, and current smokers.

Novel Microforceps Technique Developed for Endothelial Surgical Procedures.

PURPOSE: To develop a more efficient and less traumatic method of Descemet membrane removal in endothelial surgery. METHODS: A novel, vertically oriented, reverse-grasping microforceps (named the Rabiyah Descemet Membrane Removal Microforceps) were created to facilitate grasping and extraction of a host Descemet membrane. RESULTS: This new instrument has been used successfully and safely in more than 85 endothelial keratoplasty cases among 4 surgeons. CONCLUSIONS: The Rabiyah Descemet Membrane Removal Microforceps provides surgeons with a safe and an efficient option to remove Descemet membrane in endothelial surgical procedures.

Diesel exhaust and bladder cancer risk by pathologic stage and grade subtypes.

BACKGROUND: The International Agency for Research on Cancer (IARC) classifies diesel engine exhaust as carcinogenic to humans based on sufficient evidence for lung cancer. IARC noted, however, an increased risk of bladder cancer (based on limited evidence). OBJECTIVE: To evaluate the association between quantitative, lifetime occupational diesel exhaust exposure and risk of urothelial cell carcinoma of the bladder (UBC) overall and according to pathological subtypes. METHODS: Data from personal interviews with 1944 UBC cases, as well as formalin-fixed paraffin-embedded tumor tissue blocks, and 2135 controls were pooled from two case-control studies conducted in the U.S. and Spain. Lifetime occupational histories combined with exposure-oriented questions were used to estimate cumulative exposure to respirable elemental carbon (REC), a primary surrogate for diesel exhaust. Unconditional logistic regression and two-stage polytomous logistic regression were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for smoking and other risk factors. RESULTS: Exposure to cumulative REC was associated with an increased risk of UBC; workers with cumulative REC >396 µg/m3-years had an OR of 1.61 (95% CI, 1.08-2.40). At this level of cumulative exposure, similar results were observed in the U.S. and Spain, OR = 1.75 (95% CI, 0.97-3.15) and OR = 1.54 (95% CI, 0.89-2.68), respectively. In lagged analysis, we also observed a consistent increased risk among workers with cumulative REC >396 µg/m3-years (range of ORs = 1.52-1.93) for all lag intervals evaluated (5-40 years). When we accounted for tumor subtypes defined by stage and grade, a significant association between diesel exhaust exposure and UBC was apparent (global test for association p = 0.0019). CONCLUSIONS: Combining data from two large epidemiologic studies, our results provide further evidence that diesel exhaust exposure increases the risk of UBC.

Potential effect modifiers of the arsenic-bladder cancer risk relationship.

Populations exposed to arsenic in drinking water have an increased bladder cancer risk and evidence suggests that several factors may modify arsenic metabolism, influencing disease risk. We evaluated whether the association between cumulative lifetime arsenic exposure from drinking water and bladder cancer risk was modified by factors that may impact arsenic metabolism in a population-based case-control study of 1,213 cases and 1,418 controls. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between cumulative arsenic intake and bladder cancer stratified by age, sex, smoking status, body mass index (BMI), alcohol consumption and folate intake. P-values for interaction were computed using a likelihood ratio test. We observed no statistically significant multiplicative interactions although some variations in associations were notable across risk factors, particularly for smoking and BMI. Among former smokers and current smokers, those with the highest cumulative arsenic intake had elevated risks of bladder cancer (OR = 1.4, 95% CI: 0.96-2.0 and OR = 1.6, 95% CI: 0.91-3.0, respectively; while the OR among never smokers was 1.1, 95% CI: 0.6-1.9, p-interaction = 0.49). Among those classified as normal or overweight based on usual adult BMI, the highest level of cumulative arsenic intake was associated with elevated risks of bladder cancer (OR = 1.3, 95% CI: 0.89-2.0 and OR = 1.6, 95% CI: 1.1-2.4, respectively), while risk was not elevated among those who were obese (OR = 0.9, 95% CI: 0.4-1.8) (p-interaction = 0.14). Our study provides some limited evidence of modifying roles of age, sex, smoking, BMI, folate and alcohol on arsenic-related bladder cancer risk that requires confirmation in other, larger studies.

Editor's Highlight: High-Throughput Functional Genomics Identifies Modulators of TCE Metabolite Genotoxicity and Candidate Susceptibility Genes.

Trichloroethylene (TCE), an industrial chemical and environmental contaminant, is a human carcinogen. Reactive metabolites are implicated in renal carcinogenesis associated with TCE exposure, yet the toxicity mechanisms of these metabolites and their contribution to cancer and other adverse effects remain unclear. We employed an integrated functional genomics approach that combined functional profiling studies in yeast and avian DT40 cell models to provide new insights into the specific mechanisms contributing to toxicity associated with TCE metabolites. Genome-wide profiling studies in yeast identified the error-prone translesion synthesis (TLS) pathway as an import mechanism in response to TCE metabolites. The role of TLS DNA repair was further confirmed by functional profiling in DT40 avian cell lines, but also revealed that TLS and homologous recombination DNA repair likely play competing roles in cellular susceptibility to TCE metabolites in higher eukaryotes. These DNA repair pathways are highly conserved between yeast, DT40, and humans. We propose that in humans, mutagenic TLS is favored over homologous recombination repair in response to TCE metabolites. The results of these studies contribute to the body of evidence supporting a mutagenic mode of action for TCE-induced renal carcinogenesis mediated by reactive metabolites in humans. Our approach illustrates the potential for high-throughput in vitro functional profiling in yeast to elucidate toxicity pathways (molecular initiating events, key events) and candidate susceptibility genes for focused study.

Bladder Cancer and Water Disinfection By-product Exposures through Multiple Routes: A Population-Based Case-Control Study (New England, USA).

BACKGROUND: Ingestion of disinfection byproducts has been associated with bladder cancer in multiple studies. Although associations with other routes of exposure have been suggested, epidemiologic evidence is limited. OBJECTIVES: We evaluated the relationship between bladder cancer and total, chlorinated, and brominated trihalomethanes (THMs) through various exposure routes. METHODS: In a population-based case­control study in New England (n=(1,213) cases; n=(1,418) controls), we estimated lifetime exposure to THMs from ingestion, showering/bathing, and hours of swimming pool use. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression adjusted for confounders. RESULTS: Adjusted ORs for bladder cancer comparing participants with exposure above the 95th percentile with those in the lowest quartile of exposure (based on the distribution in controls) were statistically significant for average daily intake mg/d of total THMs [OR=1.53 (95% CI: 1.01, 2.32), p-trend=0.16] and brominated THMs [OR=1.98 (95% CI: 1.19, 3.29), p-trend=0.03]. For cumulative intake mg, the OR at the 95th percentile of total THMs was 1.45 (95% CI: 0.95, 2.2), p-trend=0.13; the ORs at the 95th percentile for chlorinated and brominated THMs were 1.77 (95% CI: 1.05, 2,.99), p-trend=0.07 and 1.78 (95% CI: 1.05, 3.00), p-trend=0.02, respectively. The OR in the highest category of showering/bathing for brominated THMs was 1.43 (95% CI: 0.80, 2.42), p-trend=0.10. We found no evidence of an association for bladder cancer and hours of swimming pool use. CONCLUSIONS: We observed a modest association between ingestion of water with higher THMs (>95th percentile vs.<25th percentile) and bladder cancer. Brominated THMs have been a particular concern based on toxicologic evidence, and our suggestive findings for multiple metrics require further study in a population with higher levels of these exposures. Data from this population do not support an association between swimming pool use and bladder cancer. https://doi.org/10.1289/EHP89.

Prospective study of DNA methylation at chromosome 8q24 in peripheral blood and prostate cancer risk.

BACKGROUND: Chromosome 8q24 has emerged as an important genetic susceptibility region for several cancers, including prostate cancer; however, little is known about the contribution of DNA methylation in this region to risk. METHODS: We prospectively evaluated DNA methylation at 8q24 in relation to prostate cancer using pre-diagnostic blood samples from 694 prostate cancer cases (including 172 aggressive cases) and 703 controls in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. We used logistic regression to estimate odds ratios and 95% confidence intervals. RESULTS: Although none remained significant after adjustment for multiple testing (q>0.05), of the 50 CpG sites meeting quality control, we identified 8 sites that were nominally associated with prostate cancer (Ptrend<0.05), including 6 correlated (Spearman ρ: 0.20-0.52) sites in POU5F1B and 2 intergenic sites (most significant site: Chr8:128428897 in POU5F1B, Ptrend=0.01). We also identified two correlated (ρ=0.39) sites in MYC (Chr8:128753187 and Chr8:128753154) that were associated with aggressive (Ptrend=0.02 and 0.03), but not non-aggressive disease (Ptrend=0.70 and 0.20; Pheterogeneity=0.01 and 4.6 × 10-3). These findings persisted after adjustment for the top 8q24 prostate cancer variants in our study. CONCLUSIONS: Although requiring replication, our findings provide some evidence that 8q24 DNA methylation levels may be associated with prostate cancer risk.

Long-Lasting Visuo-Vestibular Mismatch in Freely-Behaving Mice Reduces the Vestibulo-Ocular Reflex and Leads to Neural Changes in the Direct Vestibular Pathway.

Calibration of the vestibulo-ocular reflex (VOR) depends on the presence of visual feedback. However, the cellular mechanisms associated with VOR modifications at the level of the brainstem remain largely unknown. A new protocol was designed to expose freely behaving mice to a visuo-vestibular mismatch during a 2-week period. This protocol induced a 50% reduction of the VOR. In vivo pharmacological experiments demonstrated that the VOR reduction depends on changes located outside the flocculus/paraflocculus complex. The cellular mechanisms associated with the VOR reduction were then studied in vitro on brainstem slices through a combination of vestibular afferent stimulation and patch-clamp recordings of central vestibular neurons. The evoked synaptic activity demonstrated that the efficacy of the synapses between vestibular afferents and central vestibular neurons was decreased. In addition, a long-term depression protocol failed to further decrease the synapse efficacy, suggesting that the VOR reduction might have occurred through depression-like mechanisms. Analysis of the intrinsic membrane properties of central vestibular neurons revealed that the synaptic changes were supplemented by a decrease in the spontaneous discharge and excitability of a subpopulation of neurons. Our results provide evidence that a long-lasting visuo-vestibular mismatch leads to changes in synaptic transmission and intrinsic properties of central vestibular neurons in the direct VOR pathway. Overall, these results open new avenues for future studies on visual and vestibular interactions conducted in vivo and in vitro.

Pesticide use and LINE-1 methylation among male private pesticide applicators in the Agricultural Health Study.

Cancer risk may be associated with DNA methylation (DNAm) levels in Long Interspersed Nucleotide Element 1 (LINE-1), a surrogate for global DNAm. Exposure to certain pesticides may increase risk of particular cancers, perhaps mediated in part through global DNAm alterations. To date, human data on pesticide exposure and global DNAm alterations are limited. The goal of this study was to evaluate alterations of LINE-1 DNAm by pesticides in a variety of classes. Data from 596 cancer-free male participants enrolled in the Agricultural Health Study (AHS) were used to examine associations between use of 57 pesticides and LINE-1 DNAm measured via Pyrosequencing in peripheral blood leucocytes. Participants provided information on pesticide use at three contacts between 1993 and 2010. Associations of ever/never pesticide use and lifetime days of application (years of use × days per year) and LINE-1 DNAm level were assessed using linear regression, adjusting for potential confounders (race, age at blood draw, and frequency of drinking alcohol) and other moderately correlated pesticides. After adjustment, ever application of 10 pesticides was positively associated and ever application of eight pesticides was negatively associated with LINE-1 DNAm. In dose-response analyses, increases in five pesticides (imazethapyr, fenthion, EPTC, butylate, and heptachlor) were associated with increasing LINE-1 DNAm (ptrend < 0.05) and increases in three pesticides (carbaryl, chlordane, and paraquat) were associated with decreasing LINE-1 DNAm (ptrend < 0.05). This study provides some mechanistic insight into the pesticide-cancer relationship, which may be mediated in part by epigenetics.

High pesticide exposure events and DNA methylation among pesticide applicators in the agricultural health study.

Pesticide exposure has been associated with acute and chronic adverse health effects. DNA methylation (DNAm) may mediate these effects. We evaluated the association between experiencing unusually high pesticide exposure events (HPEEs) and DNAm among pesticide applicators in the Agricultural Health Study (AHS), a prospective study of applicators from Iowa and North Carolina. DNA was extracted from whole blood from male AHS pesticide applicators (n = 695). Questionnaire data were used to ascertain the occurrence of HPEEs over the participant's lifetime. Pyrosequencing was used to quantify DNAm in CDH1, GSTp1, and MGMT promoters, and in the repetitive element, LINE-1. Linear and robust regression analyses evaluated adjusted associations between HPEE and DNAm. Ever having an HPEE (n = 142; 24%) was associated with elevated DNAm in the GSTp1 promoter at CpG7 (chr11:67,351,134; P < 0.01) and for the mean across the CpGs measured in the GSTp1 promoter (P < 0.01). In stratified analyses, elevated GSTP1 promoter DNAm associated with HPEE was more pronounced among applicators >59 years and those with plasma folate levels ≤16.56 ng/mL (p-interaction <0.01); HPEE was associated with reduced MGMT promoter DNAm at CpG2 (chr10:131,265,803; P = 0.03), CpG3 (chr10:131,265,810; P = 0.05), and the mean across CpGs measured in the MGMT promoter (P = 0.03) among applicators >59 years and reduced LINE-1 DNAm (P = 0.05) among applicators with ≤16.56 ng/mL plasma folate. Non-specific HPEEs may contribute to increased DNAm in GSTp1, and in some groups, reduced DNAm in MGMT and LINE-1. The impacts of these alterations on disease development are unclear, but elevated GSTp1 promoter DNAm and subsequent gene inactivation has been consistently associated with prostate cancer. Environ. Mol. Mutagen. 58:19-29, 2017. © 2016 Wiley Periodicals, Inc.

Smoking status, usual adult occupation, and risk of recurrent urothelial bladder carcinoma: data from The Cancer Genome Atlas (TCGA) Project.

PURPOSE: Tobacco smoking and occupational exposures are the leading risk factors for developing urothelial bladder carcinoma (UBC), yet little is known about the contribution of these two factors to risk of UBC recurrence. We evaluated whether smoking status and usual adult occupation are associated with time to UBC recurrence for 406 patients with muscle-invasive bladder cancer submitted to The Cancer Genome Atlas (TCGA) project. METHODS: Kaplan-Meier and Cox proportional hazard methods were used to assess the association between smoking status, employment in a high-risk occupation for bladder cancer, occupational diesel exhaust exposure, and 2010 Standard Occupational Classification group and time to UBC recurrence. RESULTS: Data on time to recurrence were available for 358 patients over a median follow-up time of 15 months. Of these, 133 (37.2%) experienced a recurrence. Current smokers who smoked for more than 40 pack-years had an increased risk of recurrence compared to never smokers (HR 2.1, 95% CI 1.1, 4.1). Additionally, employment in a high-risk occupation was associated with a shorter time to recurrence (log-rank p = 0.005). We found an increased risk of recurrence for those employed in occupations with probable diesel exhaust exposure (HR 1.8, 95% CI 1.1, 3.0) and for those employed in production occupations (HR 2.0, 95% CI 1.1, 3.6). CONCLUSIONS: These findings suggest smoking status impacts risk of UBC recurrence, although several previous studies provided equivocal evidence regarding this association. In addition to the known causal relationship between occupational exposure and bladder cancer risk, our study suggests that occupation may also be related to increased risk of recurrence.

Elevated Bladder Cancer in Northern New England: The Role of Drinking Water and Arsenic.

BACKGROUND: Bladder cancer mortality rates have been elevated in northern New England for at least five decades. Incidence rates in Maine, New Hampshire, and Vermont are about 20% higher than the United States overall. We explored reasons for this excess, focusing on arsenic in drinking water from private wells, which are particularly prevalent in the region. METHODS: In a population-based case-control study in these three states, 1213 bladder cancer case patients and 1418 control subjects provided information on suspected risk factors. Log transformed arsenic concentrations were estimated by linear regression based on measurements in water samples from current and past homes. All statistical tests were two-sided. RESULTS: Bladder cancer risk increased with increasing water intake (Ptrend = .003). This trend was statistically significant among participants with a history of private well use (Ptrend = .01). Among private well users, this trend was apparent if well water was derived exclusively from shallow dug wells (which are vulnerable to contamination from manmade sources, Ptrend = .002) but not if well water was supplied only by deeper drilled wells (Ptrend = .48). If dug wells were used pre-1960, when arsenical pesticides were widely used in the region, heavier water consumers (>2.2 L/day) had double the risk of light users (<1.1 L/day, Ptrend = .01). Among all participants, cumulative arsenic exposure from all water sources, lagged 40 years, yielded a positive risk gradient (Ptrend = .004); among the highest-exposed participants (97.5th percentile), risk was twice that of the lowest-exposure quartile (odds ratio = 2.24, 95% confidence interval = 1.29 to 3.89). CONCLUSIONS: Our findings support an association between low-to-moderate levels of arsenic in drinking water and bladder cancer risk in New England. In addition, historical consumption of water from private wells, particularly dug wells in an era when arsenical pesticides were widely used, was associated with increased bladder cancer risk and may have contributed to the New England excess.

Analgesic use and risk of renal cell carcinoma: A case-control, cohort and meta-analytic assessment.

Analgesics are the most commonly consumed drugs worldwide. Evidence that analgesics increase kidney cancer risk has been mixed. We investigated the association between renal cell carcinoma (RCC) and analgesic use in a large population-based case-control study and a post-trial observational cohort study. Findings were used to update a recent meta-analytic review. We analyzed data from 1,217 RCC cases and 1,235 controls in the US Kidney Cancer Study and 98,807 participants in the US Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO: n = 137 RCCs). Self-reported acetaminophen, aspirin and nonsteroid anti-inflammatory drug (NSAID) use and duration information was assessed in relation to RCC. For the US Kidney Cancer Study, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression. For PLCO, we computed hazard ratios (HRs) and 95%CIs using Cox regression. Among case-control participants, RCC risk was associated with over-the-counter acetaminophen use (OR = 1.35, 95%CI = 1.01-1.83). There was a positive trend with increasing duration (p-trend = 0.01), with a two-fold risk for use ≥10 years (OR = 2.01, 95%CI = 1.30-3.12). No association with prescription acetaminophen use was detected. In PLCO, acetaminophen use was also associated with increased RCC risk (HR = 1.68, 95%CI = 1.19-2.39), although elevated risk was absent among the few long-term users. No association with RCC risk was detected for aspirin or NSAIDs use in either study. An association between acetaminophen use and kidney cancer was supported by meta-analytic cohort (n = 4; summary relative risk = 1.34; 95%CI = 1.13-1.59; p-heterogeneity = 0.40) and case-control (n = 9, summary OR = 1.20; 95%CI = 1.01-1.42; p-heterogeneity = 0.05) findings. In brief, acetaminophen use may increase the risk of developing RCC.

A case-control study of occupational sunlight exposure and renal cancer risk.

Epidemiological evidence of a relationship between vitamin D and kidney cancer risk has been inconsistent despite experimental data indicating that vitamin D and its metabolites may inhibit carcinogenesis. Previously we reported an inverse association between renal cell carcinoma (RCC) risk and occupational ultraviolet (UV) exposure among European men. In this study, we examined the association between occupational UV exposure and RCC risk among US residents and investigated whether this association varied by race and sex. Lifetime occupational data for 1,217 RCC cases and 1,235 controls in a population-based case-control study, conducted from 2002 to 2007, were assessed for occupational UV exposure. We evaluated exposure metrics in quartiles based on control exposure levels and calculated associations between RCC risk and occupational UV exposure using unconditional logistic regression adjusted for sex, race, body mass index, smoking, hypertension, center, education, family history of cancer and dietary vitamin D intake. A general pattern of decreasing RCC risk with increasing UV exposure was observed. Cases had significantly lower cumulative occupational UV exposure than controls (fourth quartile vs. first: odds ratio = 0.74 [95% confidence interval = 0.56-0.99], p-trend = 0.03). Similar results were observed for other UV exposure metrics. The association with occupational UV exposure was stronger for women than for men, but did not differ by race. Our findings suggest an inverse association between occupational UV exposure and RCC, particularly among women. Given the sex finding discrepancies in this study versus our previous study, additional research is need to clarify whether the protective effects of occupational UV exposure and RCC risk are real.

Modification of Occupational Exposures on Bladder Cancer Risk by Common Genetic Polymorphisms.

Few studies have demonstrated gene/environment interactions in cancer research. Using data on high-risk occupations for 2258 case patients and 2410 control patients from two bladder cancer studies, we observed that three of 16 known or candidate bladder cancer susceptibility variants displayed statistically significant and consistent evidence of additive interactions; specifically, the GSTM1 deletion polymorphism (P interaction ≤ .001), rs11892031 (UGT1A, P interaction = .01), and rs798766 (TMEM129-TACC3-FGFR3, P interaction = .03). There was limited evidence for multiplicative interactions. When we examined detailed data on a prevalent occupational exposure associated with increased bladder cancer risk, straight metalworking fluids, we also observed statistically significant additive interaction for rs798766 (TMEM129-TACC3-FGFR3, P interaction = .02), with the interaction more apparent in patients with tumors positive for FGFR3 expression. All statistical tests were two-sided. The interaction we observed for rs798766 (TMEM129-TACC3-FGFR3) with specific exposure to straight metalworking fluids illustrates the value of integrating germline genetic variation, environmental exposures, and tumor marker data to provide insight into the mechanisms of bladder carcinogenesis.

Evaluating Evidence for Association of Human Bladder Cancer with Drinking-Water Chlorination Disinfection By-Products.

Exposure to chlorination disinfection by-products (CxDBPs) is prevalent in populations using chlorination-based methods to disinfect public water supplies. Multifaceted research has been directed for decades to identify, characterize, and understand the toxicology of these compounds, control and minimize their formation, and conduct epidemiologic studies related to exposure. Urinary bladder cancer has been the health risk most consistently associated with CxDBPs in epidemiologic studies. An international workshop was held to (1) discuss the qualitative strengths and limitations that inform the association between bladder cancer and CxDBPs in the context of possible causation, (2) identify knowledge gaps for this topic in relation to chlorine/chloramine-based disinfection practice(s) in the United States, and (3) assess the evidence for informing risk management. Epidemiological evidence linking exposures to CxDBPs in drinking water to human bladder cancer risk provides insight into causality. However, because of imprecise, inaccurate, or incomplete estimation of CxDBPs levels in epidemiologic studies, translation from hazard identification directly to risk management and regulatory policy for CxDBPs can be challenging. Quantitative risk estimates derived from toxicological risk assessment for CxDBPs currently cannot be reconciled with those from epidemiologic studies, notwithstanding the complexities involved, making regulatory interpretation difficult. Evidence presented here has both strengths and limitations that require additional studies to resolve and improve the understanding of exposure response relationships. Replication of epidemiologic findings in independent populations with further elaboration of exposure assessment is needed to strengthen the knowledge base needed to better inform effective regulatory approaches.