Ambient polycyclic aromatic hydrocarbon exposure and breast cancer risk in a population-based Canadian case-control study.

PURPOSE: Polycyclic aromatic hydrocarbons (PAHs) represent a class of ubiquitous pollutants recognized as established human carcinogens and endocrine-disrupting chemicals. PAHs have seldom been modeled at the population-level in epidemiological studies. Fluoranthene is a prevalent PAH in urban settings and correlates with the occurrence of other PAHs. The purpose of this study was to evaluate associations between long-term residential exposure to ambient PAHs and breast cancer risk, both pre- and post-menopausal, in Canada. METHODS: Using the National Enhanced Cancer Surveillance System (NECSS), a national-scale Canadian population-based case-control study, annual fluoranthene exposures were estimated using the GEM-MACH-PAH chemical transport model on the basis of geocoded residential histories throughout a 20-year exposure window. Odds ratios (ORs) and 95% confidence intervals (CIs) controlling for potential confounders were estimated using logistic regression. Separate analyses were conducted for Ontario and national samples given a finer-resolution exposure surface and additional risk factor information available for Ontario. RESULTS: Positive associations were observed between fluoranthene exposure and premenopausal breast cancer, with inconsistent findings for postmenopausal breast cancer. For premenopausal breast cancer, adjusted ORs of 2.48 (95% CI: 1.29, 4.77) and 1.59 (95% CI: 1.11, 2.29) were observed when comparing the second highest category of exposure to the lowest, among the Ontario and national samples, respectively. For postmenopausal breast cancer, adjusted ORs were 1.10 (95% CI: 0.67, 1.80) and 1.33 (95% CI: 1.02, 1.73). Associations for the highest level of exposure, across both samples and menopausal strata, were non-significant. CONCLUSION: This study provides support for the hypothesis that ambient PAH exposures increase the risk of premenopausal breast cancer.

Maternal exposure to metals and time-to-pregnancy: The MIREC cohort study.

OBJECTIVE: To study the association between maternal exposure to arsenic, cadmium, lead, manganese and mercury, time-to-pregnancy (TTP) and infertility. DESIGN: Pregnancy-based retrospective TTP cohort study. SETTING: Hospitals and clinics from ten cities across Canada. POPULATION: A total of 1784 pregnant women. METHODS: Concentrations of arsenic, cadmium, lead, manganese and mercury were measured in maternal whole blood during the first trimester of pregnancy as a proxy of preconception exposure. Discrete-time Cox proportional hazards models generated fecundability odds ratios (FOR) for the association between metals and TTP. Logistic regression generated odds ratios (OR) for the association between metals and infertility. Models were adjusted for maternal age, pre-pregnancy body mass index, education, income, recruitment site and plasma lipids. MAIN OUTCOME MEASURES: TTP was self-reported as the number of months of unprotected intercourse to become pregnant. Infertility was defined as TTP longer than 12 months. RESULTS: A total of 1784 women were eligible for the analysis. Mean ± SD maternal age and gestational age at interview were 32.2 ± 5.0 years, and 11.6 ± 1.6 weeks, respectively. Exposure to arsenic, cadmium, manganese or mercury was not associated with TTP or infertility. Increments of one standard deviation of lead concentrations resulted in a shorter TTP (adjusted FOR 1.09, 95% CI 1.02-1.16); however, the association was not linear when exposure was modelled in tertiles. CONCLUSION: Blood concentrations of metals at typical levels of exposure among Canadian pregnant women were not associated with TTP or infertility. Further studies are needed to assess the role of lead, if any, on TTP.

Time spent in the sun and the risk of developing non-Hodgkin lymphoma: a Canadian cohort study.

PURPOSE: The objective was to explore the relationship of sun behavior patterns with the risk of developing non-Hodgkin lymphoma (NHL). METHODS: Sun behavior information from Alberta's Tomorrow Project, CARTaGENE, and Ontario Health Study were utilized. The relationship between time in the sun during summer months and risk of NHL was assessed using Cox proportional hazard models with age as the time scale and adjustment for confounders. Cohorts were analyzed separately and hazard ratios (HR) pooled with random effects meta-analysis. Joint effects of time in the sun and use of sun protection were examined. Patterns of exposure were explored via combinations of weekday and weekend time in the sun. RESULTS: During an average follow-up of 7.6 years, 205 NHL cases occurred among study participants (n = 79,803). Compared to < 30 min daily in the sun, we observed HRs of 0.84 (95% CI 0.55-1.28) for 30-59 min, 0.63 (95% CI 0.40-0.98) for 1-2 h, and 0.91 (95% CI 0.61-1.36) for > 2 h. There was suggestive evidence that > 2 h was protective against NHL with use of sun protection, but not without it. Compared to < 30 min daily, moderate exposure (30 min to 2 h on weekdays or weekend) was associated with a lower risk of NHL (HR 0.63, 95% CI 0.43-0.92), while intermittent (< 30 min on weekdays and > 2 h on weekends) and chronic (> 2 h daily) were not. CONCLUSION: This study provides evidence of a protective effect of moderate time spent in the sun on NHL risk.

An exposure-response meta-analysis of ambient PM2.5 during pregnancy and preeclampsia.

Relationships between PM2.5 exposure and preeclampsia have been the focus of four recent systematic reviews and meta-analyses. We expand on knowledge gaps in these reviews by characterizing the shape of the exposure-outcome relationship, and by assessing the heterogeneity in these associations by study characteristics. Studies of PM2.5 and preeclampsia were identified from reviews, and confounder-adjusted estimates were extracted. Estimates were derived using a random-effects model. Potential non-linearity was evaluated using a one-stage dose-response meta-analysis. Contrary to previous meta-analyses reporting stronger relationships, the overall adjusted relative risk (RR) for a 10 µg/m3 average increase in PM2.5 during pregnancy and preeclampsia was modest and not statistically significant (RR: 1.07, 95% CI: 0.99-1.15). This was mainly attributable to inclusion/exclusion decisions for studies made during this review. In addition, there was no evidence of non-linearity, and no important sub-group differences by characteristics such as region, exposure assessment, participant exclusions, and early versus late-onset preeclampsia. Overall, our analysis suggests a modest relationship between ambient PM2.5 and preeclampsia. We provide details on inclusion and exclusion decisions that were lacking in previous studies, and report novel investigations of non-linearity and heterogeneity.

The current burden of non-melanoma skin cancer attributable to ultraviolet radiation and related risk behaviours in Canada.

PURPOSE: Ultraviolet radiation (UVR) is an established cause of non-melanoma skin cancer (NMSC)-basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). The aim of this study was to estimate the current burden of BCC and SCC associated with UVR and modifiable UVR behaviours (sunburn, sunbathing, and indoor tanning) in Canada in 2015. METHODS: The current burden of BCC and SCC associated with UVR was estimated by comparing 2015 incidence rates with rates of less exposed body sites (trunk and lower limbs) after adjusting for estimated surface areas. The burden associated with modifiable UVR behaviours was estimated by using prevalence estimates among Caucasians from the Second National Sun Survey, and relative risks that are generalizable to Canadians from conducting meta-analyses of relevant studies. RESULTS: We estimated that 80.5% of BCCs and 83.0% of SCCs were attributable to UVR. Adult sunburn was associated with relative risks of 1.85 (95% CI 1.15-3.00) for BCC and 1.41 (95% CI 0.91-2.18) for SCC, while adult sunbathing was associated with relative risks of 1.82 (95% CI 1.52-2.17) for BCC and 1.14 (95% CI 0.53-2.46) for SCC. We estimated that 18.6% of BCCs and 9.9% of SCCs were attributable to adult sunburn, while 28.1% of BCCs were attributable to adult sunbathing. We estimated that 46.2% of BCCs and 17.3% of SCCs were attributable to modifiable UVR behaviours combined. CONCLUSION: Our results provide quantifiable estimates of the potentially avoidable burden of NMSCs among Canadians. These estimates can be used to motivate prevention efforts in Canada.

The effect of acute outdoor air pollution on peak expiratory flow in individuals with asthma: A systematic review and meta-analysis.

OBJECTIVES: Acute exposures to outdoor air pollution have been shown to reduce lung function in children with asthma, but the effect on adults with asthma has not been established in a meta-analysis. The objective of this study was to conduct a systematic literature review and meta-analysis of studies that assessed the relationship of outdoor air pollution and peak expiratory flow (PEF) in adults with asthma. METHODS: Studies that contained data on outdoor air pollution levels (PM10, PM2.5, or NO2) and PEF in adults with asthma were eligible for inclusion. Effect estimates were quantified for each air pollution measure using random effects models. Heterogeneity was investigated with the Q-test and I2 statistics. Meta-regression and subgroup analyses were conducted to determine differences in effect by air pollution measures and the inclusion of smokers. RESULTS: A total of 22 effect estimates from 15 studies were included in this review. A 10 µg/m3 increase in acute PM10 exposure was associated with a -0.19 L/min (95% CI: 0.30, -0.09) change in PEF. For both PM10 and PM2.5, the inclusion of current smokers was a significant source of heterogeneity among studies (meta-regression: p = 0.04 and p = 0.03). Among studies that only included non-smokers, a 10 µg/m3 increase in acute exposure to PM10 and PM2.5 was associated with changes in PEF of -0.25 L/min (95% CI: 0.38, -0.13) and -1.02 L/min (95% CI: 1.79, -0.24), respectively. CONCLUSIONS: This study provides evidence that acute increases in PM10 and PM2.5 levels are associated with decreases in PEF in adults with asthma, particularly among non-smokers.

Estimates of the current and future burden of lung cancer attributable to residential radon exposure in Canada.

Radon is widely recognized as a human carcinogen and findings from epidemiologic studies support a causal association between residential radon exposure and lung cancer risk. Our aim was to derive population attributable risks (PAR) to estimate the numbers of incident lung cancer due to residential radon exposure in Canada in 2015. Potential impact fractions for 2042 were estimated based on a series of counterfactuals. A meta-analysis was conducted to estimate the relative risk of lung cancer per 100 Becquerels (Bq)/m3 increase in residential radon exposure, with a pooled estimate of 1.16 (95% CI: 1.07-1.24). The population distribution of annual residential radon exposure was estimated based on a national survey with adjustment for changes in the population distribution over time, the proportion of Canadians living in high-rise buildings, and to reflect annual rather than winter levels. An estimated 6.9% of lung cancer cases in 2015 were attributable to exposure to residential radon, accounting for 1741 attributable cases. If mitigation efforts were to reduce all residential radon exposures that are above current Canadian policy guidelines of 200 Bq/m3 (3% of Canadians) to 50 Bq/m3, 293 cases could be prevented in 2042, and 2322 cumulative cases could be prevented between 2016 and 2042. Our results show that mitigation that exclusively targets Canadian homes with radon exposures above current Canadian guidelines may not greatly alleviate the future projected lung cancer burden. Mitigation of residential radon levels below current guidelines may be required to substantially reduce the overall lung cancer burden in the Canadian population.

The current and future burden of cancer attributable to modifiable risk factors in Canada: Summary of results.

Nearly one in two Canadians are expected to be diagnosed with cancer in their lifetime. However, there are opportunities to reduce the impact of modifiable cancer risk factors through well-informed interventions and policies. Since no comprehensive Canadian estimates have been available previously, we estimated the proportion of cancer diagnosed in 2015 and the future burden in 2042 attributable to lifestyle and environmental factors, and infections. Population-based historical estimates of exposure prevalence and their associated risks for each exposure-cancer site pair were obtained to estimate population attributable risks, assuming the exposures were distributed independently and that the risk estimates were multiplicative. We estimated that between 33 and 37% (up to 70,000 cases) of incident cancer cases among adults aged 30 years and over in 2015 were attributable to preventable risk factors. Similar proportions of cancer cases in males (34%) and females (33%) were attributable to these risk factors. Tobacco smoking and a lack of physical activity were associated with the highest proportions of cancer cases. Cancers with the highest number of preventable cases were lung (20,100), colorectal (9800) and female breast (5300) cancer. If current trends in the prevalence of preventable risk factors continue into the future, we project that by 2042 approximately 102,000 incident cancer cases are expected to be attributable to these risk factors per year, which would account for roughly one-third of all incident cancers. Through various risk reduction interventions, policies and public health campaigns, an estimated 10,600 to 39,700 cancer cases per year could be prevented by 2042.

Estimates of the current and future burden of melanoma attributable to ultraviolet radiation in Canada.

Exposure to ultraviolet radiation (UVR) is an established cause of cutaneous melanoma. The purpose of this study was to estimate the current attributable and future avoidable burden of melanoma related to exposure to UVR and modifiable UVR risk behaviors (sunburn, sunbathing, and indoor tanning). The population attributable risk (PAR) associated with UVR in 2015 was estimated by comparing Canadian melanoma incidence rates in 2015 to estimated incidence rates of a 1920 birth cohort. Rates were adjusted for changes in reporting and ethnicity. We estimated PARs for modifiable UVR risk behaviors using Caucasian prevalence data from the Second National Sun Survey and relative risks that are generalizable to Canada from meta-analyses of relevant studies. Attributable cases apply to 98.9% of melanomas in Canada that occur in Caucasians. We also estimated the future burden of UVR risk behaviors using the potential impact fraction framework and potential reductions in prevalence of 10% to 50% from 2018 to 2042. Adult sunburn and sunbathing were associated with increased risks of melanoma of 1.28 (95% CI: 1.15, 1.43) and 1.44 (95% CI: 1.18, 1.76), respectively. In 2015, we estimate that 62.3% of melanomas in Canada were attributable to exposure to UVR and that 29.7% were attributable to the combination of sunburn (7.4%), sunbathing (17.8%), and indoor tanning (7.0%). A 50% reduction in modifiable UVR behaviors could avoid an estimated 11,980 melanoma cases by 2042. Prevention strategies aimed at modifiable UVR behaviors are crucial to reduce the growing burden of melanoma in Canada.

Estimates of the current and future burden of lung cancer attributable to PM2.5 in Canada.

The International Agency for Research on Cancer has classified PM2.5 (fine particulate matter, PM2.5) as a lung cancer carcinogen in humans. We estimated the proportion of lung cancer cases attributable to PM2.5 exposure in Canada in 2015, and future avoidable cancers over the period 2016-2042 under different future exposure scenarios. A meta-analysis was conducted to estimate the relative risk of lung cancer associated with PM2.5 that was generalizable to Canada. A population-weighted Canadian distribution of residential PM2.5 exposure was estimated annually using ecological-level, satellite-derived PM2.5 data for the period 1990 to 2009. Population attributable risks (PAR) were estimated for PM2.5 and applied to lung cancer incidence from the Canadian Cancer Registry. Potential impact fractions based on counterfactual scenarios for the year 2042 were estimated, along with cumulative preventable cases from 2016 to 2042. The relative risk of lung cancer associated with PM2.5 was 1.09 (95% CI: 1.06-1.12) per an increase of 10 µg/m3. The average population-weighted exposure to PM2.5 corresponding to a 20-year exposure window from 1990 to 2009 was 8.3 µg/m3. The PAR for PM2.5 was estimated at 6.9%, accounting for 1739 attributable lung cancer cases in 2015. If patterns of decline in PM2.5 continue, over 3000 lung cancer cases could be prevented between 2016 and 2042. Exposure to PM2.5 contributes to a considerable burden of lung cancer in Canada and policies aimed at sustaining outdoor PM2.5 declines are important for lung cancer prevention in Canada.

The burden of cancer attributable to modifiable risk factors in Canada: Methods overview.

Up-to-date estimates of current and projected future cancer burden attributable to various exposures are essential for planning and implementing cancer prevention initiatives. The Canadian Population Attributable Risk of Cancer (ComPARe) study was conducted to: i) estimate the number and proportion of cancers diagnosed among adults in Canada in 2015 that are attributable to modifiable risk factors and ii) project the future avoidable cancers by 2042 under various intervention targets. We estimated the population attributable risk (with 95% confidence intervals) and the potential impact fraction of cancers associated with selected lifestyle, environmental, and infectious factors. Exposure-specific sensitivity analyses were also completed where appropriate. Several exposures of interest included active and passive smoking, obesity and abdominal adiposity, leisure-time physical inactivity, sedentary behaviour, alcohol consumption, insufficient fruit and vegetable intake, red and processed meat consumption, air pollution (PM2.5, NO2), indoor radon gas, ultraviolet radiation (UVR), hepatitis B and C virus, Helicobacter pylori, Epstein-Barr virus, human papillomavirus, human herpesvirus type 8 and human T-cell lymphotropic virus type 1. We used the 2015 cancer incidence data for 35 cancer sites from the Canadian Cancer Registry and projected cancer incidence to 2042 using historical data from 1983 to 2012. Here, we provide an overview of the data sources and methods used in estimating the current and future cancer burden in Canada. Specific methodologic details for each exposure are included in the individual articles included as part of this special issue.

Effect of outdoor particulate air pollution on FEV1 in healthy adults: a systematic review and meta-analysis.

The effect of acute and long-term exposures to outdoor particulate air pollution on lung function in healthy adults is not well established. The objective of this study was to conduct a systematic literature review and meta-analysis of studies that assessed the relationship of outdoor particulate air pollution and lung function in healthy adults. Studies that contained data on outdoor air particulate matter levels (PM10 or PM2.5) and forced expiratory volume in 1 s (FEV1) in healthy adults were eligible for inclusion. Effect estimates, in relation to long-term and acute exposures, were quantified separately using random effects models. A total of 27 effect estimates from 23 studies were included in this review. Acute exposures were typically assessed with PM2.5, while long-term exposures were predominantly represented by PM10 A 10 µg/m3 increase in short-term PM2.5 exposure (days) was associated with a -7.02 mL (95% CI -11.75 to -2.29) change in FEV1 A 10 µg/m3 difference in long-term PM10 exposure was associated with a -8.72 mL (95% CI -15.39 to -2.07) annual change in FEV1 and an absolute difference in FEV1 of -71.36 mL (95% CI -134.47 to -8.24). This study provides evidence that acute and long-term exposure to outdoor particulate air pollution are associated with decreased FEV1 in healthy adults. Residual confounding from other risk factors, such as smoking, may explain some of the effect for long-term exposures. More studies are required to determine the relationship of long-term exposure to PM2.5 and short-term exposure to PM10, which may have different biologic mechanisms.

Indoor tanning and the risk of developing non-cutaneous cancers: a systematic review and meta-analysis.

PURPOSE: Despite a strong association between indoor tanning and the risk of cutaneous cancers, the relationship between indoor tanning and non-cutaneous cancers is unknown. Our objective was to estimate the association of indoor tanning with developing non-cutaneous cancers. METHODS: We conducted a systematic literature review and meta-analysis of the association between indoor tanning and non-cutaneous cancer sites. Associations were estimated using random effects models. Heterogeneity was investigated through subgroup analyses and the Q-test and I2 statistics. RESULTS: From 15 identified studies, 33 effect estimates for 12 cancer sites were included in the review. Adjustment for sun exposure was a significant source of heterogeneity in the association of indoor tanning and non-cutaneous cancer risk (meta-regression p = 0.0043). When restricting to studies that adjusted for solar ultraviolet radiation (7 studies and 19 effect estimates) a potential increased risk was observed among ever users of indoor tanning devices with the risk of hematologic malignancies (pooled relative risk = 1.11; 95% CI 0.96-1.28), with differing effects observed by hematologic types and subtypes of non-Hodgkin lymphoma. No association was observed among solid non-cutaneous cancers (pooled relative risk = 0.98; 95% CI 0.94-1.19). Neither study design nor geographical region was significant sources of heterogeneity in these associations. CONCLUSION: When controlling for sun exposure, indoor tanning does not protect against solid non-cutaneous cancers and may increase the risk of some hematologic malignancies. Given the well-established relationship with skin cancer and potential relationship with hematologic malignancies, efforts to reduce the use of indoor tanning devices should continue.

Bulky DNA adduct levels in normal-appearing colon mucosa, and the prevalence of colorectal adenomas.

PURPOSE: Examine the association between bulky DNA adduct levels in colon mucosa and colorectal adenoma prevalence, and explore the correlation between adduct levels in leukocytes and colon tissue. METHODS: Bulky DNA adduct levels were measured using 32P-postlabelling in biopsies of normal-appearing colon tissue and blood donated by 202 patients. Multivariable logistic regression was used to examine associations between DNA adducts, and interactions of DNA adduct-DNA repair polymorphisms, with the prevalence of colorectal adenomas. Correlation between blood and tissue levels of DNA adducts was evaluated using Spearman's correlation coefficient. RESULTS: An interaction between bulky DNA adduct levels and XPA rs1800975 on prevalence of colorectal adenoma was observed. Among individuals with lower DNA repair activity, increased DNA adduct levels were associated with increased colorectal adenoma prevalence (OR = 1.41 per SD increase, 95%CI: 0.92-2.18). Conversely, among individuals with normal DNA activity, an inverse association was observed (OR = 0.60 per SD increase, 95%CI: 0.34-1.07). Blood and colon DNA adduct levels were inversely correlated (ρ = -0.20). CONCLUSIONS: Among genetically susceptible individuals, higher bulky DNA adducts in the colon was associated with the prevalence of colorectal adenomas. The inverse correlation between blood and colon tissue measures demonstrates the importance of quantifying biomarkers in target tissues.

Endogenous sex hormone exposure and repetitive element DNA methylation in healthy postmenopausal women.

PURPOSE: Epigenetic mechanisms may help to explain the complex and heterogeneous relation between sex hormones and cancer. Few studies have investigated the effects of sex hormones on epigenetic markers related to cancer risk such as levels of methylation within repetitive DNA elements. Our objective was to describe the association between endogenous sex hormone exposure and levels of LINE-1 and Alu methylation in healthy postmenopausal women. METHODS: We nested a cross-sectional study within the Alberta Physical Activity and Breast Cancer Prevention Trial (2003-2006). Study participants consisted of healthy postmenopausal women who had never been diagnosed with cancer (n = 289). Sex hormone exposures included serum concentrations of estradiol, estrone, testosterone, androstenedione, and sex hormone-binding globulin. We estimated the participants' lifetime number of menstrual cycles (LNMC) as a proxy for cumulative exposure to ovarian sex hormones. Buffy coat samples were assessed for DNA methylation. Linear regression was used to model the associations of interest and to control for confounding. RESULTS: Both estradiol and estrone had a significant positive dose-response association with LINE-1 methylation. LNMC was associated with both LINE-1 and Alu methylation. Specifically, LNMC had a non-linear "U-shaped" association with LINE-1 methylation regardless of folate intake and a negative linear association with Alu methylation, but only amongst low folate consumers. Androgen exposure was not associated with either outcome. CONCLUSION: Current and cumulative estrogen exposure was associated with repetitive element DNA methylation in a group of healthy postmenopausal women. LINE-1 and Alu methylation may be epigenetic mechanisms through which estrogen exposure impacts cancer risk.

The risk of melanoma associated with ambient summer ultraviolet radiation.

BACKGROUND: Depletion of the ozone layer has meant that ambient ultraviolet radiation (UVR) has increased in recent decades. At the same time, the incidence of skin cancers, including melanoma, has risen. The relatively few large-scale studies that linked ambient UVR to melanoma found a trend toward rising incidence closer to the equator, where UVR estimates are highest. Similar research has not been conducted in Canada, where ambient UVR is generally lower than in countries further south. DATA AND METHODS: Modelled UVR data for the months of June through August during the 1980-to-1990 period were spatially linked in Geographic Information Systems to 2.4 million white members of the 1991 Canadian Census Health and Environment Cohort and tracked for melanoma diagnosis over an 18-year period (1992 to 2009). Standard Cox proportional hazards models were used to estimate melanoma risk associated with increases of ambient summer UVR, assigned by residence at baseline. Models were adjusted for age, sex and socioeconomic (SES) characteristics. Separate analyses by body site of melanoma were conducted. Effect modification of the association between ambient UVR and melanoma by sex, age, outdoor occupation and selected SES characteristics was evaluated. RESULTS: Differences of one standard deviation (446 J/m², or 7% of the mean) in average ambient summer UVR were associated with an increased hazard ratio (HR) for melanoma of 1.22 (95% CI: 1.19 to 1.25) when adjusting for sex, age and SES characteristics. The HR for melanoma in relative UVR (per 1 standard deviation) was larger for men (HR = 1.26; 95% CI: 1.21 to 1.30) than for women (HR = 1.17; 95% CI: 1.13 to 1.22). INTERPRETATION: Ambient summer UVR is associated with a greater risk of melanoma among the white population, even in a country where most people live within a narrow latitudinal belt. A stronger association between melanoma and ambient UVR was evident among men and among people of lower SES.

Metals exposure and risk of small-for-gestational age birth in a Canadian birth cohort: The MIREC study.

BACKGROUND: Lead, mercury, cadmium and arsenic are some of the most common toxic metals to which Canadians are exposed. The effect of exposure to current low levels of toxic metals on fetal growth restriction is unknown. OBJECTIVE: The aim of this study was to examine relationships between exposure to lead, mercury, cadmium and arsenic during pregnancy, and risk of small for gestational age (SGA) birth. METHODS: Lead, mercury, cadmium and arsenic levels were measured in blood samples from the first and third trimesters in 1835 pregnant women from across Canada. Arsenic species in first trimester urine were also assessed. Relative risks and 95% confidence intervals were estimated using log binomial multivariate regression. Important covariates including maternal age, parity, pre-pregnancy BMI, and smoking, were considered in the analysis. An exploratory analysis was performed to examine potential effect modification of these relationships by single nucleotide polymorphisms (SNPs) in GSTP1 and GSTO1 genes. RESULTS: No association was found between blood lead, cadmium or arsenic and risk for SGA. We observed an increased risk for SGA for the highest compared to the lowest tertile of exposure for mercury (>1.6 µg/L, RR=1.56.; 95% CI=1.04-2.58) and arsenobetaine (>2.25 µg/L, RR=1.65; 95% CI=1.10-2.47) after adjustment for the effects of parity and smoking. A statistically significant interaction was observed in the relationship between dimethylarsinic acid (DMA) levels in urinary arsenic and SGA between strata of GSTO1 A104A (p for interaction=0.02). A marginally significant interaction was observed in the relationship between blood lead and SGA between strata of GSTP1 A114V (p for interaction=0.06). CONCLUSIONS: These results suggest a small increase in risk for SGA in infants born to women exposed to mercury and arsenic. Given the conflicting evidence in the literature this warrants further investigation in other pregnant populations.

A cross-sectional study of global DNA methylation and risk of colorectal adenoma.

BACKGROUND: The methylation of DNA is recognized as a key epigenetic mechanism and evidence for its role in the development of several malignancies is accumulating. We evaluated the relationship between global methylation in DNA derived from normal appearing colon mucosal tissue and blood leukocytes, and colorectal adenoma risk. METHODS: Patients, aged 40 to 65, scheduled for a screening colonoscopy were recruited. During the colonoscopy, two pinch biopsies of healthy, normal appearing mucosa were obtained from the descending colon. A fasting blood sample was also collected. The methylation status of LINE-1 (long interspersed nuclear element-1) repetitive sequences, as a surrogate measure of global methylation, was quantified in DNA extracted from normal colon mucosa and blood leukocytes. Statistical analysis of the relationship between global DNA methylation and adenoma risk was conducted on 317 participants, 108 subjects with at least one pathologically confirmed adenoma and 209 subjects with a normal colonoscopy. RESULTS: A statistically significant inverse relationship was observed between LINE-1 methylation in colon tissue DNA and adenoma risk for males and for both sexes combined for the lowest methylation quartile compared to the highest (adjusted ORs = 2.94 and 2.26 respectively). For blood, although the overall pattern of odds ratio estimates was towards an increase in risk for lower methylation quartiles compared to the highest methylation quartile, there were no statistically significant relationships observed. A moderate correlation was found between LINE-1 methylation levels measured in tissue and blood (Pearson correlation 0.36). CONCLUSIONS: We observed that lower levels of LINE-1 DNA methylation in normal appearing background colon mucosa were associated with increased adenoma risk for males, and for both sexes combined. Though these findings provide some support for a relationship between LINE-1 DNA methylation in colon mucosal tissue and adenoma risk, large prospective cohort studies are needed to confirm results. Until such investigations are done, the clinical usefulness of LINE-1 methylation as a biomarker of increased adenoma risk is uncertain. Regardless, this study contributes to a better understanding of the role of global DNA methylation as an early event in CR carcinogenesis with implications for future etiologic research.