Suril S. Mehta

Cancer hazard identification is the first step in preventing cancer. Robust and transparent methods for rigorous interrogation of published research are vital for a high-quality assessment of the scientific evidence resulting in cancer hazard identification. The National Toxicology Program publishes cancer hazard assessments for possible listing in the Report on Carcinogens (RoC) that are conducted using a four-part systematic review (SR) following the process described in the RoC Handbook. This Handbook provides guidance for developing a substance-specific evaluation framework, assessing study informativeness, evaluating and integrating data across studies within each evidence stream (e.g., human, experimental animal, and mechanistic studies) and then integrating evidence across evidence streams to reach a cancer hazard conclusion.The recently updated RoC Handbook incorporates advances in SR methods since the 2015 version and provides an updated suite of tools, approaches, and resources to assure scientific rigor, transparency, and confidence in conclusions reached in cancer hazard evaluations. The most significant advancements include a new fit-for-purpose SR strategy and guidance for assessing and integrating evidence from mechanistic studies, including read-across approaches, and clearer approaches for integrating evidence across evidence streams to reach causal conclusions. We also added toolkits for determining the informativeness of human, animal cancer, and mechanistic studies, and resources related to literature search strings, exposure assessment, and information on biomarkers and assays for the key characteristics of carcinogens. These innovations have significantly enhanced the transparency and scientific integrity of RoC cancer hazard assessments and can be used by the scientific community for their own assessments.

Background and Aim: Epidemiological studies conducted mostly in low- and middle-income countries have found a positive association between household combustion of wood and lung cancer. However, most studies have been retrospective, and few have been conducted in the United States where indoor wood-burning usage patterns differ. We examined the association of exposure to indoor wood smoke from fireplaces and stoves with incident lung cancer in a U.S.-wide cohort of women. Methods: We included 50,226 women without prior lung cancer participating in the U.S.-based prospective Sister Study. At enrollment (2003-2009), women reported frequency of use of wood-burning stoves and/or fireplaces in their longest-lived adult residence. Cox regression was used to estimate adjusted hazard ratios (HRadj) and 95% confidence intervals (CI) for the association between indoor wood-burning fireplace/stove use and incident lung cancer. Lung cancer was self-reported and confirmed with medical records. Results: During an average 11.3 years of follow-up, 347 medically confirmed lung cancer cases accrued. Overall, 62.3% of the study population reported the presence of an indoor wood-burning fireplace/stove at their longest-lived adult residence and 20.6% reported annual usage of ≥30 days/year. Compared to those without a wood-burning fireplace/stove, women who used their wood-burning fireplace/stove ≥30 days/year had an elevated rate of lung cancer (HRadj = 1.68; 95% CI = 1.27, 2.20). In never smokers, positive associations were seen for use 1-29 days/year (HRadj = 1.64; 95% CI = 0.87, 3.10) and ≥30 days/year (HRadj = 1.99; 95% CI = 1.02, 3.89). Associations were also elevated across all income groups, in Northeastern, Western or Midwestern U.S. regions, and among those who lived in urban or rural/small town settings. Conclusions: Our prospective analysis of a cohort of U.S. women found that increasing frequency of wood-burning indoor fireplace/stove usage was associated with incident lung cancer, even among never smokers.

Background: Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous organic compounds associated with chronic disease in epidemiologic studies, though the contribution of PAH exposure on fatal outcomes in the U.S. is largely unknown.Objectives: We investigated urinary hydroxylated PAH metabolites (OH-PAHs) with all-cause and cause-specific mortality in a representative sample of the U.S. population.Methods: Study participants were ≥20 years old from the National Health and Nutrition Examination Survey 2001–2014. Concentrations (nmol/L) of eight OH-PAHs from four parent PAHs (naphthalene, fluorene, phenanthrene, pyrene) were measured in spot urine samples at examination. We identified all-cause, cancer-specific, and cardiovascular-specific deaths through 2015 using the National Death Index. We used Cox proportional hazards regression to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between ΣOH-PAHs and mortality endpoints. We assessed potential heterogeneity by age, gender, smoking status, poverty, and race/ethnicity. Additionally, we examined the overall mixture effect using quantile g-computation.Results: In 9,739 eligible participants, there were 934 all-cause deaths, 159 cancer-specific deaths, and 108 cardiovascular-specific deaths (median 6.75 years follow-up). A log₁₀increase in ΣOH-PAHs was associated with higher all-cause mortality (HR_adj= 1.39 [95%CI: 1.21, 1.61]), and possibly cancer-specific mortality (HR_adj= 1.15 [95%CI: 0.79, 1.69]), and cardiovascular-specific mortality (HR_adj= 1.49 [95%CI: 0.94, 2.33]). We observed substantial effect modification by age, smoking status, gender, and race/ethnicity across mortality endpoints. Risk of cardiovascular mortality was higher for non-Hispanic blacks and those in poverty, indicating potential disparities. Quantile g-computation joint associations for a simultaneous quartile increase in OH-PAHs were HR_adj= 1.15 [95%CI: 1.02, 1.31], HR_adj= 1.41 [95%CI: 1.05, 1.90], and HR_adj= 0.98 [95%CI: 0.66, 1.47] for all-cause, cancer-specific, and cardiovascular-specific mortalities, respectively.Discussion: Our results support a role for total PAH exposure in all-cause and cause-specific mortality in the U.S. population.

Background: Over 800 pesticides are registered for use in the United States. Human studies indicate concern that some pesticides currently in use in large quantities may also pose a carcinogenic hazard. Our objective is to identify candidates for future hazard evaluations among pesticides used in high volumes in the United States and also classified as potential carcinogens by U.S. Environmental Protection Agency (USEPA). We also identify data gaps where further research is needed. Methods: We used a systematic, two-tiered review approach to prioritize pesticides. First, we identified currently registered pesticides classified by USEPA as “possible”, “suggestive”, or “likely” human carcinogens. Among these, we selected pesticides USEPA has listed as commonly used by volume in at least one sector (agriculture, home and garden, or industry, commercial, and/or government), and those without a published hazard evaluation in the past 5 years. Second, we searched primary literature databases for peer-reviewed human cancer studies reporting pesticide-specific data published since the last USEPA carcinogenicity evaluation for each pesticide, and created evidence maps of the number of studies meeting our criteria for each identified pesticide. No evaluation of study results or risk-of-bias assessments were conducted. Results: We identified 18 pesticides meeting our selection criteria, 16 pesticides had information from human cancer studies published after their initial carcinogenicity review. Of these, eight pesticides had at least three studies for one or more cancer sites: carbaryl, dichloropropene, dimethoate, mancozeb, metolachlor, pendimethalin, permethrin, and trifluralin. A major limitation in the literature revealed a shortage of studies reporting risk estimates for individual pesticides, rather pesticides were grouped by chemical class. Conclusions: Our scoping report provides a map of the existing literature on real-world exposures and human cancer that has accumulated on pesticides classified as potential carcinogens by USEPA and used in high volumes. We also illustrate that several pesticides which are “data-rich” may warrant updated authoritative hazard evaluations. Our two-tiered approach and utilization of evidence mapping can be used to inform future decision-making to update cancer hazard evaluations.

Systematic reviews are powerful tools for drawing causal inference for evidence-based decision-making. Published systematic reviews and meta-analyses of environmental and occupational epidemiology studies have increased dramatically in recent years; however, the quality and utility of published reviews are variable. Most methodologies were adapted from clinical epidemiology and have not been adequately modified to evaluate and integrate evidence from observational epidemiology studies assessing environmental and occupational hazards, especially in evaluating the quality of exposure assessments. Although many reviews conduct a systematic and transparent assessment for the potential for bias, they are often deficient in subsequently integrating across a body of evidence. A cohesive review considers the impact of the direction and magnitude of potential biases on the results, systematically evaluates important scientific issues such as study sensitivity and effect modifiers, identifies how different studies complement each other, and assesses other potential sources of heterogeneity. Given these challenges of conducting informative systematic reviews of observational studies, we provide a series of specific recommendations based on practical examples for cohesive evidence integration to reach an overall conclusion on a body of evidence to better support policy making in public health.

Background: Red and processed meats have been implicated as risk factors in the development of colorectal cancer in U.S. women, but associations with cooking practices are less well established. Methods: Data are from the Sister Study, a cohort of women ages 35 to 74 years from the United States and Puerto Rico who have a sister diagnosed with breast cancer. Red and processed meat consumption, meat cooking practices, and intake of common meat products were collected at baseline using self-administered questionnaires (N = 48,704). Multivariable HRs (HRadj) and 95% confidence intervals (95% CI) were estimated. Results: During a median 8.7 years' follow-up (range <1–12.7 years), 216 colorectal cancer cases were diagnosed. In categorical analyses, an increased risk of colorectal cancer was seen in the highest quartile of processed meat consumption compared with the lowest [HRadj = 1.52 (95% CI, 1.01–2.30); Ptrend = 0.02], and for specific meat products, including breakfast sausages [HRadj = 1.85 (95% CI, 1.30–2.64)] and bacon [HRadj = 1.46 (95% CI, 1.01–2.11)]. The HRadj for the highest quartile of red meat consumption was 1.04 (95% CI, 0.68–1.60), and little evidence of association was observed for cooking practices or doneness of red meat. We observed positive associations with specific red meat products when cooking methods were considered, for example, grilled/barbequed steaks [HRadj = 2.23 (95% CI, 1.20–4.14)] and hamburgers [HRadj = 1.98 (95% CI, 1.00–3.91)]. Conclusions: Higher reported daily intake of processed meats and consumption of barbecued/grilled red meat products were associated with increased risk of colorectal cancer in women. Impact: Variability in colorectal risk risk by meat type and cooking method should be considered when evaluating meat consumption.

Environmental Health Perspectives is an Open Access journal published by the National Institute of Environmental Health Sciences. Environmental Health Perspectives is an Open Access journal published by the National Institute of Environmental Health Sciences.