Association between Outdoor Air Pollution and Childhood Leukemia: A Systematic Review and Dose-Response Meta-Analysis.

BackgroundA causal link between outdoor air pollution and childhood leukemia has been proposed, but some older studies suffer from methodological drawbacks. To the best of our knowledge, no systematic reviews have summarized the most recently published evidence and no analyses have examined the dose-response relation.ObjectiveWe investigated the extent to which outdoor air pollution, especially as resulting from traffic-related contaminants, affects the risk of childhood leukemia.MethodsWe searched all case-control and cohort studies that have investigated the risk of childhood leukemia in relation to exposure either to motorized traffic and related contaminants, based on various traffic-related metrics (number of vehicles in the closest roads, road density, and distance from major roads), or to measured or modeled levels of air contaminants such as benzene, nitrogen dioxide, 1,3-butadiene, and particulate matter. We carried out a meta-analysis of all eligible studies, including nine studies published since the last systematic review and, when possible, we fit a dose-response curve using a restricted cubic spline regression model.ResultsWe found 29 studies eligible to be included in our review. In the dose-response analysis, we found little association between disease risk and traffic indicators near the child's residence for most of the exposure range, with an indication of a possible excess risk only at the highest levels. In contrast, benzene exposure was positively and approximately linearly associated with risk of childhood leukemia, particularly for acute myeloid leukemia, among children under 6 y of age, and when exposure assessment at the time of diagnosis was used. Exposure to nitrogen dioxide showed little association with leukemia risk except at the highest levels.DiscussionOverall, the epidemiologic literature appears to support an association between benzene and childhood leukemia risk, with no indication of any threshold effect. A role for other measured and unmeasured pollutants from motorized traffic is also possible. https://doi.org/10.1289/EHP4381

Mycotoxin exposure and human cancer risk : a systematic review of epidemiological studies

In recent years, there has been an increasing interest in investigating the carcinogenicity of mycotoxins in humans. This systematic review aims to provide an overview of data linking exposure to different mycotoxins with human cancer risk. Publications (2019 and earlier) of case–control or longitudinal cohort studies were identified in PubMed and EMBASE. These articles were then screened by independent reviewers and their quality was assessed according to the Newcastle–Ottawa scale. Animal, cross‐sectional, and molecular studies satisfied criteria for exclusion. In total, 14 articles were included: 13 case–control studies and 1 longitudinal cohort study. Included articles focused on associations of mycotoxin exposure with primary liver, breast, and cervical cancer. Overall, a positive association between the consumption of aflatoxin‐contaminated foods and primary liver cancer risk was verified. Two case–control studies in Africa investigated the relationship between zearalenone and its metabolites and breast cancer risk, though conflicting results were reported. Two case–control studies investigated the association between hepatocellular carcinoma and fumonisin B1 exposure, but no significant associations were observed. This systematic review incorporates several clear observations of dose‐dependent associations between aflatoxins and liver cancer risk, in keeping with IARC Monograph conclusions. Only few human epidemiological studies investigated the associations between mycotoxin exposures and cancer risk. To close this gap, more in‐depth research is needed to unravel evidence for other common mycotoxins, such as deoxynivalenol and ochratoxin A. The link between mycotoxin exposures and cancer risk has mainly been established in experimental studies, and needs to be confirmed in human epidemiological studies to support the evidence‐based public health strategies

Effects of 1,3-Butadiene, Isoprene, and Their Photochemical Degradation Products on Human Lung Cells

Because of potential exposure both in the workplace and from ambient air, the known carcinogen 1,3-butadiene (BD) is considered a priority hazardous air pollutant. BD and its 2-methyl analog, isoprene (ISO), are chemically similar but have very different toxicities, with ISO showing no significant carcinogenesis. Once released into the atmosphere, reactions with species induced by sunlight and nitrogen oxides convert BD and ISO into several photochemical reaction products. In this study, we determined the relative toxicity and inflammatory gene expression induced by exposure of A549 cells to BD, ISO, and their photochemical degradation products in the presence of nitric oxide. Gas chromatography and mass spectrometry analyses indicate the initial and major photochemical products produced during these experiments for BD are acrolein, acetaldehyde, and formaldehyde, and products for ISO are methacrolein, methyl vinyl ketone, and formaldehyde; both formed < 200 ppb of ozone. After exposure the cells were examined for cytotoxicity and interleukin-8 (IL-8) gene expression, as a marker for inflammation. These results indicate that although BD and ISO alone caused similar cytotoxicity and IL-8 responses compared with the air control, their photochemical products significantly enhanced cytotoxicity and IL-8 gene expression. This suggests that once ISO and BD are released into the environment, reactions occurring in the atmosphere transform these hydrocarbons into products that induce potentially greater adverse health effects than the emitted hydrocarbons by themselves. In addition, the data suggest that based on the carbon concentration or per carbon basis, biogenic ISO transforms into products with proinflammatory potential similar to that of BD products

Use of GIS and Exposure Modeling as Tools in a Study of Cancer Incidence in a Population Exposed to Airborne Dioxin

In environmental health research there is a recognized need to develop improved epidemiologic and statistical methods for rapid assessment of relationships between environment and health. Exposure assessment is identified as a major challenge needing attention. In this study an exposure simulation model was used to delimit almost exactly in space and time an urban population exposed to airborne dioxin. A geographic information system (GIS) was used as the electronic environment in which to link the exposure model with the demographic, migration, and cancer data of the exposed population. This information is available in Denmark on an individual basis. Standardized incidence ratios (SIRs) for both men and women in 10-year age bands were calculated for three different exposure areas. Migration patterns were outlined. SIRs showed no excess of cancer incidences during the time span chosen (13 years; 1986–1998) in the whole exposed area or in the medium or higher polluted areas. The exposure model appeared very useful in selection of the appropriate exposure areas. The integration of the model in a GIS together with individual data on addresses, sex, age, migration, and information from routine health statistics (Danish Cancer Registry) proved its usefulness in demarking the exposed population and identifying the cancers related to that population. Less than one-third of the study population lived at the same address after 13 years of observation, and only half were still residing in the area, indicating migration of people as a major misclassification

Maternal Exposure to Occupational Solvents and Childhood Leukemia

Many organic solvents are considered probable carcinogens. We carried out a population-based case–control study including 790 incident cases of childhood acute lymphoblastic leukemia and as many healthy controls, matched on age and sex. Maternal occupational exposure to solvents before and during pregnancy was estimated using the expert method, which involves chemists coding each individual’s job for specific contaminants. Home exposure to solvents was also evaluated. The frequency of exposure to specific agents or mixtures was generally low. Results were generally similar for the period ranging from 2 years before pregnancy up to birth and for the pregnancy period alone. For the former period, the odds ratio (OR), adjusted for maternal age and sex, for any exposure to all solvents together was 1.11 [95% confidence interval (CI), 0.88–1.40]. Increased risks were observed for specific exposures, such as to 1,1,1-trichloroethane (OR = 7.55; 95% CI, 0.92–61.97), toluene (OR = 1.88; 95% CI, 1.01–3.47), and mineral spirits (OR = 1.82; 95% CI, 1.05–3.14). There were stronger indications of moderately increased risks associated with exposure to alkanes (C5–C17; OR = 1.78; 95% CI, 1.11–2.86) and mononuclear aromatic hydrocarbons (OR = 1.64; 95% CI, 1.12–2.41). Risk did not increase with increasing exposure, except for alkanes, where a significant trend (p = 0.04) was observed. Home exposure was not associated with increased risk. Using an elaborate exposure coding method, this study shows that maternal exposure to solvents in the workplace does not seem to play a major role in childhood leukemia

Evidential Proximity, Independence, and the evaluation of carcinogenicity

This paper analyses the methods of the International Agency for Research on Cancer (IARC) for evaluating the carcinogenicity of various agents. I identify two fundamental evidential principles that underpin these methods, which I call Evidential Proximity and Independence. I then show, by considering the 2018 evaluation of the carcinogenicity of styrene and styrene‐7,8‐oxide, that these principles have been implemented in a way that can lead to inconsistency. I suggest a way to resolve this problem: admit a general exception to Independence and treat the implementation of Evidential Proximity more flexibly where this exception applies. I show that this suggestion is compatible with the general principles laid down in the 2019 version of IARC's methods guide, its Preamble to the Monographs

Lung Cancer Risk after Exposure to Polycyclic Aromatic Hydrocarbons: A Review and Meta-Analysis

Typical polycyclic aromatic hydrocarbon mixtures are established lung carcinogens, but the quantitative exposure–response relationship is less clear. To clarify this relationship we conducted a review and meta-analysis of published reports of occupational epidemiologic studies. Thirty-nine cohorts were included. The average estimated unit relative risk (URR) at 100 μg/m(3) years benzo[a]pyrene was 1.20 [95% confidence interval (CI), 1.11–1.29] and was not sensitive to particular studies or analytic methods. However, the URR varied by industry. The estimated means in coke ovens, gasworks, and aluminum production works were similar (1.15–1.17). Average URRs in other industries were higher but imprecisely estimated, with those for asphalt (17.5; CI, 4.21–72.78) and chimney sweeps (16.2; CI, 1.64–160.7) significantly higher than the three above. There was no statistically significant variation of URRs within industry or in relation to study design (including whether adjusted for smoking), or source of exposure information. Limited information on total dust exposure did not suggest that dust exposure was an important confounder or modified the effect. These results provide a more secure basis for risk assessment than was previously available

Kinetics of Ethylene and Ethylene Oxide in Subcellular Fractions of Lungs and Livers of Male B6C3F1 Mice and Male Fischer 344 Rats and of Human Livers

Ethylene (ET) is metabolized in mammals to the carcinogenic ethylene oxide (EO). Although both gases are of high industrial relevance, only limited data exist on the toxicokinetics of ET in mice and of EO in humans. Metabolism of ET is related to cytochrome P450-dependent mono-oxygenase (CYP) and of EO to epoxide hydrolase (EH) and glutathione S-transferase (GST). Kinetics of ET metabolism to EO and of elimination of EO were investigated in headspace vessels containing incubations of subcellular fractions of mouse, rat, or human liver or of mouse or rat lung. CYP-associated metabolism of ET and GST-related metabolism of EO were found in microsomes and cytosol, respectively, of each species. EH-related metabolism of EO was not detectable in hepatic microsomes of rats and mice but obeyed saturation kinetics in hepatic microsomes of humans. In ET-exposed liver microsomes, metabolism of ET to EO followed Michaelis-Menten-like kinetics. Mean values of Vmax [nmol/(min·mg protein)] and of the apparent Michaelis constant (Km [mmol/l ET in microsomal suspension]) were 0.567 and 0.0093 (mouse), 0.401 and 0.031 (rat), and 0.219 and 0.013 (human). In lung microsomes, Vmax values were 0.073 (mouse) and 0.055 (rat). During ET exposure, the rate of EO production decreased rapidly. By modeling a suicide inhibition mechanism, rate constants for CYP-mediated catalysis and CYP inactivation were estimated. In liver cytosol, mean GST activities to EO expressed as Vmax/Km [μl/(min·mg protein)] were 27.90 (mouse), 5.30 (rat), and 1.14 (human). The parameters are most relevant for reducing uncertainties in the risk assessment of ET and EO

New Exposure Biomarkers as Tools for Breast Cancer Epidemiology, Biomonitoring, and Prevention: A Systematic Approach Based on Animal Evidence

Background: Exposure to chemicals that cause rodent mammary gland tumors is common, but few studies have evaluated potential breast cancer risks of these chemicals in humans. Objective: The goal of this review was to identify and bring together the needed tools to facilitate the measurement of biomarkers of exposure to potential breast carcinogens in breast cancer studies and biomonitoring. Methods: We conducted a structured literature search to identify measurement methods for exposure biomarkers for 102 chemicals that cause rodent mammary tumors. To evaluate concordance, we compared human and animal evidence for agents identified as plausibly linked to breast cancer in major reviews. To facilitate future application of exposure biomarkers, we compiled information about relevant cohort studies. Results: Exposure biomarkers have been developed for nearly three-quarters of these rodent mammary carcinogens. Analytical methods have been published for 73 of the chemicals. Some of the remaining chemicals could be measured using modified versions of existing methods for related chemicals. In humans, biomarkers of exposure have been measured for 62 chemicals, and for 45 in a nonoccupationally exposed population. The Centers for Disease Control and Prevention has measured 23 in the U.S. population. Seventy-five of the rodent mammary carcinogens fall into 17 groups, based on exposure potential, carcinogenicity, and structural similarity. Carcinogenicity in humans and rodents is generally consistent, although comparisons are limited because few agents have been studied in humans. We identified 44 cohort studies, with a total of > 3.5 million women enrolled, that have recorded breast cancer incidence and stored biological samples. Conclusions: Exposure measurement methods and cohort study resources are available to expand biomonitoring and epidemiology related to breast cancer etiology and prevention. Citation: Rudel RA, Ackerman JM, Attfield KR, Brody JG. 2014. New exposure biomarkers as tools for breast cancer epidemiology, biomonitoring, and prevention: a systematic approach based on animal evidence. Environ Health Perspect 122:881–895; http://dx.doi.org/10.1289/ehp.130745