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

HPRT Mutations in Lymphocytes from 1,3-Butadiene-Exposed Workers in China

BACKGROUND: 1,3-Butadiene (BD) is an important industrial chemical and an environmental and occupational pollutant. The carcinogenicity of BD in rodents has been proved, but its carcinogenic and mutagenic molecular mechanism(s) are not fully elucidated in humans. OBJECTIVES: In the present study, we compared the mutation frequencies and exon deletions of BD-exposed workers with that of control subjects in China to identify the characteristic mutations associated with BD exposure in the human HPRT (hypoxanthine–guanine–phosphoribosyltransferase) gene. METHODS: Seventy-four workers exposed to BD via inhalation and 157 matched controls were evaluated in Nanjing, China. Molecular analysis of HPRT mutant T lymphocytes from BDexposed workers and nonexposed control subjects was conducted to identify changes in the structure of the HPRT gene. A total of 783 HPRT mutants were analyzed by multiplex polymerase chain reaction, in which 368 HPRT mutants were isolated from BD-exposed workers and 415 mutants from control subjects. RESULTS: The BD-exposed workers showed a higher mutation frequency (18.2 ± 9.4 × 10 –6) than the control subjects (12.7 ± 7.3 × 10 –6), but the difference was not significant (p> 0.05). The frequency of exon deletions in BD-exposed workers (27.4%) was significantly higher than that in control subjects (12.5%) (p < 0.05), which mainly included multiplex exon deletions (2–8 exons). CONCLUSIONS: The results of the present study suggest that BD should increase the frequency of large deletions of HPRT gene in human lymphocytes This change confirms and supports the previous findings in BD-exposed workers. KEY WORDS: 1,3-butadiene, BD, exon deletion, HPRT gene, lymphocyte, occupational exposure. Environ Health Perspect 116:203–208 (2008). doi:10.1289/ehp.10353 available vi

Antifungal effect of organic acids from lactic bacteria on Penicillium nordicum

ICFC 2017 - International Conference on Food Contaminants (Book of Abstracts)Lactic acid bacteria (LAB) have been gaining attention for the antifungal properties of some strains. The control of fungal growth is especially important since moulds are responsible for significant spoilage of food and feed. Additionally, they are able t o produce toxic compounds known as mycotoxins that cause serious health hazards. Some LAB strains have the ability to inhibit fungal growth and also the production of mycotoxins. In this work, cell free supernatants (CFS) of Lactobacillus plantarum UM55 and Lactobacillus buchneri UTAD104 were tested for the inhibition of Penicillium nordicum growth and ochratoxin A (OTA) production. Fungal growth was inhibited in only 18 and 11% by CFS of L. plantarum and L. buchneri, respectively. However, the production o f OTA was reduced approx. in 70% by both strains. In order to determine the nature of compounds responsible for this activity, CFS were subjected to heat, proteases and neutralization of pH. It was observed that CFS retained its inhibitory properties after being autoclaved and treated with proteases. However, when submitted to pH neutralization, CFS lost its activity. Some organic acids produced by these LAB strains were also tested for their inhibitory capacity. Calculation of inhibitory concentrations shown that butyric and propionic acids were the most effective in inhibiting P. nordicum growth and OTA production, followed by indole lactic acid (ILA), phenyllactic acid (PLA), acetic acid, hydroxyphenyllactic acid (OH-PLA) and lactic acid. CFS were analysed by HPLC - PDA for the quantification of those organic acids. For L. plantarum UM55 main differences were found in the levels of lactic acid, PLA, OH-PLA, and ILA. For L. buchneri UTAD104, levels of acetic, lactic and PLA were higher than in the control experiment. In conclusion, ability of LAB to inhibit mycotoxigenic fungi depends of strain capability to produce certain organic acids, and those acids may differ from strain to straininfo:eu-repo/semantics/publishedVersio

A Prospective Study of Growth and Biomarkers of Exposure to Aflatoxin and Fumonisin during Early Childhood in Tanzania

Background: Aflatoxin and fumonisin are toxic food contaminants. Knowledge about effects of their exposure and coexposure on child growth is inadequate. Objective: We investigated the association between child growth and aflatoxin and fumonisin exposure in Tanzania. Methods: A total of 166 children were recruited at 6–14 months of age and studied at recruitment, and at the 6th and 12th month following recruitment. Blood and urine samples were collected and analyzed for plasma aflatoxin–albumin adducts (AF-alb) using ELISA, and urinary fumonisin B1 (UFB1) using liquid chromatography–mass spectrometry, respectively. Anthropometric measurements were taken, and growth index z-scores were computed. Results: AF-alb geometric mean concentrations (95% CIs) were 4.7 (3.9, 5.6), 12.9 (9.9, 16.7), and 23.5 (19.9, 27.7) pg/mg albumin at recruitment, 6 months, and 12 months from recruitment, respectively. At these respective sampling times, geometric mean UFB1 concentrations (95% CI) were 313.9 (257.4, 382.9), 167.3 (135.4, 206.7), and 569.5 (464.5, 698.2) pg/mL urine, and the prevalence of stunted children was 44%, 55%, and 56%, respectively. UFB1 concentrations at recruitment were negatively associated with length-for-age z-scores (LAZ) at 6 months (p = 0.016) and at 12 months from recruitment (p = 0.014). The mean UFB1 of the three sampling times (at recruitment and at 6 and 12 months from recruitment) in each child was negatively associated with LAZ (p < 0.001) and length velocity (p = 0.004) at 12 months from recruitment. The negative association between AF-alb and child growth did not reach statistical significance. Conclusions: Exposure to fumonisin alone or coexposure with aflatoxins may contribute to child growth impairment

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

Conflicting Views on Chemical Carcinogenesis Arising from the Design and Evaluation of Rodent Carcinogenicity Studies

Conflicting views have been expressed frequently on assessments of human cancer risk of environmental agents based on animal carcinogenicity data; this is primarily because of uncertainties associated with extrapolations of toxicologic findings from studies in experimental animals to human circumstances. Underlying these uncertainties are issues related to how experiments are designed, how rigorously hypotheses are tested, and to what extent assertions extend beyond actual findings. National and international health agencies regard carcinogenicity findings in well-conducted experimental animal studies as evidence of potential carcinogenic risk to humans. Controversies arise when both positive and negative carcinogenicity data exist for a specific agent or when incomplete mechanistic data suggest a possible species difference in response. Issues of experimental design and evaluation that might contribute to disparate results are addressed in this article. To serve as reliable sources of data for the evaluation of the carcinogenic potential of environmental agents, experimental studies must include a) animal models that are sensitive to the end points under investigation; b) detailed characterization of the agent and the administered doses; c) challenging doses and durations of exposure (at least 2 years for rats and mice); d) sufficient numbers of animals per dose group to be capable of detecting a true effect; e) multiple dose groups to allow characterization of dose–response relationships, f) complete and peer-reviewed histopathologic evaluations; and g) pairwise comparisons and analyses of trends based on survival-adjusted tumor incidence. Pharmacokinetic models and mechanistic hypotheses may provide insights into the biological behavior of the agent; however, they must be adequately tested before being used to evaluate human cancer risk

Temporal Variation in the Association between Benzene and Leukemia Mortality

BackgroundBenzene is a human carcinogen. Exposure to benzene occurs in occupational and environmental settings.ObjectiveI evaluated variation in benzene-related leukemia with age at exposure and time since exposure.MethodsI evaluated data from a cohort of 1,845 rubber hydrochloride workers. Benzene exposure–leukemia mortality trends were estimated by applying proportional hazards regression methods. Temporal variation in the impact of benzene on leukemia rates was assessed via exposure time windows and fitting of a multistage cancer model.ResultsThe association between leukemia mortality and benzene exposures was of greatest magnitude in the 10 years immediately after exposure [relative rate (RR) at 10 ppm-years = 1.19; 95% confidence interval (CI), 1.10–1.29]; the association was of smaller magnitude in the period 10 to < 20 years after exposure (RR at 10 ppm-years = 1.05; 95% CI, 0.97–1.13); and there was no evidence of association ≥ 20 years after exposure. Leukemia was more strongly associated with benzene exposures accrued at ≥ 45 years of age (RR at 10 ppm-years = 1.11; 95% CI, 1.04–1.17) than with exposures accrued at younger ages (RR at 10 ppm-years = 1.01; 95% CI, 0.92–1.09). Jointly, these temporal effects can be efficiently modeled as a multistage process in which benzene exposure affects the penultimate stage in disease induction.ConclusionsFurther attention should be given to evaluating the susceptibility of older workers to benzene-induced leukemia

The association of the original OSHA chemical hazard communication standard with reductions in acute work injuries/illnesses in private industry and the industrial releases of chemical carcinogens

Background OSHA predicted the original chemical Hazard Communication Standard (HCS) would cumulatively reduce the lost workday acute injury/illness rate for exposure events by 20% over 20 years and reduce exposure to chemical carcinogens. Methods JoinPoint trend software identified changes in the rate of change of BLS rates for days away from work for acute injuries/illnesses during 1992–2009 for manufacturing and nonmanufacturing industries for both chemical, noxious or allergenic injury exposure events and All other exposure events. The annual percent change in the rates was used to adjust observed numbers of cases to estimate their association with the standard. A case‐control study of EPA's Toxic Release Inventory 1988–2009 data compared carcinogen and non‐carcinogens' releases. Results The study estimates that the HCS was associated with a reduction in the number of acute injuries/illnesses due to chemical injury exposure events over the background rate in the range 107,569–459,395 (Hudson method/modified BIC model) depending on whether the HCS is treated as a marginal or sole factor in the decrease. Carcinogen releases have declined at a substantially faster rate than control non‐carcinogens. Discussion The previous HCS standard was associated with significant reductions in chemical event acute injuries/illnesses and chemical carcinogen exposures. Am. J. Ind. Med. 57:138–152, 2014. © 2013 Wiley Periodicals, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102719/1/ajim22269.pd