Glyphosate-based herbicides (GlyBH), including Roundup, are the most widely used pesticides worldwide. Their uses have increased exponentially since their introduction on the market. Residue levels ...in food or water, as well as human exposures, are escalating. We have reviewed the toxic effects of GlyBH measured below regulatory limits by evaluating the published literature and regulatory reports. We reveal a coherent body of evidence indicating that GlyBH could be toxic below the regulatory lowest observed adverse effect level for chronic toxic effects. It includes teratogenic, tumorigenic and hepatorenal effects. They could be explained by endocrine disruption and oxidative stress, causing metabolic alterations, depending on dose and exposure time. Some effects were detected in the range of the recommended acceptable daily intake. Toxic effects of commercial formulations can also be explained by GlyBH adjuvants, which have their own toxicity, but also enhance glyphosate toxicity. These challenge the assumption of safety of GlyBH at the levels at which they contaminate food and the environment, albeit these levels may fall below regulatory thresholds. Neurodevelopmental, reproductive, and transgenerational effects of GlyBH must be revisited, since a growing body of knowledge suggests the predominance of endocrine disrupting mechanisms caused by environmentally relevant levels of exposure.
•We have reviewed the toxic effects of glyphosate and its commercial formulations.•Glyphosate-based herbicides cause teratogenic, tumorigenic and hepatorenal effects.•These effects could be explained by endocrine disruption and oxidative stress.•Some effects were detected in the range of the recommended acceptable daily intake.•Current evidence presented raises concerns and indicates the need for further studies.
Objectives Exploring lymphoma risk associated with metabolic gene polymorphisms might provide clues on the role of gene-environment interactions in lymphomagenesis. Methods We assessed polymorphisms ...in genes encoding for the metabolic enzymes CYP1A2, CYP2E1, GSTM1, GSTT1, NAT1, NAT2, NQ01, and PON1 in 255 incident lymphoma cases and 204 population controls. The OR for lymphoma overall, B lymphoma, and the diffuse large B cell lymphoma (DLBCL) and chronic lymphocytic leukaemia (CLL) subtypes, associated to the less frequent allele was calculated along with the respective 95% CI, adjusting by age and gender. Results GSTT1 gene polymorphism significantly increased risk of DLBCL (OR = 5.0, IC 95% 3.0 to 8.3). An excess risk of DLBCL was also related to polymorphisms in the CYP1A2, PON1, NAT1 and NAT2genes. CLL risk was reduced in relation to CYP1A2 polymorphisms, increased in relation to GSTM1 deletion, and strongly associated with NAT1, and NAT2 mutant haplotypes. Conclusions Caution is recommended in interpreting the high risks in our study, due its small size. However, our results suggest that polymorphisms in genes encoding for the metabolic enzymes might affect risk of specific lymphoma subtypes associated with exposure to workplace carcinogens.
Whole-genome-sequencing (WGS) of human tumors has revealed distinct mutation patterns that hint at the causative origins of cancer. We examined mutational signatures in 324 WGS human-induced ...pluripotent stem cells exposed to 79 known or suspected environmental carcinogens. Forty-one yielded characteristic substitution mutational signatures. Some were similar to signatures found in human tumors. Additionally, six agents produced double-substitution signatures and eight produced indel signatures. Investigating mutation asymmetries across genome topography revealed fully functional mismatch and transcription-coupled repair pathways. DNA damage induced by environmental mutagens can be resolved by disparate repair and/or replicative pathways, resulting in an assortment of signature outcomes even for a single agent. This compendium of experimentally induced mutational signatures permits further exploration of roles of environmental agents in cancer etiology and underscores how human stem cell DNA is directly vulnerable to environmental agents.
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•41 of 79 environmental agents yielded substitution signatures•6 agents produced double-substitution signatures and 8 produced indel signatures•Several signatures match or exhibit similarity with signatures found in human tumors•Topographical mutational asymmetries reveal mechanistic insights
The effects of a range of environmental mutagens in terms of the kinds of mutations they induce and how these are repaired by the cell is presented in the form of a resource.
Smoking tobacco preparations in a water pipe (hookah) is widespread in many places of the world, including the United States, where it is especially popular among young people. Many perceive water ...pipe smoking to be less hazardous than cigarette smoking. We studied systemic absorption of nicotine, carbon monoxide, and carcinogens from one water pipe smoking session.
Sixteen subjects smoked a water pipe on a clinical research ward. Expired carbon monoxide and carboxyhemoglobin were measured, plasma samples were analyzed for nicotine concentrations, and urine samples were analyzed for the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and polycyclic aromatic hydrocarbon (PAH) metabolite biomarker concentrations.
We found substantial increases in plasma nicotine concentrations, comparable to cigarette smoking, and increases in carbon monoxide levels that are much higher than those typically observed from cigarette smoking, as previously published. Urinary excretion of NNAL and PAH biomarkers increased significantly following water pipe smoking.
Absorption of nicotine in amounts comparable to cigarette smoking indicates a potential for addiction, and absorption of significant amounts of carcinogens raise concerns of cancer risk in people who smoke tobacco products in water pipes.
Our data contribute to an understanding of the health impact of water pipe use.
A recent review by the International Agency for Research on Cancer (IARC) updated the assessments of the > 100 agents classified as Group 1, carcinogenic to humans (IARC Monographs Volume 100, parts ...A-F). This exercise was complicated by the absence of a broadly accepted, systematic method for evaluating mechanistic data to support conclusions regarding human hazard from exposure to carcinogens.
IARC therefore convened two workshops in which an international Working Group of experts identified 10 key characteristics, one or more of which are commonly exhibited by established human carcinogens.
These characteristics provide the basis for an objective approach to identifying and organizing results from pertinent mechanistic studies. The 10 characteristics are the abilities of an agent to 1) act as an electrophile either directly or after metabolic activation; 2) be genotoxic; 3) alter DNA repair or cause genomic instability; 4) induce epigenetic alterations; 5) induce oxidative stress; 6) induce chronic inflammation; 7) be immunosuppressive; 8) modulate receptor-mediated effects; 9) cause immortalization; and 10) alter cell proliferation, cell death, or nutrient supply.
We describe the use of the 10 key characteristics to conduct a systematic literature search focused on relevant end points and construct a graphical representation of the identified mechanistic information. Next, we use benzene and polychlorinated biphenyls as examples to illustrate how this approach may work in practice. The approach described is similar in many respects to those currently being implemented by the U.S. EPA's Integrated Risk Information System Program and the U.S. National Toxicology Program.
Smith MT, Guyton KZ, Gibbons CF, Fritz JM, Portier CJ, Rusyn I, DeMarini DM, Caldwell JC, Kavlock RJ, Lambert P, Hecht SS, Bucher JR, Stewart BW, Baan R, Cogliano VJ, Straif K. 2016. Key characteristics of carcinogens as a basis for organizing data on mechanisms of carcinogenesis. Environ Health Perspect 124:713-721; http://dx.doi.org/10.1289/ehp.1509912.
LINKED CONTENT
This article is linked to Gong et al papers. To view these articles, visit
https://doi.org/10.1111/apt.17676
and
https://doi.org/10.1111/apt.17741
Excessive exposure to polycyclic aromatic hydrocarbons (PAHs) often results in lung cancer, a disease with the highest cancer mortality in the United States. After entry into the lung, PAHs induce ...phase I metabolic enzymes such as cytochrome P450 (CYP) monooxygenases, i.e. CYP1A1/2 and 1B1, and phase II enzymes such as glutathione S-transferases, UDP glucuronyl transferases, NADPH quinone oxidoreductases (NQOs), aldo-keto reductases (AKRs), and epoxide hydrolases (EHs), via the aryl hydrocarbon receptor (AhR)-dependent and independent pathways. Humans can also be exposed to PAHs through diet, via consumption of charcoal broiled foods. Metabolism of PAHs through the CYP1A1/1B1/EH pathway, CYP peroxidase pathway, and AKR pathway leads to the formation of the active carcinogens diol-epoxides, radical cations, and o-quinones. These reactive metabolites produce DNA adducts, resulting in DNA mutations, alteration of gene expression profiles, and tumorigenesis. Mutations in xenobiotic metabolic enzymes, as well as polymorphisms of tumor suppressor genes (e.g. p53) and/or genes involved in gene expression (e.g. X-ray repair cross-complementing proteins), are associated with lung cancer susceptibility in human populations from different ethnicities, gender, and age groups. Although various metabolic activation/inactivation pathways, AhR signaling, and genetic susceptibilities contribute to lung cancer, the precise points at which PAHs induce tumor initiation remain unknown. The goal of this review is to provide a current state-of-the-science of the mechanisms of human lung carcinogenesis mediated by PAHs, the experimental approaches used to study this complex class of compounds, and future directions for research of these compounds.
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