Human Cancer Risk Research Articles

Increased risk of cancer in dogs and humans: a consequence of recent extension of lifespan beyond evolutionarily-determined limitations?

Cancer is among the most common causes of death for dogs (and cats) and humans in the developed world, even though it is uncommon in wildlife and other domestic animals. We provide a rationale for this observation based on recent advances in our understanding of the evolutionary basis of cancer. Over the course of evolutionary time, species have acquired and fine-tuned adaptive cancer protective mechanisms that are intrinsically related to their energy demands, reproductive strategies, and expected lifespan. These cancer protective mechanisms are general across species and/or specific to each species and their niche, and they do not seem to be limited in diversity. The evolutionarily acquired cancer-free longevity that defines a species' life history can explain why the relative cancer risk, rate, and incidence are largely similar across most species in the animal kingdom despite differences in body size and life expectancy. The molecular, cellular, and metabolic events that promote malignant transformation and cancerous growth can overcome these adaptive, species-specific protective mechanisms in a small proportion of individuals, while independently, some individuals in the population might achieve exceptional longevity. In dogs and humans, recent dramatic alterations in healthcare and social structures have allowed increasing numbers of individuals in both species to far exceed their species-adapted longevities (by 2-4 times) without allowing the time necessary for compensatory natural selection. In other words, the cancer protective mechanisms that restrain risk at comparable levels to other species for their adapted lifespan are incapable of providing cancer protection over this recent, drastic and widespread increase in longevity.

Per-/polyfluoroalkyl substance concentrations in human serum and their associations with liver cancer

Per-/polyfluoroalkyl substances (PFASs) are widespread in global human blood, and have some toxic effects on liver. However, effects of PFAS exposure on human liver cancer (LC) risk are still not known. In this study, 203 LC patients and 203 controls were recruited, and their serum samples were collected between 2019 and 2021. We determined the residues of 12 PFASs in serum from all participants and quantified their association with LC incidence and tumor markers. PFOS (9.8 ng/mL) had the highest mean concentration in human serum, followed by PFOA (8.3 ng/mL) and 6:2 Cl-PFESA (3.9 ng/mL). We found that concentrations of PFOS and 6:2 Cl-PFESA in human serum were significantly correlated with the levels of alpha fetoprotein (AFP) (βPFOS = 0.13, 95% confidence interval (CIPFOS): 0.088, 0.17; β6:2 Cl-PFESA = 0.070, CI6:2 Cl-PFESA: 0.036, 0.10). A positive association of PFOS and 6:2 Cl-PFESA with odds ratios (OR) of LC (ORPFOS = 0.609, CIPFOS: 1.179, 4.029, P = 0.001; OR6:2 Cl-PFESA = 1.844, CI6:2 Cl-PFESA: 1.176, 2.512, P = 0.02) were found, after adjusting for different covariates. Moreover, serum PFOA concentrations were associated with carcinoembryonic antigen (CEA), but their correlation with the LC incidence was not statistically significant. This new finding supports the evidence for the positive associations among PFAS exposure, change of specific tumor marker, and LC risks.

A0034 - Urinary human papilloma virus infection and bladder cancer risk: A systematic review and a prisma-compliant meta-analysis

A0034 - Urinary human papilloma virus infection and bladder cancer risk: A systematic review and a prisma-compliant meta-analysis

Analysis of Glucosinolate Content and Metabolism Related Genes in Different Parts of Chinese Flowering Cabbage.

Glucosinolates (GSLs) are important secondary metabolites that play important defensive roles in cruciferous plants. Chinese flowering cabbage, one of the most common vegetable crops, is rich in GSLs and thus has the potential to reduce the risk of cancer in humans. Many genes that are involved in GSL biosynthesis and metabolism have been identified in the model plant Arabidopsis thaliana; however, few studies investigated the genes related to GSL biosynthesis and metabolism in Chinese flowering cabbage. In the present study, the GSL composition and content in three different organs of Chinese flowering cabbage (leaf, stalk, and flower bud) were determined. Our results showed that the total GSL content in flower buds was significantly higher than in stalks and leaves, and aliphatic GSLs were the most abundant GSL type. To understand the molecular mechanisms underlying the variations of GSL content, we analyzed the expression of genes encoding enzymes involved in GSL biosynthesis and transport in different tissues of Chinese flowering cabbage using RNA sequencing; the expression levels of most genes were found to be consistent with the pattern of total GSL content. Correlation and consistency analysis of differentially expressed genes from different organs with the GSL content revealed that seven genes (Bra029966, Bra012640, Bra016787, Bra011761, Bra006830, Bra011759, and Bra029248) were positively correlated with GSL content. These findings provide a molecular basis for further elucidating GSL biosynthesis and transport in Chinese flowering cabbage.

Circulating Clusterin Levels and Cancer Risk: A Systematic Review and Meta-Analysis.

IntroductionThe previous reports on clusterin (CLU) levels in various types of cancer have been controversial and heterogeneous. The present meta-analysis has aimed to evaluate the association between soluble CLU levels and the risk of different human cancers based on observational studies.MethodsA systematic literature review was conducted to determine the relevant eligible studies in English language from health-related electronic databases up to January 2021. Random effects models were used to calculate the summary standard mean difference (SMD) with 95% confidence intervals (CIs) to identify the correlation between CLU levels and cancer risk. The meta-regression, sensitivity, Galbraith, and subgroup analyses were performed to explore the source of between-study heterogeneity. Furthermore, the funnel plot and Egger’s linear regression tests were carried out to evaluate the risk of publication bias.ResultsAccording to 16 eligible articles, 3331 patients and 839 healthy controls were included in our meta-analysis. Overall, the CLU levels were significantly higher in various cancer cases compared to the healthy groups (SMD = 1.50, 95% CI = 0.47–2.53). Moreover, subgroup analysis based on types of cancer showed a significant correlation between CLU levels and the risk of digestive system cancers (SMD = 1.54, 95% CI = 0.91–2.18, P <0.001), especially in HCC (SMD = 1.89, 95% CI = 0.76–3.03, P = 0.001), and CRC (SMD = 1.63, 95% CI = 0.0–3.23, P = 0.048).ConclusionThe present meta-analysis indicates a significant association of CLU levels with the risk of digestive system cancers such as hepatocellular carcinoma and colorectal cancer. Therefore, CLU can be monitored as a novel molecular biomarker for the prognosis and diagnosis of various types of cancers particularly in the digestive system.

Development challenges for carcinogenicity risk assessments of topical drugs.

The nonclinical safety package to support development and approval of drugs intended to be administered by topical application generally follows International Council for Harmonisation multidisciplinary 3 (ICH M3) and topic specific safety (ICH S) guidances. However, some aspects of topical drug development may require case-by-case determination of nonclinical safety strategies. The necessity to conduct a dermal rodent carcinogenicity study is one such example that is not considered an obligate component of a nonclinical safety data package for drug approval. While absence of systemic exposure, as stated in ICH M3, is a primary reason to forego a dermal carcinogenicity assessment, there may also be other factors for consideration in determining the need for a life-time carcinogencity study by dermal route to aid in the overall human cancer risk assessment. We therefore reviewed nonclinical carcinogencity data packages from drugs approved by the FDA or PMDA over a ~25 year time period to evaluate outcomes of oral versus topical carcinogencity studies and to understand their utility for informing the overall human risk assessment. We also discuss various other properties of topical small molecules that could impact the decisions to conduct a dermal life-time rodent carcinogenicity study. Collectively, the need to conduct 2-year dermal carcinogenicity studies in rodents should be determined case-by-case and consider scientific factors such existing systemic toxicity and carcinogenicity study data, anticipated drug exposures in skin, skin evaluation from the chronic minipig toxicity study, and genetic toxicity profile.

Comorbidity Evaluation Identifies Smoking Dose Density to be Associated with TP53 Mutation in Myeloid Malignancies

Background: Inflammation and aging are factors associated with mutagenicity. In acute Myelogenous Leukemia (AML), detectable mutations (mut) are a powerful tool for identification of patients (pt) at a higher risk for relapse. One frequently observed mutation is TP53, which is particularly unresponsive to treatment. Known risk factors for TP53 acquisition include prior chemotherapy or radiation exposure. It is possible that TP53 mut initiates at low allele frequency and expands in a “permissible marrow microenvironment”. Cell extrinsic inflammation, collectively called extracellular stressor, is a theory of mutation acquisition which is gaining momentum given its recently recognized role in clonal initiation, expansion, and dominance. Smoking is one such possible extracellular stressor that dramatically increases risk of human cancer. Lung tissue directly exposed to smoking develops higher frequency of mut; however, other tissue not directly exposed (e.g. bladder, pancreas) exhibit similar mutation frequencies. This suggests that active smoking metabolites systemically induce inflammation and/or mutagenicity. Indeed, TP53 and ASXL1 mut have been associated with clonal hematopoiesis (CH). In this study, we seek to create “proof of clinical concept” for association between smoking “dose” and TP53 myeloid malignancy development when controlled by an age-adjusted effect. Methods: After IRB approval, AML and Myelodysplastic Syndrome (MDS) AML patients with available Next Generation Sequencing (NGS) were isolated from MDS/AML databases. “Smoking dose” was estimated in patients exhibiting or not exhibiting TP53 mut by standard pack-year calculation. Demographics, clinical, and laboratory categorical and continuous variables were analyzed by chi-square and t-test using SAS software. Logistic regression analysis allowed for identification of variables with independent predictive value for TP53 acquisition. Results: Our cohort represented 52 patients (pt) [AML N=47/52 (90.3%) and MDS N=5/52 (9.6%)]. 23/52 (44.2%) pt harbored TP53-mut and 29/52 pt (55.8%) were part of a genomic control group harboring ASXL1, RUNX1, FLT3, NPM1, and KRAS mut. Median age for pt with and without TP53 mut was 71 y (49-81) vs 60 y (22-88), respectively, p= 0.04 [Fig. 1B]. In TP53 mutated vs TP53 unmutated group, 14/23 (60.8%) vs 13/20 (65%) pt were male. 9/23 (39.1%) and 7/20 (35%) of pt with and without TP53 mut had available smoking history. Pack-year smoking was 53.6 [20-100] and 23.2 [10-40], in pt wit and without TP53 mut, respectively, p=0.02 [Fig. 1A]. When adjusted by age and prior chemotherapy exposure, smoking dose density was the only potential factor with relevance for TP53 acquisition (p=0.05). Conclusions: In myeloid malignancies, our data suggests that TP53 acquisition is associated with a dose dependent smoking history. This smoking dose dependency seems to be independent from aging and prior chemotherapy exposure in AML. Previous studies have demonstrated strong associations between smoking and inflammation. It is possible that higher dosages of smoking induce marrow microenvironment inflammatory changes permissible for TP53 initiation. These microenvironmental changes may be associated with mutational signatures similar to those found in other smoking-associated malignancies, including lung adenocarcinoma. Our report adds to the body of evidence for mechanistic link between magnitude of smoking exposure and marrow environmental stress to promote selective mutagenicity, though larger study is needed. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Suppression of apoptotic signaling in rat hepatocytes by non-dioxin-like polychlorinated biphenyls depends on the receptors CAR and PXR

Non-dioxin-like polychlorinated biphenyls (NDL-PCBs) represent a sub-group of persistent organic pollutants found in food, environmental samples and human and animal tissues. Promotion of pre-neoplastic lesions in rodent liver has been suggested as an indicator for a possible increased risk of liver cancer in humans exposed to NDL-PCBs. In rodent hepatocytes, suppression of DNA damage-triggered apoptosis is a typical mode of action of liver tumor promoters. Here, we report that NDL-PCBs suppress apoptosis in rat hepatocytes treated in culture with an apoptogenic dose of UV light. Suppression became less pronounced when the constitutive androstane receptor (CAR) and/or the pregnane-X-receptor (PXR) where knocked-out using siRNAs, while knocking-out both receptors led to a full reconstitution of apoptosis. In contrast, suppression of apoptosis by the CAR or PXR activators phenobarbital or dexamethasone were CAR- or PXR-specific. Induction and suppression of apoptosis were paralleled by changes in caspase 3/7, 8 and 9 activities. Our findings indicate that NDL-PCBs can suppress UV-induced apoptosis in rat hepatocytes by activating CAR and PXR. It needs further investigation if these mechanisms of action are also of relevance for human liver.

Association between telomere length and mitochondrial copy number and cancer risk in humans: A meta-analysis on more than 300,000 individuals.

In the last decades the association of leukocyte telomere length (LTL) and mitochondrial copy number (mtDNAcn) with cancer risk has been the focus of many reports, however the relation is not yet completely understood. A meta-analysis of 112 studies including 64,184 cancer cases and 278,641 controls that analysed LTL and mtDNAcn in relation to cancer risk has been conducted to further our understanding of the topic. Stratified analyses for tumor type were also performed. Overall, no association was observed for all cancer combined neither for LTL nor mtDNAcn. Significant associations were detected for these biomarkers and specific cancer type; however, a large degree of heterogeneity was present, even within the same tumor type. Alternatives approaches based on polymorphic variants, such as polygenic risk scores and mendelian randomization, could be adopted to unravel the causal correlation of telomere length and mitochondrial copy number with cancer risk.

Nutritional Quality of the Most Consumed Varieties of Raw and Cooked Rice in Spain Submitted to an In Vitro Digestion Model

Rice is one of the most consumed staple foods around the world and its trade is highly globalized. Increased environmental pollution generates a large amount of waste that, in many cases, is discarded close to culture fields. Some species are able to bioaccumulate toxic substances, such as metals, that could be transferred to the food chain. The main goal of this study was to evaluate the content of metallic (Al, Cd, Pb, and Cr) and metalloid elements (As) in 14 of the most consumed varieties of rice in Spain and their effects on human health. The samples were cooked, and human digestion was simulated by using a standard in vitro digestion method. Metallic and metalloid element levels were analysed by Inductively Coupled Plasma Optical Emission Spectrometry (ICP-OES), previous called microwave digestion. Both the human health risk index, Hazard Quotient, and Lifetime Cancer Risk did not show toxic values in any case. Rice with a higher non-digestible fraction showed a higher liberation of proteins and a lower glycemic index. There were no significant differences in the concentrations of metallic and metalloid elements in cooked rice or in the digestible fraction in all varieties analysed. However, Al concentrations were higher than other metals in all varieties studied due to its global distribution. No relationship has been observed between the digestibility of rice and the bioaccessibility of each metallic and metalloid element. All of the studied rice varieties are healthy food products and its daily consumption is safe. The regular monitoring of metals and As in rice consumed in Spain may contribute to improvements in the human health risk evaluation.

The Impact of ZIP8 Disease-Associated Variants G38R, C113S, G204C, and S335T on Selenium and Cadmium Accumulations: The First Characterization.

The metal cation symporter ZIP8 (SLC39A8) is a transmembrane protein that imports the essential micronutrients iron, manganese, and zinc, as well as heavy toxic metal cadmium (Cd). It has been recently suggested that selenium (Se), another essential micronutrient that has long been known for its role in human health and cancer risk, may also be transported by the ZIP8 protein. Several mutations in the ZIP8 gene are associated with the aberrant ion homeostasis of cells and can lead to human diseases. However, the intricate relationships between ZIP8 mutations, cellular Se homeostasis, and human diseases (including cancers and illnesses associated with Cd exposure) have not been explored. To further verify if ZIP8 is involved in cellular Se transportation, we first knockout (KO) the endogenous expression of ZIP8 in the HeLa cells using the CRISPR/Cas9 system. The elimination of ZIP8 expression was examined by PCR, DNA sequencing, immunoblot, and immunofluorescence analyses. Inductively coupled plasma mass spectrometry indicated that reduced uptake of Se, along with other micronutrients and Cd, was observed in the ZIP8-KO cells. In contrast, when ZIP8 was overexpressed, increased Se uptake could be detected in the ZIP8-overexpressing cells. Additionally, we found that ZIP8 with disease-associated single-point mutations G38R, G204C, and S335T, but not C113S, showed reduced Se transport ability. We then evaluated the potential of Se on Cd cytotoxicity prevention and therapy of cancers. Results indicated that Se could suppress Cd-induced cytotoxicity via decreasing the intracellular Cd transported by ZIP8, and Se exhibited excellent anticancer activity against not all but only selected cancer cell lines, under restricted experimental conditions. Moreover, clinical-based bioinformatic analyses revealed that up-regulated ZIP8 gene expression was common across multiple cancer types, and selenoproteins that were significantly co-expressed with ZIP8 in these cancers had been identified. Taken together, this study concludes that ZIP8 is an important protein in modulating cellular Se levels and provides insights into the roles of ZIP8 and Se in disease prevention and therapy.

Human gastric cancer risk screening: From rat pepsinogen studies to the ABC method.

We examined the development of gastric cancer risk screening, from rat pepsinogen studies in an experimental rat gastric carcinogenesis model induced with N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) and human pepsinogen studies in the 1970s and 1980s to the recent “ABC method” for human gastric cancer risk screening. First, decreased expression or absence of a major pepsinogen isozyme, PG1, was observed in the rat gastric mucosa from the early stages of gastric carcinogenesis to adenocarcinomas following treatment with MNNG. In the 1980s, decreases in PGI in the human gastric mucosa and serum were identified as markers of atrophic gastritis. In the 1990s, other researchers revealed that chronic infection with Helicobacter pylori (Hp) causes atrophic gastritis and later gastric cancer. In the 2000s, a gastric cancer risk screening method combining assays to detect serum anti-Hp IgG antibody and serum PGI and PGII levels, the “ABC method”, was established. Eradication of Hp and endoscopic follow-up examination after the ABC method are recommended to prevent gastric cancer.

Integrative eQTL-weighted hierarchical Cox models for SNP-set based time-to-event association studies

BackgroundIntegrating functional annotations into SNP-set association studies has been proven a powerful analysis strategy. Statistical methods for such integration have been developed for continuous and binary phenotypes; however, the SNP-set integrative approaches for time-to-event or survival outcomes are lacking.MethodsWe here propose IEHC, an integrative eQTL (expression quantitative trait loci) hierarchical Cox regression, for SNP-set based survival association analysis by modeling effect sizes of genetic variants as a function of eQTL via a hierarchical manner. Three p-values combination tests are developed to examine the joint effects of eQTL and genetic variants after a novel decorrelated modification of statistics for the two components. An omnibus test (IEHC-ACAT) is further adapted to aggregate the strengths of all available tests.ResultsSimulations demonstrated that the IEHC joint tests were more powerful if both eQTL and genetic variants contributed to association signal, while IEHC-ACAT was robust and often outperformed other approaches across various simulation scenarios. When applying IEHC to ten TCGA cancers by incorporating eQTL from relevant tissues of GTEx, we revealed that substantial correlations existed between the two types of effect sizes of genetic variants from TCGA and GTEx, and identified 21 (9 unique) cancer-associated genes which would otherwise be missed by approaches not incorporating eQTL.ConclusionIEHC represents a flexible, robust, and powerful approach to integrate functional omics information to enhance the power of identifying association signals for the survival risk of complex human cancers.

Human papillomavirus infection and gastric cancer risk: A meta-epidemiological review.

Gastric cancer (GC) is a multifactorial disease, and several modifiable risk factors have been reported. This review summarizes and interprets two previous quantitative systematic reviews evaluating the association between human papillomavirus (HPV) infection and GC risk. The results of two systematic reviews evaluating the same hypothesis showed a statistically significant difference in summary odds ratios and their 95% confidence intervals. Thus, it is necessary to conduct a subgroup analysis of Chinese and non-Chinese studies. Additional meta-analyses that control for heterogeneity are required. Reanalysis showed that all the Chinese studies had statistical significance, whereas the non-national studies did not. The funnel plot asymmetry and Egger's test confirmed publication bias in the Chinese studies. In addition, the proportion of HPV-positive cases in Chinese studies was 1.43 times higher than that in non-Chinese studies and 2.81 times lower in controls. Therefore, the deduced evidence is currently insufficient to conclude that HPV infection is associated with GC risk.

Changes in RAPD-DNA Markers and Plasma Protein Profile in Progesterone-Treated Chicken

The abuse of contraceptive pills as growth promoters in the poultry industry has serious health concerns. Consumption of hormonal residues in animal products results in reproductive disorders and an increased risk of cancers in humans. This study aimed to investigate the effect of treatment with progesterone hormone on the plasma proteins and RAPD-DNA markers of broiler chickens. One hundred, one-day-old broiler chicks were equally divided into 5 groups (n = 20). Four groups were treated daily with progesterone hormone either subcutaneously or orally (1.0 mg, 1.5mg/kg). The 5th group was control non-treated chicken. Sodium dodecyl sulfate polyacrylamide gel-electrophoresis (SDS-PAGE), and RAPD assays in conjunction with productive parameters such as growth rate were assessed. SDS-PAGE and RAPD-DNA patterns were significantly affected by progesterone hormone treatment. Either or oral or subcutaneous progesterone hormone treatments increased the body weight of chicks compared to control. Treatment with progesterone hormone induces effects on both DNA and plasma proteins in broiler chickens. Changes at the genomic DNA level may be due to specific modifications in RAPD patterns or arise as a consequence of hot spot DNA changes and/or mutations.

Isonicotinylation is a histone mark induced by the anti-tuberculosis first-line drug isoniazid

Isoniazid (INH) is a first-line anti-tuberculosis drug used for nearly 70 years. However, the mechanism underlying the side effects of INH has remained elusive. Here, we report that INH and its metabolites induce a post-translational modification (PTM) of histones, lysine isonicotinylation (Kinic), also called 4-picolinylation, in cells and mice. INH promotes the biosynthesis of isonicotinyl-CoA (Inic-CoA), a co-factor of intracellular isonicotinylation. Mass spectrometry reveals 26 Kinic sites in histones in HepG2 cells. Acetyltransferases CREB-binding protein (CBP) and P300 catalyse histone Kinic, while histone deacetylase HDAC3 functions as a deisonicotinylase. Notably, MNase sensitivity assay and RNA-seq analysis show that histone Kinic relaxes chromatin structure and promotes gene transcription. INH-mediated histone Kinic upregulates PIK3R1 gene expression and activates the PI3K/Akt/mTOR signalling pathway in liver cancer cells, linking INH to tumourigenicity in the liver. We demonstrate that Kinic is a histone acylation mark with a pyridine ring, which may have broad biological effects. Therefore, INH-induced isonicotinylation potentially accounts for the side effects in patients taking INH long-term for anti-tuberculosis therapy, and this modification may increase the risk of cancer in humans.

Characterization of fecal microbiome in biopsy positive prostate cancer patients

ObjectivesTo characterize the fecal microbiome in newly diagnosed prostate cancer patients.Patients and methodsForty‐nine consecutive patients who were referred for trans rectal prostate biopsy were tested. Patients who received antibiotics 3 months prior to the biopsy, patients with history of pelvic irradiation, prostate or colon cancer, inflammatory bowel disease and urinary tract infection were excluded. A rectal swab was obtained just prior to the biopsy, immediately placed in a sterile tube and kept in −80°C. Sequencing was performed for the 16S rRNA 515F + 806R gene fragment using the QIIME2 software. Analytic tests included Beta diversity (Weighted Unifrac, Unweighted Unifrac, Bray‐Curtis), Alpha diversity (Faith, Evenness), Taxa bar plots and PCoA plots.ResultsForty‐five samples were suitable for analysis with at least 8000 readings per sample. All patients were Caucasian. Twenty patients had prostate cancer and 25 had benign prostates (BPH). Among prostate cancer patients, Gleason Score was 3 + 3 in 11 patients, 3 + 4 in 5, 4 + 3 in 3, and 4 + 4 in 2. There was no statistical difference in demographic parameters between the groups. We identified over 1000 bacterial species, typical for the colonic microbiome. No significant differences in bacterial populations were found between prostate cancer versus benign prostate patients nor between age groups or between subgroups of Gleason or International Society of Uro‐pathology (ISUP) scores.ConclusionsAlthough the microbiome has previously been shown to have an impact on the human microenvironment and cancer risk, we could not demonstrate a significant difference between the flora diversity of newly diagnosed prostate cancer patients and BPH patients. Further research into distinct bacterial metabolic pathways may reveal unique risk factors for prostate cancer.

Cancer risk from chronic exposures to chemicals and radiation: a comparison of the toxicological reference value with the radiation detriment.

This article aims at comparing reference methods for the assessment of cancer risk from exposure to genotoxic carcinogen chemical substances and to ionizing radiation. For chemicals, cancer potency is expressed as a toxicological reference value (TRV) based on the most sensitive type of cancer generally observed in animal experiments of oral or inhalation exposure. A dose-response curve is established by modelling experimental data adjusted to apply to human exposure. This leads to a point of departure from which the TRV is derived as the slope of a linear extrapolation to zero dose. Human lifetime cancer risk can then be assessed as the product of dose by TRV and it is generally considered to be tolerable in a 10-6-10-4 range for the public in a normal situation. Radiation exposure is assessed as an effective dose corresponding to a weighted average of energy deposition in body organs. Cancer risk models were derived from the epidemiological follow-up of atomic bombing survivors. Considering a linear-no-threshold dose-risk relationship and average baseline risks, lifetime nominal risk coefficients were established for 13 types of cancers. Those are adjusted according to the severity of each cancer type and combined into an overall indicator denominated radiation detriment. Exposure to radiation is subject to dose limits proscribing unacceptable health detriment. The differences between chemical and radiological cancer risk assessments are discussed and concern data sources, extrapolation to low doses, definition of dose, considered health effects and level of conservatism. These differences should not be an insuperable impediment to the comparison of TRVs with radiation risk, thus opportunities exist to bring closer the two types of risk assessment.

Global Cancer Risk From Unregulated Polycyclic Aromatic Hydrocarbons.

In assessments of cancer risk from atmospheric polycyclic aromatic hydrocarbons (PAHs), scientists and regulators rarely consider the complex mixture of emitted compounds and degradation products, and they often represent the entire mixture using a single emitted compound—benzo[a]pyrene. Here, we show that benzo[a]pyrene is a poor indicator of PAH risk distribution and management: nearly 90% of cancer risk worldwide results from other PAHs, including unregulated degradation products of emitted PAHs. We develop and apply a global‐scale atmospheric model and conduct health impact analyses to estimate human cancer risk from 16 PAHs and several of their N‐PAH degradation products. We find that benzo[a]pyrene is a minor contributor to the total cancer risks of PAHs (11%); the remaining risk comes from other directly emitted PAHs (72%) and N‐PAHs (17%). We show that assessment and policy‐making that relies solely on benzo[a]pyrene exposure provides misleading estimates of risk distribution, the importance of chemical processes, and the prospects for risk mitigation. We conclude that researchers and decision‐makers should consider additional PAHs as well as degradation products.

Aryl Hydrocarbon Receptor Activation Produces Heat Shock Protein 90 and 70 Overexpression, Prostaglandin E2/Wnt/β-Catenin Signaling Disruption, and Cell Proliferation in MCF-7 and MDA-MB-231 Cells after 24 h and 14 Days of Chlorpyrifos Treatment.

The biocide chlorpyrifos (CPF) was described to increase breast cancer risk in humans, to produce breast cancer in animals, and to induce cell proliferation in MCF-7 and MDA-MB-231 cells after 1 and 14 days of treatment. The entire mechanisms related to these CPF actions remain unknown. CPF induced cell proliferation in MCF-7 and MDA-MB-231 cells after 1 and 14 days of treatment by AhR activation through the PGE2/Wnt/β-catenin pathway and HSP90 and HSP70 overexpression. Our results reveal new information on CPF toxic mechanisms induced in human breast cancer cell lines, which could assist in elucidating its involvement in breast cancer.