A Sensitive LC–MS/MS Method for the Quantification of 3-Hydroxybenzo[a]pyrene in Urine-Exposure Assessment in Smokers and Users of Potentially Reduced-Risk Products

Benzo[a]pyrene (BaP), a human carcinogen, is formed during the incomplete combustion of organic matter such as tobacco. A suitable biomarker of exposure is the monohydroxylated metabolite 3-hydroxybenzo[a]pyrene (3-OH-BaP). We developed a sensitive LC–MS/MS (liquid chromatography coupled with tandem mass spectrometry) method for the quantification of urinary 3-OH-BaP. The method was validated according to the US Food and Drug Administration (FDA) guideline for bioanalytical method validation and showed excellent results in terms of accuracy, precision, and sensitivity (lower limit of quantification (LLOQ): 50 pg/L). The method was applied to urine samples derived from a controlled clinical study to compare exposure from cigarette smoking to the use of potentially reduced-risk products. Urinary 3-OH-BaP concentrations were significantly higher in smokers of conventional cigarettes (149 pg/24 h) compared to users of potentially reduced-risk products as well as non-users (99% < LLOQ in these groups). In conclusion, 3-OH-BaP is a suitable biomarker to assess the exposure to BaP in non-occupationally exposed populations and to distinguish not only cigarette smokers from non-smokers but also from users of potentially reduced-risk products.

The Association between Blood Concentrations of PCDD/DFs, DL-PCBs and Risk of Type 2 Diabetes Mellitus and Thyroid Cancer

Background and Objectives: Dioxin, classified as a human carcinogen by International Cancer Research Institute, shows inconsistent results on type 2 diabetes mellitus (T2DM) and cancer in epidemiological studies. International Cancer Research Institute classifies dioxin as a human carcinogen, but epidemiological studies of its effects on type 2 diabetes mellitus (T2DM) and cancer show inconsistent results. Therefore, we conducted a Korean population study to ascertain if the blood concentration of dioxin-like polychlorinated biphenyls (DL-PCBs) and polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/DFs) is associated with T2DM and thyroid cancer.Methods: Within a nested case-control study, we identified 15 people diagnosed with thyroid cancer, 30 people diagnosed with T2DM, and 55 for control. Due to the 4ml human blood requirement for PCDD/DF and DL-PCB concentrations tests, a total of 500 samples were used in 100 pooling samples. The continuous variable of a pooled sample was calculated as an average value taking into account the blood weight of each sample. The odds ratios (ORs) and 95% confidence interval (95% CI) for determining the association between total dioxins and risk of T2DM and thyroid cancer were estimated using the multivariable logistic regression.Results: The study population included 100 participants from the KCPS-II (median [IQR] baseline age, 54.06 [21.04] years; 48 women). The toxic equivalents of PCDD/DFs showed a significant positive association with T2DM and thyroid cancer, after adjustments for potential confounders (T2DM ORs = 1.23; 95% CI = 1.05-1.43; Thyroid cancer ORs = 1.34; 95% CI = 1.12-1.61). These results showed a stronger association in women than in men.Conclusion: In this study, both T2DM and thyroid cancer appear to be associated with the levels of PCDD/DFs serum. The association between T2DM and levels of PCDD/DFs serum is found in women and not in men. Our findings suggest that further biochemical in vivo research and epidemiologic studies are needed to clarify the nature of the association between dioxins concentrations and diseases.

Benzo[a]pyrene-Induced Genotoxicity in Rats is Affected by Co-Exposure to Sudan I by Altering the Expression of Biotransformation Enzymes

The environmental pollutant benzo[a]pyrene (BaP) is a human carcinogen that reacts with DNA after metabolic activation catalysed by cytochromes P450 (CYP) 1A1 and 1B1 together with microsomal epoxide hydrolase. The azo dye Sudan I is a potent inducer of CYP1A1/2. Here, Wistar rats were either treated with single doses of BaP (150 mg/kg bw) or Sudan I (50 mg/kg bw) alone or with both compounds in combination to explore BaP-derived DNA adduct formation in vivo. Using 32P-postlabelling, DNA adducts generated by BaP-7,8-dihydrodiol-9,10-epoxide were found in livers of rats treated with BaP alone or co-exposed to Sudan I. During co-exposure to Sudan I prior to BaP treatment, BaP-DNA adduct levels increased 2.1-fold in comparison to BaP treatment alone. Similarly, hepatic microsomes isolated from rats exposed to Sudan I prior to BaP treatment were also the most effective in generating DNA adducts in vitro with the activated metabolites BaP-7,8-dihydrodiol or BaP-9-ol as intermediates. DNA adduct formation correlated with changes in the expression and/or enzyme activities of CYP1A1, 1A2 and 1B1 in hepatic microsomes. Thus, BaP genotoxicity in rats in vivo appears to be related to the enhanced expression and/or activity of hepatic CYP1A1/2 and 1B1 caused by exposure of rats to the studied compounds. Our results indicate that the industrially employed azo dye Sudan I potentiates the genotoxicity of the human carcinogen BaP, and exposure to both substances at the same time seems to be hazardous to humans.

Nitrosamine Impurities: Origin, Control and Regulatory Recommendations

The unexpected finding of presence of nitrosamine impurities, by USFDA and EMA in year 2018, in drugs such as Angiotensin-II Receptor Blockers (ARBs), Ranitidine, Nizatidine and Metformin, has triggered the need for a risk assessment strategy for evaluation and control of these probable human carcinogen - nitrosamine in pharmaceutical product that are at risk. This finding leads to voluntarily recall of products worldwide. The finding of nitrosamines in some types of drug products led FDA and other international regulators to conduct a detailed risk assessment of these impurities in APIs and drug products. Although nitrosamine impurities have been found in only some drug products, regulatory agencies recommended to extend risk analysis in other chemically synthesized APIs and drug products also.

Efficiency of neutral honey as a tissue fixative in histopathology

In the routine laboratory, 10% neutral buffered formalin (NBF) is the fixative of choice. However, formalin is a human carcinogen. To the best of our knowledge, neutral honey, not natural or artificial honey, has not been tested to fix histological tissues. This study aimed to examine the efficiency of neutral buffered honey and other types of honey fixatives to fix histological tissues. The most two natural common Omani honey were used as fixatives, namely Sumar and date. We tested samples of rat liver, kidney, and stomach. Nine types of fixatives were used. All tissues were treated equally. The evaluation was performed blindly by three senior biomedical scientists who work in a histopathology laboratory. Hematoxylin and eosin showed adequate staining in all groups when compared to 10% NBF. The intensity and specificity of Jones Methenamine silver stain in 10% Sumer and Date honey and 10% alcoholic Sumer honey showed similar findings of 10% NBF. The specificity and intensity of all groups for Periodic acid–Schiff were comparable with 10% neutral buffered formalin accepts for 10% Sumer honey and 10% Alcoholic Date honey. However, all honey groups showed weak staining for the reticulin fibers using Gordon and Sweets method. Vimentin showed comparable findings with 10% NBF as there were no significant differences. The findings of this study are promising. Further in depth research on honey as a possible safe substitute fixative for formalin should be conducted.

Occupational exposure to glyphosate and risk of lymphoma:results of an Italian multicenter case-control study

Background The International Agency for Research on Cancer (IARC) recently classified glyphosate, the most used herbicide worldwide, as a probable human carcinogen. We inquired into the association between occupational exposure to glyphosate and risk of lymphoma subtypes in a multicenter case-control study conducted in Italy. Methods The Italian Gene-Environment Interactions in Lymphoma Etiology (ItGxE) study took place in 2011–17 in six Italian centres. Overall, 867 incident lymphoma cases and 774 controls participated in the study. Based on detailed questionnaire information, occupational experts classified duration, confidence, frequency, and intensity of exposure to glyphosate for each study subject. Using unconditional regression analysis, we modelled risk of major lymphoma subtypes associated with exposure to glyphosate adjusted by age, gender, education, and study centre. Results Very few study subjects (2.2%) were classified as ever exposed to glyphosate. Risk of follicular lymphoma (FL) was elevated 7-fold in subjects classified as ever exposed to glyphosate with medium-high confidence, 4.5-fold in association with medium-high cumulative exposure level, 12-fold with medium-high exposure intensity, and 6-fold with exposure for 10 days or more per year. Significant upward trends were detected with all the exposure metrics, but duration. The overall p-value for an upward trend with four independent metrics was 1.88 × 10− 4. There was no association with risk of lymphoma (any subtype), Non Hodgkin Lymphoma, B-cell lymphoma, or the major lymphoma subtypes other than FL. Conclusions Our findings provide limited support to the IARC decision to classify glyphosate as Group 2A human carcinogen.

Reduction of Ochratoxin A during the Preparation of Porridge with Sodium Bicarbonate and Fructose

Ochratoxin A (OTA) is a potential human carcinogen that poses a significant concern in food safety and public health. OTA has been found in a wide variety of agricultural commodities, including cereal grains. This study investigated the reduction of OTA during the preparation of rice- and oat-based porridge by a simulated indirect steam process. The effects of sodium bicarbonate (NaHCO3) and fructose on the reduction of OTA were also investigated. During the processing, OTA in rice- and oat-porridge was decreased by 59% and 14%, respectively, from initial OTA artificially added at 20 μg/kg (dry weight basis). When 0.5% and 1% of sodium bicarbonate were added to rice porridge, increased reduction of OTA was observed as 78% and 68%, respectively. The same amounts of added sodium bicarbonate also further reduced OTA in oat porridge to 58% and 72%, respectively. In addition, increased reduction of OTA in the presence of fructose was observed. A combination of the two, i.e., 0.5% sodium bicarbonate and 0.5% fructose, resulted in a 79% and 67% reduction in rice porridge and oat porridge, respectively. These results indicate that indirect steaming may effectively reduce OTA in preparation of porridge-type products, particularly when sodium bicarbonate and/or fructose are added.

Rapid and long-lasting acceleration of zero-valent iron nanoparticles@Ti3C2-based MXene/peroxymonosulfate oxidation with bi-active centers toward ranitidine removal

Advanced oxidation processes (AOPs) can effectively degrade ranitidine, a pharmaceutical that is a typical precursor of nitrosamine dimethylamine (NDMA), an extremely potent human carcinogen. Herein, novel magnetic Ti3C2-based MXene nanosheets...