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Diet is one of the main sources of exposure to toxic chemicals with carcinogenic potential, some of which are generated during food processing, depending on the type of food (primarily meat, fish, bread and potatoes), cooking methods and temperature. Although demonstrated in animal models at high doses, an unequivocal link between dietary exposure to these compounds with disease has not been proven in humans. A major difficulty in assessing the actual intake of these toxic compounds is the lack of standardised and harmonised protocols for collecting and analysing dietary information. The intestinal microbiota (IM) has a great influence on health and is altered in some diseases such as colorectal cancer (CRC). Diet influences the composition and activity of the IM, and the net exposure to genotoxicity of potential dietary carcinogens in the gut depends on the interaction among these compounds, IM and diet. This review analyses critically the difficulties and challenges in the study of interactions among these three actors on the onset of CRC. Machine Learning (ML) of data obtained in subclinical and precancerous stages would help to establish risk thresholds for the intake of toxic compounds generated during food processing as related to diet and IM profiles, whereas Semantic Web could improve data accessibility and usability from different studies, as well as helping to elucidate novel interactions among those chemicals, IM and diet., This work is receiving support from the project RTI2018-098288-B-I00 (MCIU/AEI/FEDER, UE) and is based on concepts developed partly funded by projects TIN2017-88877-R (AEI/FEDER, UE), TIN2017-87600-P (AEI/FEDER. UE) and IDI/2018/000176 (Asturian Government GRUPIN projects). SRS is the beneficiary of a training contract financed by project RTI2018-098288-B-I00. SA is granted by a Juan de la Cierva postdoctoral contract from the Spanish Ministry of Science and Innovation (Ref. IJCI-2017-32156) and NS is the recipient of a postdoctoral contract awarded by the Fundación para la Investigación y la Innovación Biosanitaria del Principado de Asturias (FINBA).

Background: Red meat and processed meat consumption are established risk factors for colorectal cancer. One hypothesized mechanism for this association is through exposure to heterocyclic aromatic amines (HAAs), which are formed when meat is cooked at high temperature for a long duration. Although they are mutagenic and carcinogenic in nonhuman primates, the findings of epidemiologic studies that have specifically examined the association between HAA intake and colorectal cancer risk have been inconsistent. Moreover, since N-acetyltransferase 2 (NAT2) has been shown to play a critical role in the bioactivation of HAAs, an interaction between HAA intake and NAT2 on colorectal cancer has been hypothesized and the findings in the previous studies have been inconsistent. Aim: To investigate the association of meat- and fish-derived HAA intake, which were estimated by our validated food frequency questionnaire and population-specific data on HAA contents in meat and fish items with the risk of colorectal adenoma, precursor of colorectal cancer, among middle-aged and elderly Japanese in Japan and Japanese Brazilians in Sao Paulo. In addition, to test the modifying effect of NAT2 on the association of HAA intake on colorectal adenoma risk. Methods: Tokyo adenoma study includes 738 patients with adenoma and 697 controls who underwent total colonoscopy in National Cancer Center, Japan. Brazil adenoma study includes 316 patients with adenoma and 403 controls who underwent total colonoscopy in 2 hospitals in Sao Paulo. HAA intake was estimated from meat and fish intake based on an HAA database that was validated against 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) values measured in human hair. NAT2 acetylation genotype was inferred using 2 SNPs in the NAT2 gene. Logistic regression models were used to calculate odds ratios (ORs) and 95% confidence interval (CI) for the association between HAA intake and colorectal adenoma risk after adjusting for potential confounders. Results: Tokyo adenoma study showed that high intake of 2-amino-3,4-dimethylimidazo[4, 5-f]quinoline (MeIQ) and total HAA was significantly associated with an increased risk of colorectal adenoma in women but not in men. No clear association with PhIP or 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) intakes and no effect modification by NAT2 genotype was observed. Brazil adenoma study found no association for HAAs and no effect modification by NAT2 genotype. Conclusion: Tokyo Adenoma Study suggests that high MeIQ and total HAA intakes are positively associated with colorectal adenoma risk among Japanese women in Japan. However, Brazil adenoma study failed to observe positive associations. The possible explanations of inconsistent findings and the difficulty of the studies will be discussed.

Background N -nitroso compounds are recognized as important dietary carcinogens. Accurate assessment of N -nitroso intake is fundamental to advancing research regarding its role with cancer. Previous studies have not used a quantitative database to estimate the intake of these compounds in a US population. Objective To address this gap, a database of N -nitroso values was developed in conjunction with an existing food frequency questionnaire (FFQ). In this article we report on the relative validity of the FFQ instrument modified to estimate intake of N -nitroso compounds. Design Intake estimates of 23 N -nitroso compounds from the FFQ were compared with those from 7-day food records in a cross-sectional study conducted from January 2005 through June 2006. Subjects A sample of 98 healthy adult subjects (aged 50.42±12.84 years) completed an FFQ and then recorded foods and beverages consumed on 7-day food records. Results Crude and energy-adjusted N -nitroso compounds intakes were significantly higher in the FFQ than the 7-day food records ( P N -nitroso intakes ranged from 0.004 to 0.48. By tertiles of N -nitiroso compounds, there was moderate agreement (κ>0.30) for five compounds. Higher estimates of N -nitroso compounds by FFQ was explained by a greater proportion of subjects who reported eating foods high in N -nitroso compounds on FFQ than reported on 7-day food records. Conclusion The modified FFQ with N -nitroso values is a useful tool for assessing N -nitroso intakes relative to a group, and captures all food items with N -nitroso compounds, including those foods with high concentrations and eaten sporadically.

Dietary carcinogens readily cross the placenta, but we don’t know whether this leads to childhood cancer

Humans have been in contact with metals almost since the beginning of our existence. In fact, one cannot even think on human evolution without considering the great role played by metals in mankind's development. Metals are common moieties of molecules involved in a wide variety of biological processes, and hence are found in virtually all living organisms. Some metals are essential for human nutrition; others are found as contaminants in foodstuffs. One feature of the normal human diet which is frequently found is the simultaneous presence of both essential and toxic metals. Other factors important in the risk-evaluation analysis of metals are their pharmacokinetics, interactions among them and with other major components of the diet, and, especially, the great differences in the dietary habits of different populations and in the regional distribution of metals. In attempting to understand the role which dietary metals could play in human carcinogenesis, we found that the many factors involved and the lack of specific information made it difficult to reach firm conclusions on the hazards of dietary metals. We hope that this paper will raise the interest of genetic toxicologists in the subject and will consequently facilitate a risk analysis of the carcinogenic potential of dietary metals.

In modern times, potent dietary carcinogens are key contributors for neoplastic development. For oral squamous cell carcinoma (OSCC), one of the leading cancer types in developing countries, main oncogenic inducers/enhancers, including areca nut chewing, tobacco smoking, and alcohol consumption, were shown to promote cancer initiation/progression. Over decades, studies from different laboratories have identified underlying cellular and molecular mechanisms for carcinogen-induced OSCC. In this review, we will give an overview of where we are in understanding potential oral carcinogenic factors stimulated OSCC tumorigenesis, especially those associated with areca nut chewing in Asians, aiming to provide future scope of possible interception.

Consumption of dietary carcinogens contributes to the prevalence of cancer in society [...].

1 Introduction 2 Cyanosis 3 Analytical Methods for Environmental Detection and Sampling of Anilines 4 Carcinoma 5 Mechanism of Bladder Cancer 6 Specific Aromatic Amines 7 Environmental Fate 8 Regulation and Legislation 9 Aromatic Amines as Dietary Carcinogens 10 Conclusion Keywords: aromatic amines in coal-tar dye industry; understanding developments in toxicology and industrial hygiene; aniline mutagenicity and/or carcinogenicity; aryl amine intermediate in sulfonamide and risk to workers; aniline toxicological and environmental aspects; bladder cancer mechanism; carcinogenic substances regulation and aryl amine restrictions; aromatic amines as dietary carcinogens

Colorectal cancer remains a significant cause of morbidity and mortality throughout the world. The incidence of colorectal cancer is nearly four-fold higher in more-developed as compared with less-developed regions of the world. At present an early detection of colorectal cancer remains a crucial step in determining the therapeutic outcomes. Screening programmes have been introduced in an effort to detect colorectal cancer at an early stage or at a precancerous colonic polyp stage. These programmes should be used by the health professionals as an opportunity to educate the public regarding the use of chemoprevention in colorectal cancer, which is the main focus of this review and an attractive concept needing further evaluation.

UDP-glucuronosyltransferase (UGT) 1A1 glucuronidates bilirubin, estrogens, and exogenous compounds, including dietary carcinogens. The UGT1A1*28 polymorphism, characterized by variation in the number of thymine-adenine repeats in the promoter region, modulates UGT1A1 transcription. Observational and in vitro studies suggest that certain phytochemicals may increase UGT activity. We investigated, in a randomized, controlled, crossover feeding trial, whether approximately 10 servings/d (doses adjusted for body weight) of crucifers, soy, and citrus for 2 wk compared with a fruit- and vegetable-free basal diet affected UGT1A1 activity as measured by serum bilirubin concentrations and whether effects were modulated by the UGT1A1*28 polymorphism. Healthy men (n = 32) and women (n = 31), aged 20-40 y, enrolled based on UGT1A1 genotype, completed the study. We measured bilirubin in blood collected at d 8 and d 15 of each feeding period. Overall, fruit and vegetables (FV) did not affect serum bilirubin; however, among 7/7 individuals, d 8 total (P = 0.057) and indirect (unconjugated) (P = 0.051) bilirubin tended to be lower when individuals consumed the FV diet (28.97 +/- 2.36 micromol/L and 25.97 +/- 2.15 micromol/L) compared with the basal diet (32.46 +/- 2.63 micromol/L and 29.31 +/- 2.43 micromol/L). We no longer detected this difference at d 15, by which time bilirubin had also decreased when participants consumed the basal diet. Additionally, intervention effects on bilirubin were restricted to women with 7/7 genotype (P = 0.002). These results suggest that serum bilirubin glucuronidation is modulated by dietary intervention, but factors such as UGT1A1 genotype and sex may affect the response to diet.

Cooking foods clearly has a beneficial impact for humans; the microbial content can be decreased, proteins made more digestible and the flavor and texture improved. But at the same time, amino acids, creatine and sugars, which occur naturally in meats, may be involved in reactions that generate heterocyclic amine (HA) carcinogens during cooking. Recently, another amine carcinogen, acrylamide, was found at relatively high levels in cooked carbohydrate-rich foods, especially potatoes. In this commentary acrylamide will be compared with the meat carcinogens (HAs) with respect to formation, human intake and health consequences--it's a meat and potato war. What conclusion about risks from these dietary carcinogens can we make from the available scientific data?

Heterocyclic amines (HCAs) are carcinogenic and mutagenic compounds found at a level of parts per billion in grilled fish and meats. Since the connection between consumption of dietary carcinogens and risk of different cancers in humans has been established, it is necessary to explore effective inhibitors that can prevent or reduce the formation of HCAs in cooked meats. Cooking meat with natural antioxidants decreases or eliminates HCAs in meat. Our objective was to study the inhibition of five HCAs in beef steaks marinated using commercial ingredients that are natural antioxidants.

Metals Toxicology Section Edited by Y. James Kang Methods of Metals Toxicology, A. Naganuma, J. Yoshinaga, Y. Aoki, A. Yasutake, K. Hirayama, Y. Imai, and S. Koizumi Occupational and Environmental Exposures, C. Winder, C.-L. Bai, and N.H. Stacey Metal Metabolism and Toxicities, D.M. Medeiros, R. Wildman, and R. Liebes Cellular and Molecular Mechanisms of Metal Toxicities, M.D. Enger and Y.J. Kang Tissue Uptake and Subcellular Distribution of Mercury, E.J. Massaro Nutrition and Toxicology Section Edited by Gregory D. Miller Using Food Consumption Data to Determine Exposure to Toxins, J.S. Douglass, K.H. Fleming, L.M Barraj, and J.T Heimback Nutrition, Pharmacology, and Toxicology: A Dialectic, D. Raiten Toxic Agents, Chemosensory Function, and Diet, K. Rankin and R. Mattes Essential and Nonessential Mineral Interactions, G.D. Mill and S. Groziak Naturally Occurring Orally Active Dietary Carcinogens, J. Scimeca Inhalation Toxicology Section Edited by Daniel L. Morgan Structure and Function of the Respiratory Tract, K.E. Pinkerton, J.R. Harkema, D.M. Hyde, J.T. McBride, R.R. Mercer, K.T. Morgan, C.G. Plopper, J.A. St. George, and W.S. Tyler Disposition of Inhaled Toxicants, R.B. Schlesinger, A. Ben-Jebria, and A.R. Dahl Respiratory Responses to Inhaled Toxicants, J.Q. Koenig and D.L. Luchtel Methods in Human Inhalation Toxicology, L.J Folinsbee, C.S. Kim, H.R. Kehrl, J.D. Prah, and R.B. Devlin Immunotoxicology Section Edited by Kathleen E. Rodgers Introduction, K.E. Rodgers Immunotoxicology Methods, R.V. House Immunotoxicology of Therapeutic Patients, E.E. Sikorski and H.G. Haggerty Effects of Drugs on Immune System Parameters, W.-J. Wu, E.J. Carson, S.D. Collier, D. Keil, P.A. Weiss, and S. Pruett Metal Immunotoxicology, J. Zelikoff, T.P. McManus, and M.D. Cohen Effects of Pesticides and Organic Solvents on Immune System Parameters, J. Barnett Reproductive and Developmental Toxicology Section Edited by James L. Schardein Biology of Reproduction and Methods in Assessing Reproductive and Developmental Toxicity in Humans, I.O. Obasanjo and C.L. Hughes Male Reproductive Toxicity, S.M. Schrader Female Reproductive Toxicity, A.R. Scialli and C.F. Colie Developmental Toxicity, D.A. Beckman, L.B. Fawcett, and R.L. Brent Index

Grilled or fried meat and fish contain various mutagenic heterocyclic amines, and structures of at least 19 compounds have already been determined. Among these, 10 have been examined for long term carcinogenicity, all proving to be positive. 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), for example, preferentially induced mammary adenocarcinomas in 47% of Fischer 344 female rats when supplemented into the diet at a concentration of 400 parts per million (ppm) for 52 weeks. Moreover, 100 ppm of PhIP for 104 weeks yielded the same incidence. PhIP in the diet for 48 weeks also induced mammary cancer in Sprague-Dawley female rats with incidences of 72 and 25% at 200 ppm and 100 ppm. 2-Amino-3,4-dimethylimidazo[4,5-f]quinoline in the diet at 300 ppm also induced a 25% incidence of mammary adenocarcinomas within 40 weeks. Analysis of PhIP-induced rat mammary carcinomas for ras mutations by polymerase chain reaction-single-strand conformation polymorphism and direct sequencing revealed Ha-ras activation in 3 of 17 carcinomas; all were G--A transitions at the second letter of codon 12 replacing glycine by glutamic acid. A p53 gene mutation was also found in 1 of 10 carcinomas examined; a G--T transversion was detected at the third letter of codon 130, with a substitution of asparagine for lysine. PhIP is the most abundant mutagenic and carcinogenic heterocyclic amine in grilled meat, and, therefore, a role for this compound in human carcinogenesis is strongly implied.

Known mutagens and carcinogens in the diet were compiled and the risk of cancer was estimated on the basis of average exposure levels in Switzerland and carcinogenic potencies from rodent bioassays. The analysis showed that, except for alcohol, the sum of all known dietary carcinogens could only explain a few percent of the cancer deaths attributed by epidemiologists to dietary factors. The discrepancy was explained by a "carcinogenicity" of excess macronutrients. This hypothesis was based on an evaluation of dietary restriction experiments in rats and mice, where a dramatic reducing effect on spontaneous tumour formation was seen. From these experiments, a "carcinogenic potency" was deduced for food in excess (TD50 approximately 16 g/kg per day). Overnutrition in Switzerland was converted into excess food intake and the cancer risk estimated on the basis of the TD50 value. The resulting risk of 60,000 cases per one million lives would allow to explain by overnutrition almost all "diet-related" cancer deaths in humans.

The interrelationships of diet and carcinogenesis are discussed with the focus on aging. To establish whether the elderly are more susceptible to dietary carcinogens and whether dietary prevention of cancer is a reasonable goal for this population, the mechanisms of chemical carcinogenesis, the age-related metabolic and physiologic changes, and the current cancer preventive dietary strategies are reviewed. Vulnerability to dietary carcinogens results from a combination of factors that may increase or decrease the occurrence of cancer in the elderly, and it is, therefore, a very individualized feature, unpredictable when based solely on a subject's age. Dietary prevention of cancer may be effective in advanced age, and the dietary guidelines of the National Academy of Sciences should be implemented in this population.

The scientific understanding of cancer and degenerative disease is being aided by new methodologies which are now used to approach the problem of environmental and occupational carcinogens and anticarcinogens. This paper reviews these powerful new tools and relates them to "natural" mutagens and carcinogens in food. It also discusses the use of oxygen radicals as a cause of degenerative disease associated with aging. Since no human diet can be totally free of carcinogens or mutagens, it is necessary to consider the risks of alternative courses of actions and to quantitate the magnitude of the risks through the "quantification" of these risks. Since carcinogens and anticarcinogens differ in their potency in animals over one million fold, the extrapolation of risks from rodents to humans is difficult but it is a first step. Despite better understanding of all of these risks, it is important to realize that the overall trend in life expectancy in the United States is continuing steadily to improve.

Changes in human dietary habits can be correlated with changes in the incidence of certain human epithelial cancers such as cancer of the colon and stomach. From this it can be inferred that the diet may harbor chemicals that may cause cancer. It can also be similarly postulated that factors that help to prevent cancer exist in the diet. New testing techniques for mutagenicity and carcinogenicity enable one to identify a considerable number of dietary chemicals. Some of these chemicals influence carcinogenesis by reacting with initiating carcinogens. This presents the exciting possibility that certain cancerous diseases may be prevented by eliminating or binding dietary carcinogens. Although simple in concept, this approach to cancer control is hampered by a lack of carcinogenicity data for dietary carcinogens in humans, and by the logistics of such an endeavor.

Interest has increased recently in the possible human carcinogenic effects of plant metabolites in the diet. Some psoralens, some pyrrolizidine alkaloids and 'bracken carcinogen' may be dietary carcinogens, the latter two via contamination of food products from animals ingesting toxic plants. With the exception of 'bracken carcinogen', the structures of these compounds have been established. Further research to quantify the levels of these compounds in foodstuffs and to correlate these with the amounts of the compounds having toxic effects in laboratory animals would be valuable. Epidemiological studies on critical-intake consumer groups would also be of value in defining the hazard, if any, the presence of these compounds in the diet poses to the consumer.

Since the early beginnings of research in the field of chemical carcinogenesis scientists have suspected that factors in the environment may contribute to the genesis of human cancers. Because the human diet is essentially a compilation of many and varied chemical nutrients, it has been logical to assume that some of the nutrients could be related to the carcinogenic process. We live, however, in a sea of environmental chemicals. Many of these agents, which may lack nutritional properties, can pass through the oral gateway and into the digestive tract where they may be involved figuring in some way in initiation and promotion, the two conceptual divisions of chemical carcinogenesis.

The concentrations of 2-amino-3-methylimidazo(4,5-f) quinoline (IQ) and 2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline (MeIQx), a family of mutagenic and carcinogenic heterocyclic amines, in the plasma of normal subjects (10 cases), patients with uremia receiving maintenance hemodialysis treatment (9 cases) and patients with uremia just before induction of hemodialysis treatment (5 cases) were determined by a high-performance liquid chromatography method. The plasma levels of IQ and MeIQx in uremic patients just before induction of hemodialysis treatment were 12.6 +/- 4.1 nM (mean +/- S.D., n = 5) and 10.0 +/- 2.3 nM (n = 5), respectively. In patients with uremia receiving maintenance hemodialysis treatment, IQ and MeIQx were detected in 4 and 2 out of 9 cases, respectively and the levels of those in the plasma were 4.1 nM (n = 4) and 1.7 nM (n = 2), respectively. However, IQ and MeIQx could not be detected in all normal subjects. These results indicate that uremic patients just before induction of hemodialysis treatment are actually exposed to higher levels of the carcinogenic heterocyclic amines, as compared with normal subjects and uremic patients receiving maintenance hemodialysis treatment.

To systematically examine the extent of correlation of risk factors, such as age, consumed dietary habit and familial predisposition with somatic Tp53 molecular lesion causal to elevate carcinogenesis severity of esophageal squamous cell carcinoma (ESCC) among the Kashmiri population of Northern India.All cases (n = 51) and controls (n = 150) were permanent residents of the Kashmir valley. Genetic alterations were determined in exons 5-8 of Tp53 tumor suppressor gene among 45 ESCC cases histologically confirmed by PCR-SSCP analysis. Data for individual cancer cases (n = 45) and inpatient controls (n = 150) with non-cancer disease included information on family history of cancer, thirty prevailing common dietary risk factors along with patient's age group. Correlation of genetic lesion in p53 exons to animistic data from these parameters was generated by Chi-square test to all 45 histologically confirmed ESCC cases along with healthy controls.Thirty-five of 45 (77.8%) histologically characterized tumor samples had analogous somatic mutation as opposed to 1 of 45 normal sample obtained from adjacent region from the same patient showed germline mutation. The SSCP analysis demonstrated that most common p53 gene alterations were found in exon 6 (77.7%), that did not correlate with the age of the individual and clinicopathological parameters but showed significant concordance (P0.05) with familial history of cancer (CD = 58), suggesting germline predisposition at an unknown locus, and dietary habit of consuming locally grown Brassica vegetable "Hakh" (CD = 19.5), red chillies (CD = 20.2), hot salty soda tea (CD = 2.37) and local baked bread (CD = 1.1).Our study suggests that somatic chromosomal mutations, especially in exon 6 of Tp53 gene, among esophageal cancer patients of an ethnically homogenous population of Kashmir valley are closely related to continued exposure to various common dietary risk factors, especially hot salty tea, meat, baked bread and "Hakh", that are rich in nitrosoamines and familial cancer history.