Carcinogenicity assessment of tegoprazan in Sprague-Dawley (Crl:CD) rats and ICR (Crl:CD1) mice.

Tegoprazan is a novel potassium-competitive acid blocker (P-CAB) that reversibly inhibits the proton pump in gastric parietal cells and has been approved for the treatment of acid-related diseases in Korea. This study aimed to evaluate the carcinogenic potential of tegoprazan in Sprague-Dawley rats and CD-1 mice. Tegoprazan was administered daily by oral gavage to rats for up to 94 weeks and mice for up to 104 weeks. Evidence of carcinogenic potential of tegoprazan was identified in rats only and was limited to benign and/or malignant neuroendocrine cell tumors at exposures >7-fold of the recommended human dose. Glandular stomach findings were considered secondary to the expected pharmacology of tegoprazan, characterized by their location in the fundic and body regions of the stomach. Overall, tegoprazan induced gastric enterochromaffin-like (ECL) cell tumors in SD rats, but did not produce any treatment-related statistically significant increase in the incidence of neoplasms relevant to humans when administered to SD rats and CD-1 mice by gavage at doses up to 300 and 150 mg/kg/day, respectively. Gastric ECL cell tumors are thought to be induced by the exaggerated indirect pharmacological effect of tegoprazan, similar to that reported for proton pump inhibitors (PPIs) and other P-CABs.

Assessment of hydrogeochemical characteristics and quality of groundwater resources in relation to risk of gastric cancer: comparative analysis of high- and low-risk areas in Iran.

The chemical quality of groundwater supplies in two high-risk area (HRA) and low-risk area (LRA) for gastric cancer in Iran was assessed through hydrogeochemical analysis and water quality indices. For this aim, Piper and Schoeller diagrams and water quality index (WQI) were applied. In addition, exposure to nitrate via drinking water and its corresponding risk were also assessed using Monte Carlo simulation technique. Data on physicochemical properties of groundwater resources were obtained from Iran Water Resources Management Company. Sampling and analysis of tap water for nitrate concentration were conducted in two cities of Shiraz (as a representative of LRA) and Ardabil (as a representative of HRA). According to Piper diagrams, the dominant hydrogeochemical facies of groundwater supplies in HRA and LRA were Na-HCO3 (43.75%) and Ca-HCO3 (41.77%), respectively. The predominant cations in groundwater resources of HRA were found to be Na+ (68.06%) and Ca2+ (31.94%). For LRA, the typical cations were in decreasing trend: Ca2+ (39.64%) > Mg2+ (18.35%) > Na+ (17.26%). For two areas, HCO3-, SO42- and Cl- were, respectively, the most frequent anions. Two-sample Wilcoxon test showed that there were statistically significant difference between two areas in terms of anions and cations concentrations (p value < 0.05). The mean of total hardness (Ca2+ + Mg2+) concentration of water supplies in LRA (528.1 mg/L) was higher than HRA (263.1 mg/L), whereas the mean of Na+ concentration was found to be lower in LRA (90.6 mg/L) compared with HRA (108.1 mg/L). The sum of nitrate intake and its risk in LRA was higher than HRA. WQI results showed that drinking water quality in HRA and LRA ranged from excellent to poor and most water resources were of a good quality class. Further studies are suggested to investigate the role of drinking water in the etiology of gastric cancer in Iran.

Is administration of proton pump inhibitors in functional dyspepsia worth the risk of developing gastric cancer: a Markov model to bridge the gap between scientific evidence and clinical practice.

OBJECTIVE: To formulate a decision analysis model based on recently published data that addresses the dilemma, whether improvement in quality of life rationalises continued proton pump inhibitors (PPI) use despite the risk of gastric cancer (GC) in patients with functional dyspepsia (FD). DESIGN: A Markov model consisting of an initial decision regarding treatment with PPI (denoting it by PPI strategy) or any other treatment without PPI (denoting it by placebo strategy) was designed. DATA SOURCES: Data from prospective cross-sectional studies indicating risk stratification for GC after the use of PPI, combined with a Markov model that comprised the following states: Live, GC stages 1-4, Death. OUTCOME MEASURES: The primary outputs included quality-adjusted life years (QALYs) and life expectancy (LE). The improvement in utility in FD without PPI as compared with PPI use was tested (PPI vs placebo strategies). Sensitivity analyses were performed to evaluate the robustness of the model and address uncertainty in the estimation of model parameters. SETTING: We considered only patients whose symptoms were relieved with PPIs and thus, had a better quality of life compared with patients who did not receive PPIs. RESULTS: The base case model showed that PPIs compared with placebo decreased LE by 58.4 days with a gain of 2.1 QALY. If utility (quality of life of patients with FD using PPI compared with patients with FD without PPI) improved by more than 0.8%, PPI use is considered better than placebo. Older patients benefited less from PPI treatment than did younger patients. CONCLUSION: To bridge the gap between evidence and decision making, we found that even a small improvement in the QALY justified continuing PPI treatment.

Personalized risk assessment for dynamic transition of gastric neoplasms.

BACKGROUND: To develop an individually-tailored dynamic risk assessment model following a multistep, multifactorial process of the Correa's gastric cancer model. METHODS: First, we estimated the state-to-state transition rates following Correa's five-step carcinogenic model and assessed the effect of risk factors, including Helicobacter pylori infection, history of upper gastrointestinal disease, lifestyle, and dietary habits, on the step-by-step transition rates using data from a high-risk population in Matsu Islands, Taiwan. Second, we incorporated information on the gastric cancer carcinogenesis affected by genomic risk factors (including inherited susceptibility and irreversible genomic changes) based on literature to generate a genetic and epigenetic risk assessment model by using a simulated cohort identical to the Matsu population. The combination of conventional and genomic risk factors enables us to develop the personalized transition risk scores and composite scores. RESULTS: The state-by-state transition rates per year were 0.0053, 0.7523, 0.1750, and 0.0121 per year from normal mucosa to chronic active gastritis, chronic active gastritis to atrophic gastritis, atrophic gastritis to intestinal metaplasia, and intestinal metaplasia to gastric cancer, respectively. Compared with the median risk group, the most risky decile had a 5.22-fold risk of developing gastric cancer, and the least risky decile around one-twelfth of the risk. The median 10-year risk for gastric cancer incidence was 0.77%. The median lifetime risk for gastric cancer incidence was 5.43%. By decile, the 10-year risk ranged from 0.06 to 4.04% and the lifetime risk ranged from 0.42 to 21.04%. CONCLUSIONS: We demonstrate how to develop a personalized dynamic risk assessment model with the underpinning of Correa's cascade to stratify the population according to their risk for progression to gastric cancer. Such a risk assessment model not only facilitates the development of an individually-tailored preventive strategy with treatment for H. pylori infection and endoscopic screening but also provides short-term and long-term indicators to evaluate the program effectiveness.

Assessment of the mode of action underlying development of forestomach tumors in rodents following oral exposure to ethyl acrylate and relevance to humans.

Chronic repeated gavage dosing of high concentrations of ethyl acrylate (EA) causes forestomach tumors in rats and mice. For two decades, there has been general consensus that these tumors are unique to rodents because of: i) lack of carcinogenicity in other organs, ii) specificity to the forestomach (an organ unique to rodents which humans do not possess), iii) lack of carcinogenicity by other routes of exposure, and iv) obvious site of contact toxicity at carcinogenic doses. In 1986, EA was classified as possibly carcinogenic to humans by the International Agency for Research on Cancer (IARC). However, by applying a MOA analyses and human relevance framework assessment, the weight-of-evidence supports a cytotoxic MOA with the following key events: i) bolus delivery of EA to forestomach lumen and subsequent absorption, ii) cytotoxicity likely due to saturation of enzymatic detoxification, iii) chronic regenerative hyperplasia, and iv) spontaneous mutation due to increased cell replication and cell population. Clonal expansion of initiated cells thus results in late onset tumorigenesis. The key events in this 'wound and healing' MOA provide high confidence in the MOA as assessed by evolved Bradford-Hill Criteria. The weight-of-evidence supported by the proposed MOA, combined with a unique tissue that does not exist in humans, indicates that EA is highly unlikely to pose a human cancer hazard.

Socio-economic and occupational risk factors for gastric cancer: a cohort study in Sweden.

The effects of socio-economic/occupational factors on gastric cancer at various subsites (including corpus, cardia and unspecified cancers) are not well known. To investigate this issue, we carried out a follow-up study on the economically active Swedish population, based on the Swedish Family-Cancer Database. We calculated standardized incidence ratios and 95% confidence intervals for different occupational groups, adjusted for age, period, region and socio-economic status. The reference group was all the economically active population. Manual workers and farmers were at an increased risk of stomach cancer. An increased risk of corpus cancer was observed for male miners and quarry workers, fishermen, construction workers, packers, loaders and warehouse workers, clerical workers and female assistant nurses and postal workers. For cardia cancer, significantly increased standardized incidence ratios were observed for gardeners, transport workers, bricklayers and chemical process workers among men. Only male miner and quarry workers showed significantly increased risk of unspecified cancer. In conclusion, the present study indicates that socio-economic groups differ in risk by almost a factor of two for corpus and unspecified cancers, and less for cardia cancers. Cement and mineral dusts appear as major occupational risk factors.

Review of studies concerning the tumorigenicity of 2-butoxyethanol in B6C3F1 mice and its relevance for human risk assessment.

The U.S. National Toxicology Program (NTP) has completed 2-yr inhalation exposures in rats and mice with 2-butoxyethanol (BE). This review concerns the most significant findings from those studies and describes recent research into the mechanistic aspects of BE-mediated tumorigenesis in the mouse and the relevance of such effects to humans. Two tumor types were increased in B6C3F1 mice leading to the classification of "some evidence" of carcinogenicity: liver hemangiosarcomas in male mice and forestomach tumors in female mice (primarily benign papillomas). The results of research collected to date indicate that the tumorigenesis noted for BE was produced by indirect mechanisms. In particular, the occurrence of liver hemangiosarcomas in male mice has been linked to oxidative damage subsequent to red blood cell hemolysis and iron deposition in this organ. Oral administration of BE in mice up to 600 mg/kg/d for up to 90 d produces a dose-related increase in iron (Perl's staining) in Kupffer cells and hepatocytes, increased DNA synthesis in endothelial cells, and enhanced oxidative damage. Further, iron alone, and not BE or BAA, is responsible for producing oxidative damage in cultured hepatocytes from rats or mice. Forestomach neoplasms in female mice were most likely a result of prolonged exposure-induced irritation with compensatory hyperplasia and subsequent tumor promotion. This mechanism is supported by studies indicating elevated levels of BE and BAA in the mouse forestomach tissues and stomach contents following multiple routes of exposure, forestomach epithelial cell cytotoxicity and cell proliferation following administration of BE and BAA, and the increased capacity of forestomach tissues from female mice to metabolize BE to the more irritating metabolite, BAA. The current article summarizes the results of a number of in vivo and in vitro studies designed to elucidate the underlying mechanisms of tumorigenesis by BE in the mouse and discusses the relevance of these for human risk.

Association between gastric cancer mortality and nitrate content of drinking water: ecological study on small area inequalities.

The carcinogenic feature of N-nitroso compounds has been well established. Similarly, the transformation of ingested nitrate to N-nitroso compounds in the stomach has been thoroughly documented, nevertheless nitrates' carcinogenic effect has not been proved convincingly in human. The present study was aimed to investigate a population of small villages provided by drinking water with high and widely variable nitrate content (72 mg/l median, 290.7 mg/l 95-percentile concentration). Empirical Bayes estimates for settlement-specific age-, sex-, and year-standardised mortality ratios of gastric cancer (GC) were related to the settlement level average nitrate concentrations in drinking water controlling for confounding effects of smoking, ethnicity and education. The log-transformed average nitrate concentration showed significant positive association with stomach cancer mortality in linear regression analysis (p = 0.014). The settlements were aggregated according to the nitrate concentration into 10-percentile groups and the standardised mortality ratios (SMRs) were calculated. Those groups with higher than 88 mg/l average nitrate concentration showed substantial risk elevation and the log-transformed exposure variables proved to be significant predictors of mortality (p = 0.032) at this level of aggregation also. The association seemed to be fairly strong (r2 = 0.46). Although this investigation constituting an ecological study has certain limitations, it supports the hypothesis that the high level of nitrate in drinking water is involved in the development of GC.

[Sodium chloride in food rations and dinners in mass catering institutions]. / Chlorek sodu w racjach pokarmowych i posilkach obiadowych wydawanych w wybranych zakladach zywienia zbiorowego.

The sodium chloride content in meals given by mass catering institution in all over country in 1988-1998 years was estimated. This study included daily food rations from 183 mass catering institution as hospitals, sanatoriums for both children and adults, boarding schools, infant schools and social welfare homes. We assessed also school dinners from 422 randomized selected schools and dinners from 55 internal and 56 surgical departments of provincial and regional hospitals in Poland. The mass of each meal was evaluated and sodium chloride content by Mohr's method was assessed. In most cases the salt content by 100 g of meal of 1000 kcal was calculated. The dinners and daily food rations analyze showed that sodium chloride content in meals was much higher than value recommended by World Health Organization (WHO). Salt amount in daily food rations of both children and adults was above 16 g. This value didn't include salt added to meals by boarders. School dinners provided about 7-10 g of salt. The average sodium chloride content in hospital dinners was about 16-20 g. In each studied group the NaCl content per 100 g of meal was similarly high and was 0.7-0.9 g. The results of this study show that meals given by mass catering institutions can increase risk of hypertension, strokes and gastric cancers because of high sodium chloride content.

Induction of glutathione S-transferase pi as a bioassay for the evaluation of potency of inhibitors of benzo(a)pyrene-induced cancer in a murine model.

There is a growing need for short-term and cost-effective bioassay to assess the efficacy of potential chemo-preventive agents. We report that the induction of glutathione (GSH) S-transferase pi (mGSTP1-1) by a chemo-preventive agent can be used as a reliable marker to assess its efficacy in retarding chemical carcinogenesis induced by benzo(a)pyrene (BP), which is a widespread environmental pollutant and believed to be a risk factor in human chemical carcinogenesis. This conclusion is based on 1) the relative contribution of mGSTP1-1 of the liver and forestomach of female A/J mice in the detoxification of the ultimate carcinogenic metabolite of BP, (+)-anti-7,8-dihydroxy-9, 10-oxy-7,8,9, 10-tetrahydrobenzo(a)pyrene [(+)-anti-BPDE]; and 2) a positive correlation between the induction of hepatic and forestomach mGSTP1-1 by 5 naturally occurring organosulfides (OSCs) from garlic (diallyl sulfide, diallyl disulfide, diallyl trisulfide, dipropyl sulfide and dipropyl disulfide) and their effectiveness in preventing BP-induced forestomach neoplasia in mice. In the liver, the combined contribution of other GSTs in the detoxification of (+)-anti-BPDE was far less than the contribution of mGSTP1-1 alone. Likewise, in the forestomach, the contribution of mGSTP1-1 far exceeded the combined contribution of other GSTs. Studies on the effects of OSCs against BP-induced forestomach neoplasia revealed a good correlation between their chemo-preventive efficacy and their ability to induce mGSTP1-1 expression in the liver (r = -0.89; p < 0.05) as well as in the forestomach (r = -0.97; p < 0.05). Our results suggest that the induction of mGSTP1-1 may be a reliable marker for evaluating the efficacy of potential inhibitors of BP-induced cancer in a murine model.

Salt and public health--policies for dietary salt in the Nordic countries.

OBJECTIVE: To review current knowledge about excess dietary salt as a risk factor for diseases and to compare and discuss the national policies for dietary salt in the Nordic countries. DESIGN: Literature review, questionnaire and interviews. Nordic comparative study. SETTING: The Medline bibliographic system and authorities responsible for the national nutritional policies in the Nordic countries. SUBJECTS: Scientific articles published since 1988 concerning the impact of excess dietary salt on health and key persons with responsibilities for the formulation of national recommendations about dietary salt in each of the five Nordic countries. MAIN OUTCOME MEASURES: Articles dealing with (i) epidemiological observations, (ii) sensitive groups, (iii) underlying biological mechanisms concerning the contents of the latest national recommendations and the wording of legislation and decrees about salt in food-stuffs in the Nordic countries. RESULTS: The impact of excess dietary salt on health mainly concerns hypertension, gastric cancer, osteoporosis and bronchial hyperreactivity. The national policy for dietary salt in Finland differs from the other Nordic countries. In Finland salt is a food additive and a variety of special regulations exist. Finland has chosen a more active way to achieve the existing Nordic recommendation of 5 g salt per day. The daily intake is about 10 g per day in all the Nordic countries. CONCLUSIONS: There is need for further epidemiological studies of the relationship between excess dietary salt and gastric cancer, osteoporosis, and bronchial hyperreactivity. The knowledge of the relationship between dietary salt and raised blood pressure is sufficient to put force behind the implementation of existing Nordic recommendations.

[Development of criteria and identification of areas most hazardous for the health of the population due to chemicals present in the environment. II. Choice of health indicators and synthetic taxonomic measures]. / Opracowanie kryteriów i wyznaczenie obszarów o najwiekszym zagrozeniu zdrowia ludnosci substancjami chemicznymi wystepujacymi w srodowisku. II. Wybór mierników zdrowotnych i syntetycznej miary taksonomiczej.

The aim of the study was: 1. to choose health indicators related with hazards caused by chemicals in order to identify areas of the greatest health hazards, following the criteria proposed in Part I; 2. to apply different methods of variable aggregation, to evaluate their efficency and to choose a method most useful for identifying the areas most hazardous for health because of chemicals present in the environment. On the basis of the analysis performed, according to criteria proposed, and the analysis of the frequency of individual phenomena, the following health indicators were chosen to assess chemical hazards: incidence of low birth weight (under 2500), mortality of infants with low birth weight; male and female mortality from diseases of the circulatory system, and male mortality from lung and stomach neoplasm in the 30-59 age groups; mortality females above 60 years od age, and the rate of premature deaths in the 30-64 age group. For a comprehensive assessment of negative health effects three synthetic measures were applied: according to Hellwig, Strahl and Klima and Wydymus. Upon the analysis of rank concordance according to measures obtained and the sum of ranks of individual indicators based on correlation coefficient od Spearman's rank, the measure according to Strahl proved to be most accurate. This measure has been proposed for identifying areas most hazardous for the population health because of chemicals present in the environment.

Ethylene oxide: an assessment of the epidemiological evidence on carcinogenicity.

Mortality from cancer among workers exposed to ethylene oxide (EtO) has been studied in 10 distinct cohorts that include about 29,800 workers and 2540 deaths. This paper presents a review and meta-analysis of these studies, primarily for leukaemia, non-Hodgkin's lymphoma, stomach cancer, pancreatic cancer, and cancer of the brain and nervous system. The magnitude and consistency of the standardised mortality ratios (SMRs) were evaluated for the individual and combined studies, as well as trends by intensity or frequency of exposure, by duration of exposure, and by latency (time since first exposure). Exposures to other workplace chemicals were examined as possible confounder variables. Three small studies by Hogstedt initially suggested an association between EtO and leukaemia, but in seven subsequent studies the SMRs for leukaemia have been much lower. For the combined studies the SMR = 1.06 (95% confidence interval (95% CI) 0.73-1.48). There was a slight suggestion of a trend by duration of exposure (p = 0.19) and a suggested increase with longer latency (p = 0.07), but there was no overall trend in risk of leukaemia by intensity or frequency of exposure; nor did a cumulative exposure analysis in the largest study indicate a quantitative association. There was also an indication that in two studies with increased risks the workers had been exposed to other potential carcinogens. For non-Hodgkin's lymphoma there was a suggestive risk overall (SMR = 1.35, 95% CI 0.93-1.90). Breakdowns by exposure intensity or frequency, exposure duration, or latency did not indicate an association, but a positive trend by cumulative exposure (p = 0.05) was seen in the largest study. There was a suggested increase in the overall SMR for stomach cancer (SMR = 1.28, 95% CI 0.98-1.65 (CI 0.73-2.26 when heterogeneity among the risk estimates was taken into account)), but analyses by intensity or duration of exposure or cumulative exposure did not support a causal association for stomach cancer. The overall SMRs and exposure-response analyses did not indicate a risk from EtO for pancreatic cancer (SMR = 0.98), brain and nervous system cancer (SMR = 0.89), or total cancer (SMR = 0.94). Although the current data do not provide consistent and convincing evidence that EtO causes leukaemia or non-Hodgkin's lymphoma, the issues are not resolved and await further studies of exposed populations.

Mechanism-based cancer risk assessment of butylated hydroxyanisole.

The evidence for BHA-induced carcinogenicity is restricted to the rodent non-glandular stomach, which is not found in humans. Although an argument can be made that an effect in this target organ could be indicative of potential carcinogenicity in other tissues, particularly the esophagus, studies have not revealed such a correlation. BHA-induced proliferative effects, which appear to be critical for the tumorigenic response, show a NOEL at a dose below that yielding benign tumors. The NOEL of this BHA-induced proliferative effect demonstrates a substantial margin of safety compared to human intake of BHA. Thus based on both dose-response considerations and the species-specific response, the use of BHA as a food additive does not pose a carcinogenic risk in humans.

Assessment of gastric antisecretory effects of phenoxyisobutyrate derivatives in the rat and the mouse.

After the observation of a low incidence of gastric carcinoid tumours in rats, but not in mice, given ciprofibrate for 2 years, ciprofibrate and related compounds were investigated for gastric antisecretory activity. A significant inhibition of gastric secretion, similar to that induced by comparable doses of cimetidine, was observed in the fischer rat 1.5 h after a single oral (200 or 500 mg kg-1) or intraduodenal (100 or 300 mg kg-1) administration of ciprofibrate, bezafibrate, and clofibric acid. Ciprofibrate had prolonged antisecretory activity when compared with bezafibrate or ranitidine. Prolonged inhibition of gastric secretion is proposed as the primary cause of gastric carcinoids in the rat, since in a comparative evaluation, antisecretory activity was observed in the rat but not in the mouse.

Genotoxicity and carcinogenicity of fluorocarbons: assessment by short-term in vitro tests and chronic exposure in rats.

Two short-term in vitro tests for mutagenicity (Salmonella reverse mutation and BHK21 cell transformation) were conducted on a series of fluorocarbons. Some of these materials (FC22, FC31, FC142b, FC143, and FC143a) were found to be positive in one or both of the tests and could therefore be considered as being potentially carcinogenic to animals. Such activity was not anticipated for what were previously considered inert materials and in consequence several examples of these fluorocarbons, which represented different combinations of short-term test results, were tested for carcinogenicity in limited in vivo bioassays. In these studies, rats were dosed for 1 year by gavage 5 days a week with either FC22, FC31, FC133a, FC134a, or FC143a dissolved in a corn-oil at a single dosage of 300 mg/kg body weight. The animals were then observed until week 125 with detailed necropsy at termination. The study revealed that FC31 was a potent carcinogen (to the rat stomach), a result which reflected the short-term test predictions, but FC133a, which gave a negative response in both the in vitro assays, induced a high incidence of reproductive tract tumors. The weak bacterial mutagens FC22 and FC143a did not induce tumors in this study, and the nonmutagenic FC134a was without overt carcinogenic activity. It is concluded that, while recognizing the limitations of the in vivo component of this study, the short-term tests were only partially successful in identifying potential carcinogens for this series of chemicals. Fluorocarbon 31 was a potent carcinogen which was first identified by bacterial mutation and cell transformation, whereas the equally potent carcinogen FC133a was not so identified. The lack of genotoxic activity with this particular compound leads us to believe that the carcinogenic activity may be due to mechanisms other than those which involve direct DNA interactions.

Endogenous synthesis of volatile nitrosamines: model calculations and risk assessment.

A kinetic model for estimating the gastric synthesis of N-nitroso compounds and a method for estimating the risk from exposure to volatile nitrosamines are described. A tentative calculation of the possible risks for human gastric cancer, based on extrapolating from literature data on the induction of tumours in rats, suggests that the endogenous formation of non-volatile N-nitroso compounds is more important than that of volatile nitrosamines.