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Arsenic is a known carcinogen for the lungs, the bladder, and the skin, while systematic evidence on other cancer types is lacking, especially for occupational exposure. Thus, we aimed to systematically summarize current evidence on the association between occupational arsenic exposure and digestive cancers, including head and neck cancer (HNC). We conducted a systematic review on Pubmed, Web of Science, and Embase search engines. We computed pooled relative risks (RRs) and corresponding 95% confidence intervals (CIs) using DerSimonian and Laird random-effects model. Occurrence of publication bias was assessed using contour-enhanced funnel plots and Egger's test. Twenty-two studies on digestive cancers and 11 on HNC were included in the meta-analysis. RRs for the association with occupational exposure to arsenic of 1.23 (95% CI: 1.07-1.40; I 2  = 72.3%, p < 0.001) and 1.08 (95% CI: 0.76-1.53; I 2  = 76.6%, p < 0.001) for digestive cancer and HNC, respectively, were observed. As for specific cancer types, arsenic was associated with rectal cancer (RR: 1.51; 95% CI: 1.003-2.28; I 2  = 37.0%, p = 0.174), but not with other investigated cancer types. No clear evidence of publication bias was found. The results of our study suggest that the observed association between occupational arsenic exposure and digestive cancer might be mainly driven by a positive association for rectal cancer, while arsenic exposure did not appear to be associated with HNC. However, further high-quality studies with detailed assessment of arsenic exposure are warranted to clarify the potential association of arsenic with digestive cancers and HNC., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Paolo Boffetta reports a relationship with Arsenic Science Task Force that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

The objective of this study was to explore the causal relationship between the use of proton pump inhibitors (PPIs) and 16 types of digestive system tumors. We utilized a 2-sample Mendelian randomization (MR) approach to investigate this relationship. We obtained exposure and outcome data from the UK Biobank and the Finland Biobank, respectively. The genetic data used in the analysis were derived from genome-wide association studies (GWAS) studies conducted on European populations. We screened single nucleotide polymorphisms significantly associated with the use of omeprazole, a commonly used PPIs, as instrumental variables. We then performed MR analyses using the inverse variance weighting (IVW) method, MR-Egger regression, and the weighted median method to evaluate the causal effect of omeprazole use on the 16 types of digestive system tumors. Our MR analysis revealed a significant causal relationship between the use of omeprazole and pancreatic malignancies, but not with any other types of digestive system tumors. The IVW analysis showed an odds ratio of 4.33E-05 (95%CI: [4.87E-09, 0.38], P = .03) and the MR-Egger analysis showed an odds ratio of 5.81E-11 (95%CI: [2.82E-20, 0.12], P = .04). We found no significant heterogeneity or pleiotropy, and sensitivity analysis confirmed the robustness of our results. Furthermore, statistical power calculations suggested that our findings were reliable. Conclusion The use of PPIs is a protective factor for pancreatic malignancies, but no causal relationship has been found with other digestive system tumors., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: For the past two decades, dispute on whether proton pump inhibitor (PPI) leads to digestive tract cancer remains, and emerging studies in recent years still demonstrate inconsistent results, which continues to perpetuate concerns over the safety of PPI use. We performed a systematic review and meta-analysis, with comprehensive evaluation by Bradford Hill criteria of causation, to assess the effect of PPI use on digestive tract cancers., Methods: Medline, Embase and Web of Science databases were searched for observational studies published up to 15th January 2021. Pooled relative risks (RRs) were estimated via random effects models. Cumulative defined daily dose- and duration-risk relationships using restricted cubic spline and fractional polynomial models were investigated. Bradford Hill criteria were applied to evaluate causation. PROSPERO Registration: CRD42020211103., Results: Thirty-two publications containing 4,355,254 participants were included. PPI use is associated with an increased risk of overall digestive tract cancers (RR = 1.63, 95% confidence interval (CI) 1.33 to 2.00). PPI use is correlated with increased risks of gastric cancer (RR = 1.78, 95% CI 1.38 to 2.31), pancreatic cancer (RR = 1.72, 95% CI 1.05 to 2.82) and liver cancer (RR = 1.62, 95% CI 1.04 to 2.52), but not of esophageal cancer (RR = 2.06, 95% CI 0.65 to 6.57) and colorectal cancer (RR = 1.24, 95% CI 0.93 to 1.66). The association between PPI and digestive tract cancers is stronger in people with minimal exposure. When cumulative defined daily dose or duration increases, the risks decline and become non-significant. Evaluation by Bradford Hill criteria indicates weak evidence of causation., Conclusions: A causal relationship between PPI use and digestive tract cancers is not supported by the evidence in the current review. Concerns over carcinogenic side-effects of PPI might be unfounded., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objectives: To evaluate the risk of cancers of digestive system with incretin-based therapies among patients with type 2 diabetes mellitus., Research Design and Methods: Medline, Embase, Cochrane Library and ClinicalTrials.gov databases were searched for randomized controlled clinical trials that compared incretin-based drugs with placebo or other antidiabetic drugs. Paired reviewers independently screened citations, extracted data and assessed risk of bias of included studies. Network meta-analysis was performed, followed by subgroup analysis. The Grading of Recommendations Assessment, Development and Evaluation system was used to assess the quality of evidence., Results: A total of 84 studies (n=101 595) involving cancers of digestive system were identified (a median follow-up of 30 weeks). The risk of cancers of digestive system with incretin-based therapies was comparable with insulin (OR: 0.86, 95% CI 0.27 to 2.69), metformin (OR: 0.32, 95% CI 0.07 to 1.38), sodium-glucose co-transporter 2 (OR: 5.26, 95% CI 0.58 to 47.41), sulfonylureas (OR: 1.27, 95% CI 0.68 to 2.39), thiazolidinediones (OR: 0.42, 95% CI 0.13 to 1.42), alpha-glucosidase inhibitors (OR: 2.98, 95% CI 0.12 to 73.80), and placebo (OR: 0.87, 95% CI 0.71 to 1.05). The results of subgroup analysis based on the type of digestive system cancers indicated that incretin-based therapies did not increase the risk of gastrointestinal cancers, respectively. The results of subgroup analysis based on age, duration, mean HbA1c, trial duration, and sample size did not indicate the risk of digestive system cancers., Conclusions: Moderate to high Grading of Recommendations Assessment, Development and Evaluation evidence suggests that incretin-based therapies were not associated with an increased risk of cancer of digestive system in patients with type 2 diabetes mellitus., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: The aim of this study was to examine mortality causes and cancer incidence in a population cohort that have resided in close proximity to highly metal-contaminated sources, characterized by contamination of, in particular, arsenic (As), cadmium (Cd), and lead (Pb)., Methods: Data from Swedish registers were used to calculate standardized mortality and cancer incidence ratios. An attempt to relate cancer incidence to metal contamination levels was made., Results: Significantly elevated cancer incidences were observed for overall malignant cancers in both genders, cancer in the digestive system, including colon, rectum, and pancreas, and cancers in prostate among men. Dose-response relationships between Cd and Pb levels in soil and cancer risks were found., Conclusions: Cancer observations made, together with previous studies of metal uptake in local vegetables, may imply that exposure to local residents have occurred primarily via oral intake of locally produced foodstuffs.

In patients with inflammatory bowel disease (IBD), chronic inflammation is a major risk factor for the development of gastrointestinal malignancies. The pathogenesis of colitis-associated cancer is distinct from sporadic colorectal carcinoma and the critical molecular mechanisms underlying this process have yet to be elucidated. Patients with IBD have also been shown to be at increased risk of developing extra-intestinal malignancies. Medical therapies that diminish the mucosal inflammatory response represent the foundation of treatment in IBD, and recent evidence supports their introduction earlier in the disease course. However, therapies that alter the immune system, often used for long durations, may also promote carcinogenesis. As the population of patients with IBD grows older, with longer duration of chronic inflammation and longer exposure to immunosuppression, there is an increasing risk of cancer development. Many of these patients will require cancer treatment, including chemotherapy, radiation, hormonal therapy, and surgery. Many patients will require further treatment for their IBD. This review seeks to explore the characteristics and risks of cancer in patients with IBD, and to evaluate the limited data on patients with IBD and cancer, including management of IBD after a diagnosis of cancer, the effects of cancer treatment on IBD, and the effect of IBD and medications for IBD on cancer outcomes.

Objective: To analyze the relationship between N-nitrosodimethylamine(NDMA)and the risk of digestive tract cancers., Methods: The papers about the relationship between NDMA and the risk of digestive tract cancers published from 1980 to 2012 were retrieved following databases: Chinese BioMedical Literature Database(CBM), the Chinese Journal Full-text Database(CNKI), Wanfang Database, PubMed and EBSCO. The fix and random effect model was used and statistical analyses were conducted by using RevMan 5.1 software., Results: Thirteen papers were found, in which 7 about digestive tract cancers were used in this Meta analysis. The NDMA had significant positive effect on the incidence of digestive tract cancers(RR=1.12, 95% CI: 1.03-1.21). The relationship between NDMA and esophageal cancer was not significant(RR=1.18, 95%CI: 0.98-1.41)but NDMA could increase the risk of gastric cancer(RR=1.08, 95% CI: 1.00-1.18). For the subtypes of esophageal and gastric cancer, NDMA had positive relationship with esophageal squamous cell carcinoma(RR=1.72, 95% CI: 1.01-2.96), but had no significant relationship with esophageal adenocarcinoma, cardiac carcinoma and gastric adenocarcinoma., Conclusion: The population-based cohort studies have showed that the NDMA could significantly increase the risk of digestive tract cancers, but the effects differed with subtypes of esophageal and gastric cancer. However, it is necessary to collect more evidence due to the limited studies and obvious differences in the study design, sampling and exposure measurement of these cohort studies.

Background: PCB carcinogenicity to humans is still controversial. Cohort mortality studies in PCB-exposed workers reported elevated risks for the following causes of death: liver, stomach, digestive, brain, prostate cancers and non-Hodgkin lymphoma., Objectives: The purpose of this study was to update as of December 2006 the mortality experience of two Italian cohorts of workers employed in the manufacture of capacitors impregnated with PCBs., Methods: Age-gender-and calendar period adjusted Standardized Mortality Ratios (SMRs) and 95% Confidence Intervals (CI) were calculated using regional rates. Analyses by duration of employment and time since first employment were performed Results: Vital status was ascertained for 98.9% of the study subjects. Mortality from biliary tract cancer among males (SMR 3.91; 95%CI 1.47-10.41), digestive cancer "not otherwise specified" in the whole cohort (SMR 2.54; 95%CI 1.21-5.34), and brain cancer in Plant I (SMR 2.13; 95%CI 1.02-4.48), were significantly increased. Increased risks were also observed for Hodgkin's and non-Hodgkin lymphoma. No linear associations between mortality and duration of employment or latency were observed for these cancers. Mortality from stomach cancer did not differ from expectation in the whole cohort, however an increasing risk with increasing duration of employment was detected (p for trend=0.02)., Conclusions: The current update suggests possibly increased cancer risks in PCB-exposed workers, affecting in particular the digestive system, brain, and lymphohemopoietic tissue. However the limited sample size, the lack of clear trends with duration of employment or with latency period, preclude to derive definite conclusions about PCB exposure and the increased cancer risks.

Objective: Although the major cause of morbidity and mortality in patients with diabetes mellitus (DM) is cardiovascular disease, DM is also associated with certain site-specific cancers. However, whether DM is associated with an increased risk of cancer of the digestive tract remains undetermined. A nationwide, population-based database in Taiwan was analyzed to explore the relationship between DM and cancer of the digestive organs., Methods: From 2000 to 2007, a study cohort consisting of 39,515 patients with newly diagnosed diabetes without a previous diagnosis of gastrointestinal (GI) cancer was identified from the National Health Insurance Research Database in Taiwan. A control cohort of 79,030 age- and sex-matched non-diabetic subjects was selected to compare the occurrence of GI malignancies between the two groups. The association between the incidence of GI cancers and the use of glucose-lowering therapies was also investigated., Results: During the 7-year follow-up period, GI cancers developed in 929 diabetic patients (2.35%) and 1,126 subjects (1.42%) in the comparison cohort. DM was associated with a 2.75-fold (95% confidence interval (CI), 2.51-3.02) higher risk of developing GI malignancy. Among GI cancers, the incidences of stomach (adjusted hazard ratio (HR), 1.49; 95% CI, 1.16-1.92), liver (adjusted HR, 2.65; 95% CI, 2.29-3.07), colon (adjusted HR, 1.58; 95% CI, 1.28-1.94) and pancreatic cancers (adjusted HR, 4.35; 95% CI, 2.93-6.47) were significantly increased in the patients with DM. An analysis of the effects of various glucose-lowering therapies in the diabetic patients revealed the use of α-glucosidase inhibitors to be associated with a lower risk of hepatic cancer (adjusted HR, 0.62; 95% CI, 0.4-0.94). Thiazolidinedione (TZD) treatment was associated with lower stomach (adjusted HR, 0.11; 95% CI, 0.02-0.82) and hepatic cancer risks (adjusted HR, 0.46; 95% CI, 0.29-0.73), while sulfonylurea use was associated with a lower colon cancer risk (adjusted HR, 0.74; 95% CI, 0.51-1.09) and a higher pancreatic cancer risk (adjusted HR, 2.36; 95% CI, 1.21-4.61)., Conclusion: Patients with DM have an increased risk of GI malignancy that may be affected by the use of different categories of glucose-lowering therapies.

The authors have studied a correlation between the intake of the precursors of N-nitroso compounds from drinking water in Tashkent residents and the digestive malignancy morbidity rates. With the average urban value of 4.1-6.6 mg/l, the drinking water levels of nitrates are found to vary in different administrative districts of Tashkent: the highest values (range 73-20.3 mg/l) are annually recorded in the Khamzin and Yakkasaray districts and the lowest ones (1.0-1.4 mg/l) in the Yunusabad, Shaikhantakhur, Mirzo-ulugbek, and Uchtepin districts. There is a direct average correlation (r = 0.5-0.6) between the intake of nitrates and the digestive malignancy morbidity rates in the majority of administrative districts of the city and a high one (r = 0.7-0.9) when the values are compared, by taking into account the 3-5 year delay effect.

Fumonisins are mycotoxins that contaminate maize, disrupt the folate and sphingolipid metabolism, are associated with neural tube defects, and are considered by the International Agency for Research on Cancer (IARC) as possible human carcinogens. Since maize-based foods are significant components of the Mexican diet and there is a high prevalence of genetic susceptibility for folate deficiency among Mexicans, this essay presents international and national evidence of fumonisin exposure and the relevance that such exposure represents for Mexico.

Bile first attracted man's interest long ago. The actual tumour-promoting effects of a bile acid were reported in 1939 for deoxycholic acid. Ever since, much evidence has accumulated that supports an important role for bile acids as cancer promoters in humans through DNA damage and selection for apoptosis-resistant cells, both of which can lead to increased mutation rates. The evidence reviewed here indicates that, in humans, bile acids are likely to be implicated in the aetiology of a number of different important cancers in terms of morbidity and mortality, such as cancer of the colon, oesophagus, stomach, pancreas, gall bladder and cancer of the breast.

Objective: To determine if there are excessive risks of malignant tumors or not among workers exposed to asbestos by applying a meta-analysis technique., Methods: All data meeting the criteria of cohort studies on cancer mortality of digestive system among workers exposed to asbestos would be incorporated into the meta-analysis. The pooled standardized mortality ratios (SMR) and their corresponding 95% confidence intervals (CIs) for main cancer sites of digestive system were calculated by using two approaches of un-weighted ratio and random effects model. The heterogeneity and its sources of the results were examined with a Q-statistic and Z-score test., Results: 69 asbestos-exposed cohorts were summarized. The significantly elevated meta-SMR for all deaths (1.16), all cancers (1.42), cancer of digestive system (1.15) and cancer of stomach (1.20) among workers exposed to chrysotile alone or mixed asbestos were observed (P < 0.01). The stomach cancer SMR was significantly increased in the asbestos cement workers, the screening mine workers and the insulators, (1.27, 1.21 and 2.13 respectively) (P < 0.05). meta-SMR for cancers at other sites of digestive system including esophagus, colon, rectum and liver were not significant., Conclusion: There are likely excessive risks of cancer of stomach among workers exposed to asbestos. However, there is likely no convincing indication of an etiological association between asbestos exposure and cancers at other sites of digestive system.

Substance abuse and addiction represent a worldwide problem and cause a number of family, social and health problems. Digestive system damage caused by substance intake is an increasing problem amoung drug addicts. Many studies show that substances can cause cancer of all parts of the digestive system. Alcohol consumption was significantly associated with colon and rectal cancer. For rectal cancer, the risk was increased in association with drinking of alcoholic beverages, specialy for beer consumption. Sinthetic drugs such as ecstasy may lead also to digestive and hepatic damage, as well as vascular complications of the stomach. Many studies show the existance of supstance associated enterocolitis as well as ishemic colitis. Diagnosis of ishemic colitis is based on the presence of rectal bleeding, abdominal pain, a history of substance use, supportive endoscopic and histopathologic findings, and the absence of other etiologic mechanisms of ischemic colitis. Great damage to the digestive system is also produced by smuggling narcotics packed into small pages that are afterwards been swallowed or implemented on other sorts of ways inside the smugglers natural body spaces as the rectum or vagina. In the paper authors reviewed literature conserning digestive system damage caused by substance abuse and drug smuggling.

In industrialized countries alcohol and tobacco are the main risk factors of upper digestive tract cancer. With regard to the pathogenesis of these cancers, there is strong epidemiological, biochemical and genetic evidence supporting the role of the first metabolite of alcohol oxidation--acetaldehyde--as a common denominator. Alcohol is metabolized to acetaldehyde locally in the oral cavity by microbes representing normal oral flora. Poor oral hygiene, heavy drinking and chronic smoking modify oral flora to produce more acetaldehyde from ingested alcohol. Also, tobacco smoke contains acetaldehyde, which during smoking becomes dissolved in saliva. Via swallowing, salivary acetaldehyde of either origin is distributed from oral cavity to pharynx, oesophagus and stomach. Strongest evidence for the local carcinogenic action of acetaldehyde provides studies with ALDH2-deficient Asian drinkers, who form an exceptional human model for long-term acetaldehyde exposure. After drinking alcohol they have an increased concentration of acetaldehyde in their saliva and this is associated with over 10-fold risk of upper digestive tract cancers. In conclusion, acetaldehyde derived either from ethanol or tobacco appears to act in the upper digestive tract as a local carcinogen in a dose-dependent and synergistic way.

Chronic alcohol consumption increases the risk for cancer of the organs and tissues of the respiratory tract and the upper digestive tract (i.e., upper aerodigestive tract), liver, colon, rectum, and breast. Various factors may contribute to the development (i.e., pathogenesis) of alcohol-associated cancer, including the actions of acetaldehyde, the first and most toxic metabolite of alcohol metabolism. The main enzymes involved in alcohol and acetaldehyde metabolism are alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), which are encoded by multiple genes. Because some of these genes exist in several variants (i.e., are polymorphic), and the enzymes encoded by certain variants may result in elevated acetaldehyde levels, the presence of these variants may predispose to certain cancers. Several mechanisms may contribute to alcohol-related cancer development. Acetaldehyde itself is a cancer-causing substance in experimental animals and reacts with DNA to form cancer-promoting compounds. In addition, highly reactive, oxygen-containing molecules that are generated during certain pathways of alcohol metabolism can damage the DNA, thus also inducing tumor development. Together with other factors related to chronic alcohol consumption, these metabolism-related factors may increase tumor risk in chronic heavy drinkers.

Recent National Toxicology Program (NTP) cancer bioassay data for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF), 3,3',4,4',5-pentachlorobiphenyl (PCB 126), and a mixture of these three compounds offer opportunities to assess the accuracy of current World Health Organization (WHO) 1998 toxic equivalency factors (TEFs) for these compounds under a variety of assumptions. An evaluation of the current TEF values for these compounds using body burden in nanograms per kilogram as the dose metric is presented. Average lifetime body burdens were estimated for all compounds at all dose groups based on measured tissue concentrations at 4 time points during the 2-yr NTP studies. Poly-3 adjusted tumor incidences for hepatocellular adenomas, cholangiocarcinomas, and the two tumors combined were modeled using a quantal multistage model and the Hill model with lifetime average body burden as the dose metric. Benchmark doses for a 10% response (BMD10) for each compound and the mixture were estimated. With TCDD as the reference standard, relative potency (REP) estimates were derived from ratios of the BMD10 estimates for PCB 126, 4-PeCDF, and for the toxic equivalent (TEQ) mixture. On a body-burden basis, PCB 126 and 4-PeCDF were 2- to 3-fold and 10- to 12-fold less potent than predicted based on the WHO TEFs, respectively, while the TEQ mixture was approximately 3- to 5-fold less potent than predicted by the TEFs. The current WHO TEF values, which were derived from data on noncancer endpoints evaluated on an administered dose basis, overpredict the carcinogenic potency of these compounds on a body-burden basis compared to TCDD.

Carcinogenicity and chronic toxicity of vinyl acetate monomer (VA) were examined in male and female Crj:BDF1 mice and F344/DuCrj Rats. Groups of 50 mice and 50 rats of each sex were orally administered VA in drinking water containing 0, 400, 2,000 or 10,000 ppm (g/g) VA for 104 wk. Squamous cell tumors were clearly evident in the upper digestive tract of treated mice and rats, and in the larynx of treated mice of both sexes. In mice, squamous cell carcinomas and papillomas were observed in the oral cavity, esophagus, forestomach and larynx of the 10,000 ppm group, together with basal cell hyperplasia, squamous cell hyperplasia and epithelial dysplasia. In rats, incidences of squamous cell carcinomas and papillomas were increased in the oral cavity of the 10,000 ppm group of both sexes, and an esophagus squamous cell carcinoma was observed in a 10,000 ppm female. Pre-neoplastic hyperplasias were also noted. Mapping of the neoplastic and pre-neoplastic lesions in the oral cavity of the 10,000 ppm group revealed that both the lesions occurred predominantly at Level V in mice and at Level VI in rats. A lower confidence limit of a benchmark dose (BMDL10) of 477 mg/kg/d was obtained from a dose-response relationship between combined incidence of squamous cell carcinomas and papillomas in the oral cavity of mice and rats and the estimated daily VA intakes per body weight, and compared with literature values.

Background: This study is an extension of a previously published analysis of cancer mortality in a transformer manufacturing plant where there had been extensive use of mineral oil transformer fluid. The objectives of the present study were to update the mortality analysis and include deaths for the past 6 years as well as to do an analysis of cancer incidence of the cohort., Methods: A cohort of 2,222 males working at a transformer manufacturing plant between 1946 and 1975 was constructed. Using a classical historical cohort study design, cancer incidence and mortality were determined through record linkage with Canadian provincial and national registries. The rates of cancer incidence and mortality experienced by this cohort were compared to that of the Canadian male population., Results: A statistically significant increased risk of developing and dying of pancreatic cancer was found but not an increase in overall cancer mortality. This was consistent with the previous report from this group. Interestingly, the cohort demonstrated a statistically significant risk of overall cancer incidence and specific increased incidence of gallbladder cancer., Conclusions: This study contributes further evidence to the growing body of literature indicating the carcinogenic properties of mineral oils used in occupational settings, in particular those used prior to 1970s., (Copyright 2003 Wiley-Liss, Inc.)

Background: Due to a point mutation, aldehyde dehydrogenase-2 (ALDH2) isoenzyme is deficient in 30% to 50% of Asians. Among Asian ALDH2-deficient heavy drinkers, the risk for digestive tract cancers is markedly increased (odds ratio 3.4-54.2). The reason for this is unknown but could be due to the local carcinogenic action of acetaldehyde., Methods: Salivary and blood acetaldehyde levels were determined in 20 healthy Asians after a moderate dose of alcohol (0.5 g/kg of body weight). Salivary acetaldehyde production capacity from ethanol in vitro was measured also. ALDH2 genotype of the Asians was determined from isolated leukocyte-deoxyribonucleic acid by polymerase chain reaction/restriction fragment length polymorphism method. Acetaldehyde content of parotid gland saliva was measured in three ALDH2-deficient Asians and three White subjects with normal ALDH2 after the same dose of ethanol., Results: Seven of the Asians were heterozygous for the mutant ALDH2*2 allele (flushers). They had two to three times higher salivary acetaldehyde levels than the Asians (n = 13) with normal ALDH2 throughout the follow-up period of 240 min (p < 0.001). Only in the flushers did the parotid gland contribute to salivary acetaldehyde production. The in vitro capacity of saliva to produce acetaldehyde from ethanol was equal in both groups. The flushers' blood acetaldehyde levels were only one ninth of the levels in saliva., Conclusions: By using this human "knockout model" for deficient acetaldehyde removal, we found that in addition to oral microflora, acetaldehyde in saliva may also originate from the oxidation of ethanol in the parotid gland. When combined with earlier epidemiological data, these results offer a strong evidence for the local carcinogenic action of acetaldehyde in humans.

Background: Tobacco smoking is an established risk factor for cancers of the upper aerodigestive tract, and measurement of chromosomal aberrations, i.e., chromatid breaks, induced in lymphocytes in vitro by bleomycin has been shown to be a predictor of risk for these cancers. In a case-control study, we recruited case subjects who were previously treated with surgery and/or radiotherapy for stage I or stage II squamous cell carcinoma of the head and neck to test the hypothesis that lymphocytic chromatid breaks induced by benzo[a]pyrene diol epoxide (BPDE), a tobacco mutagen, may also be associated with risk of developing cancers of the upper aerodigestive tract., Methods: Case subjects were matched to control subjects on the basis of age, sex, ethnicity, and smoking status. Primary lymphocytes from 67 case subjects and 81 control subjects were treated with 2 microM BPDE for 24 hours, and the frequency of induced chromatid breaks was determined. All statistical tests were two-sided., Results: Lymphocytes from case subjects compared with lymphocytes from control subjects showed significantly more breaks per cell induced by BPDE (mean+/-standard deviation, 0.77+/-0.38 versus 0.49+/-0.25; P<.001). Lymphocytes from 64.2% of case subjects were sensitive to BPDE (using a cutoff value of > or =0.60 break per cell). Subjects in the highest quartile of chromatid breaks had an approximately 20-fold increased risk of cancer compared with those in the lowest quartile after adjustment for age, sex, ethnicity, and smoking status. The association between BPDE sensitivity and cancer risk was higher in former smokers than in current smokers and higher in younger patients than in older patients. Subjects with sensitivity to both BPDE and bleomycin were at a 19.2-fold increased risk of cancer compared with those who were not sensitive to either agent., Conclusions: Mutagen sensitivity assays may aid in identifying individuals at risk of cancer, and use of parallel assays with two mutagens may improve risk predictability.

The long-term health effects of human exposure to polybrominated biphenyls are not known. In this nested case-control study, we evaluated the association between site-specific cancer risk and serum polybrominated biphenyl levels among a Michigan cohort accidentally exposed to polybrominated biphenyls in 1973. The Michigan Department of Public Health has followed 3,899 people through 1993, among whom 195 primary cancers were identified in 187 persons. Controls were 696 randomly selected cancer-free individuals who were frequency matched to cases by sex and age (in 5-year strata). Baseline serum polybrominated biphenyl levels were measured using standard methods. We found an increasing dose-response relation for digestive system cancer risk with higher serum polybrominated biphenyl category [4-20 parts per billion (ppb), 21-50 ppb, and > 50 ppb] after adjustment for age, family cancer history, cigarette smoking, alcohol drinking, and baseline serum polychlorinated biphenyl level. Adjusted odds ratios (ORs) for each category were 8.23 [95% confidence interval (CI) = 1.27-53.3], 12.3 (95% CI = 0.80-191), and 22.9 (95% CI = 1.34-392), respectively. Univariate analysis for polybrominated biphenyl level and lymphoma risk also showed a dose-response relation, with corresponding ORs of 3.24 (95% CI = 0.24-95.9), 20.5 (95% CI = 1.51-608), and 32.6 (95% CI = 3.33-861).

To examine the risk of upper aerodigestive tract cancers (UADC: oral cavity, pharynx, larynx, and esophagus) associated with dietary heterocyclic amine (HCA) exposure, a case-control study involving 140 cases and 286 controls was conducted in Montevideo, Uruguay. Beef and red meat intakes were positively associated with risk of UADC [odds ratio (OR) for red meat intake = 2.8, 95% confidence interval (CI) = 1.4-6.0], whereas no association was observed with white meat (poultry plus fish) intake. When meat intake was examined by cooking method, no association was observed for fried meat. On the other hand, broiled and boiled meat were associated with a significant increase in risk of UADC (OR for broiled meat = 2.0, 95% CI = 1.0-4.3). Total HCA intake was associated with an increased risk (OR = 2.2, 95% CI = 1.1-4.2) of UADC. The HCA effect was similar among the different cancer sites.

The prevalence of cigarette smoking is higher among African Americans than among whites. African Americans have higher rates of lung cancer than whites, although they smoke fewer cigarettes. To explore this black-white difference in lung cancer rates, I examine various aspects of tobacco use in African-American smokers, including the age of initiation of smoking, quantity of cigarettes smoked, quit rates, level of nicotine dependence, biochemical differences, and brand preferences, specifically menthol brand cigarettes. I also review briefly the sequelae of patterns of tobacco use, including rates of lung and other tobacco-related cancers. A preference for mentholated cigarettes by African Americans is well documented and is one of the most striking differences between African-American and white smokers. Menthol brand preference has been investigated in an attempt to explain the black-white differences in rates of cancers of the lungs and the upper respiratory and digestive tracts. Also, studies have evaluated smoking behavior both with and without menthol and have explicitly examined the question of whether menthol use helps explain the black-white difference in lung cancer rates. The results of these studies are so far inconclusive with regard to the use of menthol and the risk of lung cancer developing. I provide practical suggestions for clinicians in counseling African-American smokers to quit smoking and to maintain a nonsmoking status.

Objective: To assess the risk of cancer from inhalation of mineral acid mists., Methods: A cohort study and nested case-control study of upper aerodigestive tumours were carried out in men employed since 1950 at two battery plants and two steel works in Britain. The cohort was identified from personnel records and included 2678 men with definite exposure to acid mists (mainly sulphuric acid), 367 with possible exposure, and 1356 who were unexposed. Mortality was compared with that in the national population by the person-years method. Cases of upper aerodigestive cancer were identified from death certificates and cancer registrations, and their exposure to acids was compared with that of age matched controls (five per case) from the same plant by conditional logistic regression., Results: In follow up to 31 December 1993, 93% of men were traced, including 1277 who had died. Among the men definitely exposed to acid mists, overall mortality was less than in the national population (standardised mortality ratio (SMR) 0.92, 95% confidence interval (95% CI) 0.85-0.98) as was mortality from all cancers (SMR 0.92, 95% CI 0.79-1.05) and specifically from cancer of the larynx (SMR 0.48, 95% CI 0.01-2.70) and lung (SMR 0.98, 95% CI 0.78-1.22). A total of 15 incident or fatal cases of upper aerodigestive cancer were identified during follow up. When these men were compared with controls, risk was moderately increased in those who had worked for at least five years in jobs entailing exposures to sulphuric or hydrochloric acid in excess of 1 mg/m3 (OR 2.0, 95% CI 0.4-10)., Conclusions: These findings are consistent with those from other studies which have indicated a hazard of upper aerodigestive cancer from acid mists. However, they indicate that any risk from exposures to sulphuric and hydrochloric acid below 1 mg/m3 is small.

A mortality study was carried out among workers employed in a plant producing different kinds of dyes, including benzidine. The cohort comprised 8,523 males and 2,006 females whose vital status was recorded between Jan 1, 1945 and Dec. 31, 1991. They had worked in this plant for, at least, 3 months between Jan. 1, 1945 and Dec 31, 1974. The cohort was divided into 4 subcohorts: I. those exposed only to benzidine: II. those exposed to benzidine and other occupational hazards; III. those involved directly in the dye production but not exposed to benzidine, and IV. those not involved directly in the dye production-mainly administrative staff. Death risk was estimated on the basis of standardized mortality ratio (SMR) determined by means of the person-years method. The general population of Poland was taken as a reference group. The observed number of deaths in the cohort and each subcohort was compared with expected deaths. The comparison was based on national rates by adjustment for age, gender and calendar time. Significant excessive mortality due to cancer of urinary bladder was observed in the male subcohort I (SMR = 14.69), II (SMR = 16.34) and III (SMR = 3.17); due to malignant neoplasm of pancreas in the male subcohort II (SMR = 3.26); due to malignant neoplasm of testis in the male subcohort III (SMR = 3.17); due to malignant neoplasm of pancreas in the male subcohort II (SMR = 3.26); due to malignant neoplasm of testis in the male subcohort III (SMR = 3.23). Significant excessive mortality due to malignant neoplasm of liver and intrahepatic bile ducts was found in the female subcohort IV (SMR = = 2.36).

The effects of X-irradiation on N-methyl-N-nitrosourea (MNU)-induced multi-organ carcinogenesis were examined in both sexes of ACI/N rats. At 6 weeks of age, rats in groups 1 (25 males, 25 females) and 3 (24 males, 23 females) received a single i.p. injection of MNU (25 mg/kg body weight), while those in groups 2 (25 males, 26 females) and 4 (25 males, 25 females) were administered the carcinogen at a dose of 50 mg/kg body weight. At 10 weeks of age, groups 3 and 4 were X-irradiated at a dose of 3 Gy. Group 5 (24 males, 24 females) received X-irradiation alone. Group 6 (21 males, 21 females) served as an untreated control. As a result, neoplasms developed mainly in the digestive tract, kidney, uterus, and hematopoietic organ in groups 1-5. The incidences of adenocarcinoma in small and large intestines of male rats of group 4 (50 mg/kg MNU and X-irradiation) (small intestine: 48%, large intestine: 32%) were significantly higher than those of group 2 (50 mg/kg MNU) (small intestine: 17%, P < 0.05; large intestine: 8%, P < 0.05), and also the frequency of adenocarcinoma in the large intestine of males of group 3 (25 mg/kg MNU and X-irradiation) (22%) was significantly greater than that of group 1 (25 mg/kg MNU) (0%, P < 0.05). These results indicated that X-irradiation enhanced the development of intestinal neoplasms induced by MNU in male ACI/N rats.

Nitrates originating from food and particularly from water are supposedly precursors of carcinogenic N-nitroso compound (NOC) formed within the organism. According to Correa and al. these transformations could be a consequence of bacterial gastric pullulation resulting from certain hypochlorhydric conditions. Much epidemiological research has tried to establish a relationship between exposure to nitrates in drinking water and cases of gastric cancer. The present article deals with research into this relationship in France, in a region where the rate of nitrates in water supplies is among the highest. Death statistics (from cancers of the digestive and urinal tracts) are issued by INSERM and these of the population by INSEE. Towns are classified according to nitrate concentration and the number of deaths is established according to tumour detection by sex and age. Research into death rate divergencies is found by chi 2 and the correlated coefficient. The average relative risk for any age group is calculated for all types of cancer. Research on frequency is carried out from tumour records. Comparative frequency rates are established by direct standardisation according to the structural age of any one European population. Results are analysed in relation to (1) mortality rates and (2) incidence rates. (1) None of the cancers studied, of the digestive or urinary systems, whatever the age on sex, is significantly linked to the quantity of nitrates in water supplies. When all these cancers are taken into account, the death rate does not vary significantly for increasing concentration of nitrates. Towns exceeding the maximum concentration permitted by law do not have a higher mortality rate than other towns.(ABSTRACT TRUNCATED AT 250 WORDS)

Environmental factors are important mediators of many diseases of the digestive system, defined as the alimentary tract and the accessory organs of digestion, the liver and pancreas. In this review, we principally focus on the action of chemical agents which are classified as (1) naturally occurring compounds, (2) occupational hazards, (3) therapeutic drugs, and (4) constituents of substances of abuse. In addition, the putative role of dietary habits in the pathogenesis of malignant diseases of the digestive system is discussed.

The long term carcinogenic effect of nitrosomorpholine (NM) was tested in Syrian golden hamsters (Mesocricetus auratus W.). Groups of 30 females and 30 males were given 0.010%, 0.005% and 0.001% NM in their drinking water. The animals developed neoplasms in the larynx, and trachea (papillary polyps, papillomas and epidermoid carcinomas) and in the liver (hepatocellular adenomas and carcinomas). In addition to these, cholangiocellular and endothelial liver tumours were observed. The overall tumour frequency was dose dependent.

The effects of vitamin A (VA) deficiency on 1-propyl-1-nitrosourethan (PNUR)-induced tumorigenesis in the upper digestive tract were investigated in male F344 rats. Starting at 6 weeks old, animals were given PNUR in the drinking water (200 ppm) for one week, and starting 2 weeks later, were divided into 3 groups (30 rats/group) and maintained on VA-deficient diet, VA-supplemented diet (semipurified diet) or standard diet (CRF-1), respectively. An additional control group (10 rats) was fed VA-deficient diet without PNUR treatment. The experiment was terminated at 41 weeks after the beginning of PNUR administration, and development of tumors in the upper digestive tract was determined histopathologically. Squamous cell tumors were observed in the oral cavity, tongue and forestomach of all PNUR treated groups, while no tumors developed in the control group. Significantly higher incidences of forestomach papillomas were observed in the groups administered VA-deficient or VA-supplemented diets, as compared with that receiving standard diet (p less than 0.01, p less than 0.05, respectively). These results thus suggest that the higher incidences of forestomach tumors were probably due to general dietary differences (semipurified vs. standard diets) and not to the VA deficiency per se.

The OSHA standard for coke oven emissions, which went into effect in January 1977, sets a permissible exposure limit to coke oven emissions of 150 micrograms/m3 benzene-soluble fraction of total particulate matter (BSFTPM). Review of the epidemiologic evidence for the standard indicates an excess relative risk for lung cancer as high as 16-fold in topside coke oven workers with 15 years of exposure or more. There is also evidence for a consistent dose-response relationship in lung cancer mortality when duration and location of employment at the coke ovens are considered. Dose-response models fitted to these same data indicate that, while excess risks may still occur under the OSHA standard, the predicted levels of increased relative risk would be about 30-50% if a linear dose-response model is assumed and 3-7% if a quadratic model is assumed. Lung cancer mortality data for other steelworkers suggest the predicted excess risk has probably been somewhat overestimated, but lack of information on important confounding factors limits further dose-response analysis.

A study of mortality among 1,879 male workers employed in a New Jersey chromium pigment factory was carried out, with follow-up from 1940 to 1982. Vital status of 1,737 (92%) of the eligible cohort members was determined. For all malignant neoplasms, 101 deaths were observed while 108.8 were expected, SMR = 93 (standardized mortality ratio; n.s.). For the entire study group, no significant excess was observed for respiratory cancer or cancer at other sites. However, the total number of years of employment in the factory and the total number of years of exposure to chromate dusts were both statistically significantly (p less than .05, for trend) associated with an increased risk for lung cancer. The excess risk for lung cancer associated with duration of exposure to chromate dusts was, however, only clearly apparent for subjects followed for 30 years or more after initial employment. For this group, the SMRs were 81, 139, 201, and 321 for the subjects with 0 years, less than 1 year, 1-9 years, and 10+ years of exposure to chromate dusts (p less than .01, for trend), respectively. The risk for digestive cancer was only weakly associated with exposure to chromate dusts.

Nitrosodi-n-propylamine, nitrosodi-n-butylamine and the ketone nitrosobis(2-oxopropyl)amine were administered by gavage to F344 rats at doses of 1 and 2 mmol for 30 weeks. The higher level of nitrosodipropylamine led to death of all the animals with carcinomas of the liver, nasal cavity and esophagus by the 40th week. At the lower level the rats died of these tumors but survived to week 60. In contrast, 1 mmol of nitrosobis(2-oxopropyl)amine did not cause death of all the animals until week 95, and fewer than half of them had liver carcinomas; none had tumors of the esophagus or nasal cavity. Nitrosodi-n-butylamine was a much weaker carcinogen than nitrosodipropylamine, since 80% of the rats given 2 mmol survived until week 83. Although, with this compound, the lifespan of the rats was not greatly shortened, a large variety of tumors was induced; about 60% of the animals had liver carcinomas, 50% forestomach carcinomas and 35% transitional cell carcinomas of the urinary bladder.

Specimens from the liver, kidney, stomach and various intestinal segments of BD IX male rats were analyzed for mitotic index (MI) and the proportion of karyorrhectic figures (karyorrhectic index, KI) at various intervals after a s.c. injection of 1,2-dimethylhydrazine. In the intestinal specimens, a severe drop in MI (maximum after 12--14 h) and rise in KI (maximum after 6 h) were observed, with all karyorrhectic figures found in the proliferative compartment of the mucosa. Within the large intestine, there was a good correlation between the KI of each segment and its susceptibility to further tumor development.

In the first part of this paper, we show that intraperitoneal injection of adenosine into newborn mice causes multiple neural crest tumors, neural crest hyperplasia, and heterotopic melanin pigmentation. In the second part, we review published data to propose (1) that microtubule proteins, phosphorylated through the action of calmodulin-dependent kinase and cyclic adenosine monophosphate and the adenosine A2 receptor of neural crest cells, may participate in neurotransmission and (2) that at least some neural crest tumors may be associated with disorders of neurotransmission in embryonic neural crest cells.

N-Nitroso(2-hydroxypropyl)(2-oxopropyl)amine (HPOP) proved to be a potent carcinogen in Syrian golden hamsters. The compound is an in vivo metabolite of N-nitrosobis(2-hydroxypropyl)amine, N-nitrosobis(2-oxopropyl)amine (BOP), and N-nitroso-2,6-dimethylmorpholine and a postulated proximate pancreatic carcinogen in hamsters. As with BOP, HPOP induced a higher incidence of pancreatic ductular adenocarcinomas than did N-nitrosobis(2-hydroxypropyl)amine and N-nitroso-2,6-dimethylmorpholine, and these neoplasms showed a great tendency for invasion and metastasis. Also, HPOP induced tumors of the forestomach, liver, gallbladder, kidneys, and vagina (as did BOP). However, HPOP [unlike BOP, but like N-nitrosobis(2-hydroxypropyl)amine and N-nitroso-2,6-dimethylmorpholine] led to tumor development in the nasal cavity, larynx, trachea, intestine, Harderian gland, lips, and flank organ. The possible mechanisms of HPOP carcinogenicity are discussed.

Male and female F344/DuCrj rats were administered N-butyl-N-nitrosourea at a concentration of 400 ppm in their drinking water. By the 50th week of the experiment, the cumulative incidence of upper-digestive-tract tumors was as high as 35/39 (90%) and 34/39 (87%) in male and female rats, respectively. Among these, esophageal and forestomach tumors occurred most frequently. Except one female rat with fibroma, upper-digestive-tract neoplasms were of the epithelial type -- papilloma, squamous-cell carcinoma or adenocarcinoma. In female rats, vaginal tumors were induced in 16 (41%) animals. Ear-duct tumors and hematopoietic neoplasms were also induced in both sexes of rats, with incidence of less than 21%.

Forty male and 40 female inbred F344 rats were given a solution of 400 mg N-ethyl-N-nitrosourea/liter in their drinking water. Digestive tract tumors were induced in 32 males (an incidence rate of 80%) and in 28 females (an incidence rate of 70%). Among these digestive tract neoplasms, duodenal tumors occurred most frequently. Most were of the epithelial type, such as adenoma or adenocarcinoma. Tumors in hematopoletic organs were also found in 15 males (38% incidence) and in 17 females (43% incidence).

Recent studies identify digestive cancer excesses among workers exposed to cutting fluids, abrasive dusts, and oil smoke. Standardized proportional mortality and mortality odds ratio studies were carried out for a ball bearing plant. Cause of death and work histories were obtained for 702 of 768 hourly employees with ten or more years' service who died between 1969 and 1982. Union and company records were used to define exposure measures. The major findings were significant excesses in proportional mortality ratios (PMR) from stomach cancer (PMR = 2.0) and rectal cancer (PMR = 3.1) among white men. After control for age at death, there was a significant association between stomach cancer and precision grinding exposures, consisting primarily of direct contact with water-based cutting fluids (usually emulsified oils) and their aerosols. Some straight oils and synthetic cutting fluids were used as well. The pattern of stomach cancer is consistent with previous findings and suggests an association with the soluble oil cutting fluids.

7-Methylguanine was found in hydrolysates of liver and pancreas DNA from Syrian golden hamsters given a single dose of N-[1-14C]nitrosobis(2-oxopropyl)amine (BOP). This led us to examine the carcinogenicity of a potential methylating metabolite of BOP, N-nitrosomethyl(2-oxopropyl)amine (MOP). MOP was found to be a potent pancreatic carcinogen by either single or weekly s.c. injections. A single MOP treatment (25 mg/kg body weight) induced ductular adenomas and/or adenocarcinomas in 80% of the hamsters. A higher incidence of these neoplasms was found in 93% and 87% of animals receiving, respectively, 3.5 and 1.75 mg MOP per kg body weight weekly for life. However, the lower dose (0.87 mg/kg body weight) was less effective, resulting in a 33% tumor incidence. Compared with the known potent pancreatic carcinogen BOP, MOP seemed to have a greater affinity for the pancreas since considerably lower doses were required to induce similar incidences of equivalent pancreatic tumors. Like BOP, MOP caused tumors of the liver (7 to 100% incidence), kidneys (7 to 80% incidence), and vascular system (7 to 27% incidence). However, in contrast to BOP, which was noncarcinogenic to the upper respiratory tract, MOP-treated animals developed a high incidence of nasal cavity tumors (40% after a single treatment and 27 to 100% after weekly injections). The mutagenesis studies using hamster liver cell-mediated V79 cells confirmed the stronger effect of MOP compared to BOP. The assumption that MOP might be a proximate carcinogenic metabolite of BOP could not be substantiated by our methods for determining the in vivo and in vitro metabolites of BOP.

A survey was carried out throughout Europe to establish a Registry of Experimental Digestive Tumours, including cancers of the oesophagus, stomach, colon, rectum and pancreas, transplantable tumour lines in animal models, and human digestive tumours grafted into nude mice or immunosuppressed animals. Cell lines from human and animal digestive tract cancers are also included. This registry is to provide information and facilitate communication between interested research workers.

N-Nitroso-1,2,3,6-tetrahydropyridine (N-nitroso-delta3-piperidine), N-nitroso-1,2,3,4-tetrahydropyridine (N-nitroso-delta2-piperidine) and N-nitroso-3,4-epoxypiperidine were tested for carcinogenicity in Fischer 344 rats. The unsaturated nitrosamines were administered in drinking water (100 mg/l). The epoxide was administered by gavage in corn oil (11.5 mg/ml, 0.2 ml twice a week). Both of the unsaturated nitrosamines were potent carcinogens (most of the animals died by the 35th week), and both produced many esophageal tumors, a property which they have in common with the parent compound, N-nitrosopiperidine. The spectrum of the other tumors formed, however, was different. The delta3-isomer produced hemangioendothelial sarcomas in the liver, which were absent in the tumor spectrum of the delta2-isomer and N-nitrosopiperidine. The delta2-isomer, on the other hand, produced tumors of the forestomach and the oropharynx, which were essentially absent in the rats treated with the delta3-isomer. N-nitroso-3,4-epoxypiperidine was a toxic compound (8 deaths in the first 5 weeks), but most of the remaining animals survived to 40 weeks. Of these, 8 animals died of induced tumors (esophagus and liver). The delta2- and the delta3-isomers were administered by gavage to groups of rats and the blood of these animals was withdrawn at timed intervals. Analysis of the serum revealed that both of the nitrosamines were cleared rapidly from circulation but that at the same time the delta3-isomer was being isomerized to the delta2. The reverse transformation did not occur in vivo.

Feeding N,N'-2,7-fluorenylenebisacetamide (CAS:304-28-9) at 0.025% to 15 male and 15 female mastomys considerably shortened their life-span. At death every treated mastomys had several primary tumors; untreated animals at comparable ages had none. Several mastomys with hepatoblastomas and 1 with giant cell hepatitis and a metastasizing pancreatic carcinoma are first reported here. The tumor load per animal averaged 4.0 for treated females, 2.6 for treated males, 1.5 for untreated females, and 0.6 for untreated males. Of 24 hepatic tumors in treated mastomys, 11 metastasized, compared to none of the incipient tumors in 8 of 26 untreated animals. Pancreatic adenomas developed in 27 treated and 1 untreated mastomys, and a metastasizing adenocarcinoma developed in 1 treated animal. All treated females, 3 treated males, and 1 untreated female developed multiple villous adenomas in the small intestine. One untreated female and 8 treated females developed mammary cancers, 4 of which metastasized. Primary tumors of other sites occurred infrequently.