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PubMed2005

Structure-based thresholds of toxicological concern--guidance for application to substances present at low levels in the diet.

Health-based guidance values, such as the ADI, use chemical-specific data to determine the highest intake that would be without significant adverse health effects. A threshold of toxicological concern (TTC) is a level of intake predicted to be without adverse effects based on the toxicity of structurally related compounds. The main advantage of the use of TTCs is that the risk of low exposures can be evaluated without the need for chemical-specific animal toxicity data. TTCs have been used for many years for screening the safety of packaging migrants by the FDA in the USA, and of flavoring substances, by the JECFA. A recent reassessment of the use of TTCs, organized by ILSI Europe, has developed a decision tree which allows a systematic approach to the evaluation of low levels of diverse chemicals in food. The decision tree incorporates a series of increasing TTC values into a step-wise approach. Potentially genotoxic carcinogens are considered first, based on the presence of known structural alerts. Aflatoxin-like, azoxy- and nitroso-compounds are removed from consideration because they are the most potent, and a practical TTC could not be established. Other compounds with structural alerts for genotoxicity are allocated a TTC of 0.15 microg/person per day. Compounds without structural alerts for genotoxicity are evaluated based on chemical structure and intake using a series of TTC values derived by the application of a 100-fold uncertainty factor to the 5th percentile of the distribution of NOAELs from chronic studies on compounds sharing similar structural characteristics.

Carcinogens↗
PubMed2001

Chemistry of the diazeniumdiolates. 3. Photoreactivity.

We have found O(2)-substituted diazeniumdiolates, compounds of structure R(2)N-N(O)=NOR' that are under development for various possible pharmaceutical uses, to be rather photosensitive. With R = ethyl and R' = methyl, benzyl, or 2-nitrobenzyl, the observed product distributions suggest that two primary pathways are operative. A minor pathway involves the extrusion of nitrous oxide (N(2)O) with simultaneous generation of R(2)N(*) and R'O(*), which may then form amines, aldehydes, and alcohols. The major reaction pathway is an interesting photochemical cleavage of the N=N bond to form a nitrosamine (R(2)NN=O) and an oxygen-substituted nitrene (R'ON). The intermediacy of the O-nitrene was inferred from the production of abundant oxime, via rearrangement of the O-nitrene to a C-nitroso compound (R'ON --> O=NR'), and subsequent tautomerization to the more stable oxime. Involvement of the O-nitrene was confirmed by trapping with 2,3-dimethyl-2-butene to form the aziridine and with oxygen to generate the nitrate ester. 2-Nitro substitution on the benzyl derivative had surprisingly little effect on the reaction course. For each compound examined, minor amounts of nitric oxide (NO), presumably produced by secondary photolysis of the nitrosamine, were observed. Time-resolved infrared experiments provided additional support for the above reaction pathways and confirmed that the nitrosamine is a primary photoproduct. We have also found that the relative contributions of the reaction pathways can be altered in certain derivatives. For example, when R' = 2,4-dinitrophenyl, the contribution of the nitrosamine/O-nitrene-forming pathway was diminished. Pharmacological implications of these results are discussed.

Drug Compounding↗
PubMed1984

Caffeic and ferulic acid as blockers of nitrosamine formation.

Caffeic acid and ferulic acid, which are naturally occurring phenols present in a wide variety of plants, were examined for their ability to react with nitrite in vitro and to inhibit nitrosamine formation in vivo. Their activities were compared with other phenols (butylated hydroxyanisole and Trolox) and with a non-phenolic polyhydroxylated compound, glycerol guaiacolate. In simulated gastric fluid, caffeic acid and ferulic acid reacted rapidly and completely with an equimolar quantity of sodium nitrite. In rats receiving aminopyrine and nitrite, caffeic acid and ferulic acid blocked the elevation of serum N-nitrosodimethylamine (NDMA) levels and the serum glutamic pyruvic transaminase levels associated with hepatotoxicity. Neither phenol had any effect on serum levels of NDMA in rats treated with NDMA. In both the in vitro (reaction with nitrite) and in vivo (inhibition of hepatotoxicity) systems, caffeic acid was more effective than ferulic acid. Butylated hydroxyanisole and Trolox were partially effective, and glycerol guaiacolate was inactive. The results of this study suggest that dietary caffeic acid and ferulic acid may play a role in the body's defense against carcinogenesis by inhibiting the formation of N-nitroso compounds.

Alanine Transaminase↗
PubMed1987

Evidence for cytosolic glutathione transferase-mediated denitrosation of nitrosocimetidine and 1-methyl-2-nitro-1-nitrosoguanidine.

Nitrosocimetidine (NC) and 1-methyl-2-nitro-1-nitrosoguanidine (MNNG) are closely related N-nitrosamidines. NC is the nitrosated derivative of cimetidine (Tagamet), an orally administered compound used extensively in the treatment of gastric ulcers. MNNG is a potent carcinogen capable of initiating tumors close to the site of administration and used experimentally to produce stomach cancer. It has become evident that the primary metabolic fate of both of these agents is denitrosation. We have discovered an activity in the cytosol fraction of hamster liver which is capable of denitrosating these nitrosamidines with an efficiency approaching 100%. The activity is heat sensitive and requires reduced glutathione as a cofactor. Inhibition of the denitrosating activity with compounds which inhibit in parallel the conjugation of glutathione with 1-chloro-2,4-dinitrobenzene (CDNB) provides evidence that the activity is glutathione transferase. One molecule of reduced glutathione is consumed in each denitrosation event. Nitrite is formed as denitrosation proceeds with a yield equivalent to 25-50% of the denitrosated product produced. Glutathione disulfide is a minor reaction product, representing 3% of the denitrosation product yield in the MNNG case and 12% in the NC case. Thus far in our survey of N-nitrosamines, N-nitrosamides and N-nitrosamidines, only the nitrosamidines appear to be vulnerable to the cytosolic denitrosating activity. In an attempt to evaluate the importance of the glutathione-dependent reaction in the intact hamster, we have depleted glutathione by pretreatment with the commonly used agents diethyl maleate (DEM) and L-buthionine-S,R-sulfoximine (L-BSO). Nitroso compound was administered i.v. and the circulating blood levels of intact and denitrosated compound 5 min after dosing quantified. NC- and MNNG-derived methylation of organ DNA was also monitored. Pretreatment had no effect on the cytosolic denitrosating or CDNB-conjugating activities. L-BSO pretreatment had no apparent effect on the denitrosative metabolism of NC or MNNG. With DEM pretreatment we obtained clear indications of a decreased rate of denitrosation and observed a 10-fold increase in MNNG-derived liver DNA methylation. The differential effects of these pretreatments are taken as an indication that DEM-sensitive processes other than those requiring glutathione dominate N-nitrosamidine denitrosation in the hamster.

Animals↗
PubMed1994

Antimutagens as cancer chemopreventive agents in the diet.

It has been suggested that the use of antimutagens and anticarcinogens in everyday life will be the most effective procedure for preventing human cancer and genetic disease. There are several ways in which mutagenesis can be reduced or prevented. Chemicals which act to interfere with DNA repair or with mutagen metabolism can be effective antimutagens: however such compounds may also increase the probability of mutations by different chemicals or at different sites. In contrast, mutagen scavengers may be less prone to increase mutations by other chemicals. Selected examples illustrate that antimutagenic effects are often specific to certain classes of mutagen and/or certain test systems. Thus, if antimutagens are to have any impact on human disease, it is essential that they are specifically directed against the most common mutagens in daily life. On our current understanding, these are quite diverse in nature, so that combinations of antimutagens will probably be necessary. Two groups of mutagen scavengers (porphyrins and some types of dietary fibre) show some selectivity for large planar and hydrophobic types of carcinogen, which appear to be common in a normal Western diet. Increasing consumption of vitamins C and E, either through increased consumption of fruit and vegetables or through dietary supplementation might reduce formation of N-nitroso compounds, another common class of mutagens. Similarly, carotenoids and related compounds, already present at high quantities in some fruits and vegetables, have excellent antioxidant properties and should be able to counteract effects of endogenous metabolism and other events which generate oxidising species and free radicals. Still other types of antimutagen might be necessary to act against smaller non-planar carcinogens, but there is some question as to the importance of this type of carcinogen in a normal Western diet. It may be necessary to adjust the selection of antimutagens for different population groups, or as our understanding of mutagens in the diet develops further. Current assays for cancer chemoprevention in animals are unlikely to detect some important types of antimutagens, such as mutagen scavengers. A structured testing strategy is suggested, progressing from in vitro to in vivo antimutagenicity tests against a selected range of mutagens. Optimal use of antimutagens might be as a dietary supplement, additional to practical advice on increasing consumption of fruit and vegetables.

Animals↗
PubMed1993

Measurement of nitric oxide in biological models.

Nitric oxide (NO) is a small, gaseous, paramagnetic radical with a high affinity for interaction with ferrous hemoproteins such as soluble guanylate cyclase and hemoglobin. Interest in NO measurement increased exponentially with the discovery that NO or a related compound is the endothelium-derived relaxing factor (EDRF). In addition to being a potent endogenous vasodilator, NO has a role in inflammation, thrombosis, immunity, and neurotransmission. Measurement of NO is important as many of its effects (e.g., vasodilatation, inhibition of platelet aggregation) are similar to those of other substances produced by the endothelium, such as prostacyclin. NO is formed in small amounts in vivo and is rapidly destroyed by interaction with oxygen, making measurement difficult. A computerized search of the past five year's literature found NO measurements reported in fewer than 50 of 955 articles dealing with EDRF. Inhibitors of NO synthesis such as the arginine analogs or agents that inactivate NO, such as reduced hemoglobin, are commonly used as specific probes for NO, in vivo and in vitro; however, none of the NO inhibitors is completely specific. The most widely used assays use one of three strategies to detect NO: 1) NO is "trapped" by nitroso compounds, or reduced hemoglobin, forming a stable adduct that is detected by electron paramagnetic resonance (EPR) (detection threshold approximately 1 nmol); 2) NO oxidizes reduced hemoglobin to methemoglobin, which is detected by spectrophotometry (detection threshold approximately 1 nmol); 3) NO interacts with ozone producing light, "chemiluminescence" (detection threshold approximately 20 pmol). These assays can be performed to exclusively detect NO, or by adding acid and reducing agents to the sample, can measure NO and related oxides of nitrogen such as nitrite. Several new amperometric microelectrode assays offer the potential to measure smaller amounts of NO (10(-20) M), permitting NO measurement in intact issues and from single cells. This review describes the pharmacology and toxicology of NO and reviews the major techniques for measuring NO in biological models.

Animals↗
PubMed2001

Final report on the safety assessment of Lecithin and Hydrogenated Lecithin.

Lecithin is a naturally occurring mixture of the diglycerides of stearic, palmitic, and oleic acids, linked to the choline ester of phosphoric acid, commonly called phosphatidylcholine. Hydrogenated Lecithin is the product of controlled hydrogenation of Lecithin. Bilayers of these phospholipids in water may form liposomes, a spherical structure in which the acyl chains are inside and not exposed to the aqueous phase. Lecithin and Hydrogenated Lecithin are used in a large number of cosmetic formulations as skin conditioning agents-miscellaneous and as surfactant-emulsifying agents. Hydrogenated Lecithin is also used as a suspending agent-nonsurfactant. Historical data on concentration of use of Lecithin reveals that 0.1% to 1.0% is the concentration range most frequently seen, with concentrations up to 50% reported for two moisturizing products. A solution of 65% Lecithin is currently reported to be used at concentrations up to 3% in cosmetics. Nonocclusive application of Lecithin-containing liposomes to murine skin resulted in 30% penetration to the subdermis. In piglet skin, the same application resulted in 99% accumulating in the stratum corneum. In general, liposomes are considered effective in capturing other compounds inside their spherical structure and delivering any such captured compound through the skin barrier. As a result, caution should be exhibited in formulating cosmetic products that contain these ingredients in combination with other ingredients whose safety is based on their lack of absorption or where dermal absorption is a concern. Lecithin is virtually nontoxic in acute oral studies, short-term oral studies, and subchronic dermal studies in animals. Lecithin is not a reproductive toxicant, nor is it mutagenic in several assays. In an oral carcinogenicity study, brain neoplasms were found in mice exposed to Lecithin. In a subcutaneous carcinogenicity study, no neoplasms were found in mice and rats exposed to Lecithin. Adverse reactions to Lecithin in a metered-dose inhaler have been reported. Lecithin and Hydrogenated Lecithin were generally nonirritating and nonsensitizing in animal and human skin. Based on the available data, Lecithin and Hydrogenated Lecithin are safe as used in rinse-off cosmetic products; they may be safely used in leave-on products at concentrations up to 15%, the highest concentration tested in clinical irritation and sensitization studies; but the safety of use could not be substantiated in cosmetic products likely to be inhaled. Because of the possibility of formation of nitrosamines, these ingredients should not be used in cosmetic products in which N-nitroso compounds may be formed.

Administration, Inhalation↗
PubMed1988

Epithelial restitution and cellular proliferation after gastric mucosal damage caused by hypertonic NaCl in rats.

Hypertonic NaCl enhances gastric cancer in rats induced by N-nitroso compounds. This study was designed to examine the structural changes and alterations in mitotic activity occurring after mucosal exposure to hypertonic NaCl. Wistar rats were given one ml of 4.5 M NaCl by gastric tube and groups of 4-5 animals were sacrificed at different time intervals up to 120 h. An i.p. injection of thymidine was given 1 h before death. Samples of antral and corpus mucosa were prepared for microscopy and autoradiography. Hypertonic NaCl caused uniform destruction of surface mucous cells and pits in the corpus and antrum. Epithelial restitution with the formation of a thin epithelial layer occurred within one h of damage. The mucosa changed towards normal within 24-48 h. The distance between mucosal surface and the replicating cells decreased during the first 2 h. The proliferation zone remained in the middle of the glandular layer throughout the experiment. The proliferative activity increased during the first 24 h after mucosal damage. The number of labelled cells per unit area of mucosa was somewhat larger in the corpus than the antrum, but in the corpus the distance between proliferating cells and mucosal surface was double that of the antrum. Hypertonic NaCl causes a series of changes in the gastric mucosa. The increased mitotic activity can only partly explain the cocarcinogenic effect, since N-nitroso-induced adenocarcinomas occur predominantly in the antrum while the mitotic activity is maximal in the corpus.

Analysis of Variance↗
PubMed1990

The initiator tRNA acceptance assay as a short-term test for carcinogens. 6. Results with 78 polycyclic aromatic compounds.

A total of 78 polycyclic aromatic compounds (PAH), including pure hydrocarbons, PAH metabolites, aromatic amines and nitroarenes, were tested in the initiator tRNA acceptance assay (tR assay) for carcinogens. Among the pure hydrocarbons, all strong carcinogens were highly active in the tR assay. Some weak carcinogens showed moderate positive responses, others as well as all possible non-carcinogens were inactive. Various PAH metabolites, including phenols, dihydrodiols, arene oxides, dihydrodiol epoxides, quinones and benzylic sulfate esters, were positive as well. Strikingly, however, their effects rarely reached the levels observed with the strong carcinogens among the pure hydrocarbons. Moreover, the correlation with carcinogenicity was less clear, partially due to limitations in the available carcinogenicity data. The activities in the tR assay were also compared with the mutagenicity in Salmonella typhimurium. No appreciable correlation was observed. For example, trans-9,10-dihydroxy-9,10-dihydrobenzo[c]chrysene, in the absence of a mammalian metabolic system, was highly active in the tR assay, but non-mutagenic. Upon addition of rat liver enzymes, the reverse result was obtained. syn-Benzo[c]chrysene-9,10-dihydrodiol-11,12-oxide, on the other hand, was a potent direct mutagen, but required the presence of liver microsomes for a positive response in the tR assay. Thus, the metabolic basis for these two activities is different, and not yet understood for the tR assay. The partial correlations in the tR assay and in the Salmonella mutagenicity assay with carcinogenicity, and the pronounced discrepancies between these in vitro tests, may suggest that they detect different mechanisms involved in carcinogenicity. However, the tR assay was less predictive for the carcinogenicity of PAHs as compared to the previously investigated N-nitroso compounds and mycotoxins.

Carcinogenicity Tests↗
PubMed1997

Mutations of O6-methylguanine-DNA methyltransferase gene in esophageal cancer tissues from Northern China.

Epidemiologic studies have implicated the involvement of environmental factors in the etiology of esophageal cancer (EC). Our previous data have indicated that EC patients and their blood relatives show genomic instability and are deficient in repair of DNA damage induced by N-nitroso-compounds and related genotoxic agents. Thus, exposure to high levels of N-alkylnitrosamines, which are known animal carcinogens and which induce alkyl adducts in DNA, may be causally linked to EC. Among the alkyl adducts, O6-alkylguanine was shown to be the critical one related to carcinogenic lesions; its repair varies widely in a tissue-specific fashion. O6-methylguanine-DNA methyltransferase (MGMT) is responsible for its repair. Hence, inactivating mutations in this protein would impair the efficiency of the repair process. To screen for possible mutations in the MGMT polypeptide in EC patients, we analyzed a highly conserved region of the MGMT gene in 40 EC tissues and lymphocytes of 6 high-risk EC family members from high EC areas of Northern China by polymerase chain reaction single-strand conformation polymorphism and by direct sequencing of PCR products. Ten base substitutions (point mutations) within 8 codons of 7 EC samples were identified. However, no germline mutation was found in the high EC families studied so far. Concurrent study in 30 pairs of fresh EC tissues and their adjacent normal mucosa by Southern blot and Western blot analyses showed deletion of the MGMT gene in 2 samples. Thus, the high frequency of mutations (7/40) and deletions (2/30) of the MGMT gene may be partially responsible for the overall high mutation rate observed in EC tissues.

Base Sequence↗
PubMed1998

Diet and nasopharyngeal cancer in a low-risk population.

Asian studies have reported that risk of nasopharyngeal cancer (NPC) is increased in individuals who frequently consume salted fish, which contains high levels of N-nitroso compounds. As part of a collaborative, population-based, case-control study in the U.S., where the annual incidence of the disease is low, we investigated whether dietary intake of preformed nitrosamines or nitrosamine precursors, or of antioxidants including vitamin C and carotenoids, was associated with altered risk of NPC overall, or of specific histologic subtypes of disease. Cases (n = 133) identified at 5 population-based cancer registries and controls (n = 212) identified through random digit dialing completed a telephone interview and self-administered food frequency questionnaire. Dietary exposures were expressed as quartiles of intake, and odds ratios (ORs) calculated using the lowest quartile of intake as the reference category. Risk of non-keratinizing and undifferentiated tumors of the nasopharynx was increased in frequent consumers of preserved meats, which contain high levels of added nitrites. ORs in the 2nd, 3rd and highest quartile were 1.99, 4.35 and 4.59, although 95% confidence intervals did not exclude 1.0. Risk of differentiated squamous cell carcinoma, but not other histologic types, was significantly reduced in individuals with vitamin C intake above the lowest quartile (ORs 0.30, 0.33 and 0.30 in the 2nd, 3rd and highest quartiles, respectively). This association was markedly stronger among non-smokers and former smokers than among current smokers. Finally, individuals who reported consuming supplemental vitamins were at an approximately 50% reduced risk of NPC. Our results indicate that future studies should consider the effects of dietary risk factors on the risk of specific histologic subsets of NPC, and not assume that the disease is etiologically homogeneous.

Adolescent↗
PubMed1999

Elevated mortality from nonalcohol-related chronic liver disease among female rubber workers: is it associated with exposure to nitrosamines?

BACKGROUND: Despite several case reports describing liver toxicity of nitrosamines and the fact that some N-nitroso compounds are used to induce cirrhosis of the liver in animal models, this association has not been investigated in epidemiological studies. METHODS: A cohort of 2,875 female rubber workers who were active on January 1, 1976, or hired thereafter, and who had been employed for at least 1 year in one of five plants producing tires or technical rubber goods was followed for mortality from January, 1976, through December, 1991. Work histories were reconstructed using routinely documented "cost center codes" and classified into six work areas. Age and calendar year standardized mortality ratios (SMR) and 95% confidence intervals (95% CI) were calculated and stratified by plant, work area, year of hire, and years of employment in the respective work area. RESULTS: The excess mortality from cirrhosis of the liver was most pronounced for nonalcohol-related cirrhosis of the liver (ICD-9 571.4-571.9: 10 deaths, SMR 202; 95% CI 97-372). Mortality from alcohol-related cirrhosis of the liver (ICD-9 571.0-571.3: 3 deaths, SMR 153; 95% CI 31-446) and from other alcohol-related diseases (organic psychoses, injury, and poisoning) was not statistically significantly elevated. All 10 cases of nonalcohol-related cirrhosis had worked in production of technical rubber goods (SMR 279; 95% CI 134-514) and risks increased with earlier years of hire and with longer duration of employment in this work area. DISCUSSION: Although our results must be interpreted with caution, they suggest that the observed excess deaths from cirrhosis of the liver are associated with occupational risk factors. In light of additional evidence from case reports and animal data, exposure to nitrosamines may be a plausible risk factor for the observed excess mortality.

Adult↗
PubMed1996

Incidence of p53 and Ha-ras gene mutations in chemically induced rat mammary carcinomas.

To determine whether p53 alterations, which are frequent in human breast cancers, are also common in rat mammary tumors, we examined 40 tumors from 24 rats treated with 7,12-dimethylbenz[a]anthracene (DMBA) and 34 tumors from 14 rats treated with N-nitroso-N-methylurea (NMU) (an N-nitroso compound). DMBA and NMU are known genotoxic mutagens. The entire coding regions of the p53 and Ha-ras genes were examined for mutations by polymerase chain reaction single-strand conformational polymorphism analysis and by direct sequencing. One of the 40 DMBA-induced mammary tumors had a p53 mutation, a single-base substitution (AGC-->GGC) at codon 307, resulting in an amino-acid change from Ser to Gly. No mutations were found in NMU-induced tumors. The incidence of Ha-ras gene mutation was 79% (27 of 34) at codon 12 in the NMU group and 23% (nine of 40) at codon 61 in the DMBA group. Thus, p53 mutation, in contrast to Ha-ras mutation, did not seem to be a prerequisite for carcinogenesis in chemically induced rat mammary tumors.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1998

Putative environmental factors in Type 1 diabetes.

Various environmental triggers, e.g. certain viruses and dietary factors, are thought to initiate the autoimmune process, leading to the destruction of pancreatic beta-cells and consequent Type 1 diabetes. A genetic predisposition is another prerequisite allowing the autoimmune process to progress. Twin studies, major geographical variations in incidence rates, temporal trends in the incidence and findings in migrant studies indicate that environmental factors play a crucial role in the development of Type 1 diabetes. In the present review the major focus is on dietary factors, and among them particularly the possible role of cow's milk proteins. The cow's milk and Type 1 diabetes hypothesis was developed more than 10 years ago, and the issue is still not settled. Among viral infections, enteroviruses are today the most interesting group of viruses in this respect, as recent prospective studies indicate that these viruses may trigger and potentiate existing beta-cell autoimmunity. Among toxins, particularly N-nitroso compounds are of potential interest, as they are probably involved in the aetiology of some cases. Finally, psychosocial factors and the interaction between genetic predisposition and environmental factors are briefly discussed.

Animals↗
PubMed1977

The epidemiology of oral cavity, pharyngeal and esophageal cancer outside of North America and Western Europe.

Geographical variations in the incidence of oral cavity, pharyngeal, and esophageal cancer were studied, with special reference to rates in countries outside of the United States and Western Europe. Although reporting techniques differ greatly and comparisons must be made with caution, significant variations are evident. Tracing such differences often reveals possible etiologic factor for these forms of cancer. The roles are discussed of known environmental carcinogens, such as N-nitroso compounds, polycyclic aromatic hydrocarbons, and such cultural habits as smoking or chewing tobacco, excessive consumption of alcoholic beverages, as well as other possible factors in the etiology of these cancer types.

Asia↗
PubMed1986

Carcinogens and mutagens that may occur in foods.

The principal carcinogens and mutagens that have been identified in human foods are reviewed. These agents may occur in foods as naturally occurring components (e.g., metabolites made by plant or fungal cells), components of contaminating plants or microorganisms, food additives (usually unintentional), or products that arise during processing or cooking. In the mixed diets of developed countries the levels of the known carcinogens and mutagens are very low. However, serious contamination of foods by the potent hepatocarcinogen aflatoxin B1 has occurred in some parts of the world; contamination by N-nitroso compounds or their precursors is another important concern. Extrapolation of the data on the carcinogenicity and mutagenicity of chemicals that can occur in foods to an accurate estimation of the potential hazard to human populations is not yet possible.

Animals↗
PubMed2002

Environmental factors in the etiology of type 1 diabetes.

Type 1 diabetes is considered to be an autoimmune disease in which T lymphocytes infiltrate the islets of pancreas and destroy the insulin producing beta cell population. Besides antigen specificity, the quality of immune reactivity against islet cell antigen(s) is an important determinant of the beta cell destruction. Much evidence indicates that the function of the gut immune system is central in the pathogenesis, as the regulation of the gut immune system may be aberrant in type 1 diabetes. The role of virus infections in the pathogenesis of type 1 diabetes has been supported by substantial new evidence suggesting that one virus group, enteroviruses, may trigger the beta-cell damaging process in a considerable proportion of patients. The latest evidence comes from studies indicating the presence of viral genome in diabetic patients and from prospective studies confirming epidemiological risk effect. If this association holds still true in ongoing large-scale studies, intervention trials should be considered to confirm causality. Of the dietary putative etiological factors, cow's milk proteins have received the main attention. Many studies indicate an association between early exposure to dietary cow's milk proteins and an increased risk of type 1 diabetes. The question will be answered by a large scale, prospective, randomized, international intervention trial. Another dietary factor in need of more studies is the deficiency of vitamin D. Among toxins, N-nitroso compounds are the main candidates. An interaction of genetic and environmental factors is important in evaluating the possible role of a certain environmental factor in the etiology of type 1 diabetes.

Animals↗