A general dose-response relationship for chronic chemical and other health stressors and mixtures based on an emergent illness severity model.

Current efforts to assess human health response to chemicals based on high-throughput in vitro assay data on intra-cellular changes have been hindered for some illnesses by lack of information on higher-level extracellular, inter-organ, and organism-level interactions. However, a dose-response function (DRF), informed by various levels of information including apical health response, can represent a template for convergent top-down, bottom-up analysis. In this paper, a general DRF for chronic chemical and other health stressors and mixtures is derived based on a general first-order model previously derived and demonstrated for illness progression. The derivation accounts for essential autocorrelation among initiating event magnitudes along a toxicological mode of action, typical of complex processes in general, and reveals the inverse relationship between the minimum illness-inducing dose, and the illness severity per unit dose (both variable across a population). The resulting emergent DRF is theoretically scale-inclusive and amenable to low-dose extrapolation. The two-parameter single-toxicant version can be monotonic or sigmoidal, and is demonstrated preferable to traditional models (multistage, lognormal, generalized linear) for the published cancer and non-cancer datasets analyzed: chloroform (induced liver necrosis in female mice); bromate (induced dysplastic focia in male inbred rats); and 2-acetylaminofluorene (induced liver neoplasms and bladder carcinomas in 20,328 female mice). Common- and dissimilar-mode mixture models are demonstrated versus orthogonal data on toluene/benzene mixtures (mortality in Japanese medaka, Oryzias latipes, following embryonic exposure). Findings support previous empirical demonstration, and also reveal how a chemical with a typical monotonically-increasing DRF can display a J-shaped DRF when a second, antagonistic common-mode chemical is present. Overall, the general DRF derived here based on an autocorrelated first-order model appears to provide both a strong theoretical/biological basis for, as well as an accurate statistical description of, a diverse, albeit small, sample of observed dose-response data. The further generalizability of this conclusion can be tested in future analyses comparing with traditional modeling approaches across a broader range of datasets.

Single and combined genotoxicity effects of six pollutants on THP-1 cells.

The objective of this study was to evaluate the single and combined genotoxic effects of six food pollutants (Chrysoidine G, Sudan I, acid orange II, malachite green, acrylamide, and potassium bromate) on THP-1 cells through comet assay. The results of the single tests indicated that the pollutants increased the percentage of tail DNA (% tail DNA) in a dose-dependent manner. Moreover, the % tail DNA values induced by synthetic colorants (Chrysoidine G, Sudan I, acid orange II, and malachite green) were significantly higher than those by acrylamide or potassium bromate at most concentrations. In the combined tests, Chrysoidine G (422 µmol/L) or acrylamide (400 µmol/L) was mixed with different concentrations of the other five pollutants respectively. In the first combined tests, most mixtures significantly increased the % tail DNA values with the exception of Chrysoidine G and acid orange II. In the second tests, there were no significant differences in the % tail DNA values between the single and combined tests at most cases.

Vanillin mitigates potassium bromate-induced molecular, biochemical and histopathological changes in the kidney of adult mice.

The present study aimed to explore the ability of vanillin to ameliorate the adverse effects induced by potassium bromate (KBrO3) in the renal tissue. Our results showed a significant increase in hydrogen peroxide, superoxide anion, malondialdehyde, advanced oxidation protein product and protein carbonyl levels in the kidney of KBrO3 treated mice, compared with the control group. Nephrotoxicity was evidenced by a decrease in plasma uric acid and kidney glutathione levels, Na(+)-K(+)-ATPase, lactate dehydrogenase and catalase activities. Additionally, creatinine and urea levels significantly increased in the plasma and declined in the urine. Also, Kidney glutathione peroxidase, superoxide dismutase, metallothionein (MT1 and MT2) mRNA expression remarkably increased. These modifications in biochemical and molecular values were substantiated by histopathological data. Co-treatment with vanillin restored these parameters to near control values. Interestingly, vanillin proved to possess, in vitro, a stronger scavenging radical activity than vitamin C and Trolox. Thus, vanillin inhibited KBrO3-induced damage via its antioxidant and antiradical activities as well as its capacity to protect genes expression and histopathological changes.

Chemoprotective effect of taurine on potassium bromate-induced DNA damage, DNA-protein cross-linking and oxidative stress in rat intestine.

Potassium bromate (KBrO3) is widely used as a food additive and is a major water disinfection by-product. It induces multiple organ toxicity in humans and experimental animals and is a probable human carcinogen. The present study reports the protective effect of dietary antioxidant taurine on KBrO3-induced damage to the rat intestine. Animals were randomly divided into four groups: control, KBrO3 alone, taurine alone and taurine+ KBrO3. Administration of KBrO3 alone led to decrease in the activities of intestinal brush border membrane enzymes while those of antioxidant defence and carbohydrate metabolism were also severely altered. There was increase in DNA damage and DNA-protein cross-linking. Treatment with taurine, prior to administration of KBrO3, resulted in significant attenuation in all these parameters but the administration of taurine alone had no effect. Histological studies supported these biochemical results showing extensive intestinal damage in KBrO3-treated animals and greatly reduced tissue injury in the taurine+ KBrO3 group. These results show that taurine ameliorates bromate induced tissue toxicity and oxidative damage by improving the antioxidant defence, tissue integrity and energy metabolism. Taurine can, therefore, be potentially used as a therapeutic/protective agent against toxicity of KBrO3 and related compounds.

Taurine ameliorates potassium bromate-induced kidney damage in rats.

Potassium bromate (KBrO3) is widely used as a food additive and is a major water disinfection by-product. Several studies have shown that it causes nephrotoxicity in humans and experimental animals. We have investigated the potential role of the sulfonic amino acid taurine in protecting the kidney from KBrO3-induced damage in rats. Animals were randomly divided into four groups: control, KBrO3 alone, taurine alone and taurine + KBrO3. Administration of single oral dose of KBrO3 alone caused nephrotoxicity as evident by elevated serum creatinine and urea levels. Renal lipid peroxidation and protein carbonyls were increased while total sulfhydryl groups and reduced glutathione levels were decreased suggesting the induction of oxidative stress. The enzymes of renal brush border membrane were inhibited and those of carbohydrate metabolism were altered. There was an increase in DNA damage and DNA-protein cross-linking. Treatment with taurine, prior to administration of KBrO3, resulted in significant attenuation in all these parameters but the administration of taurine alone had no effect. Histological studies supported these biochemical results showing extensive renal damage in KBrO3-treated animals and greatly reduced tissue injury in the taurine + KBrO3 group. These results show that taurine is an effective chemoprotectant against bromate-induced renal damage and this amino acid could prove to be useful in attenuating the toxicity of this compound.

Attenuation of KBrO3-induced renal and hepatic toxicity by cloudy apple juice in rat.

The aim of the study was to evaluate a protective effect of apple juice on KBrO3-induced oxidative stress in rats. Male Wistar rats were administered apple juice per os, 10 ml/kg b.w. for 28 days. On 27 day of the experiment, some rats were given i.p. a single 125 mg/kg b.w. dose of KBrO3 . Markers of oxidative damage and clinical chemistry parameters were determined. Treatment with apple juice prior to KBrO3 challenge prevented an increase in hepatic and renal microsomal lipid peroxidation by 25 and 44%, respectively, increased the activity of antioxidant enzymes in the liver by 29 - 59% and decreased the plasma content of carbonyl groups by 19%. Aminotransferases activity in plasma was reduced by 19% and 36%, concentrations of plasma bilirubin, cholesterol and creatinine were suppressed by 21%, 16% and 26%, respectively, in rats supplemented with juice before KBrO3 injection. No protective effect of apple juice on nuclear DNA was observed. Supplementation with cloudy apple juice to some extent attenuated oxidative damage induced by KBrO3 in the liver and kidney of rats as evidenced by alterations of certain oxidative stress markers and clinical chemistry parameters.

[Intermixture of politics and science in the GDR. The investigation of deaths at the Department of Neurology and Psychiatry at Leipzig University under Müller-Hegemann in 1963]. / Vermischung von Politik und Wissenschaft in der DDR. Die Untersuchung der Todesfälle an der Leipziger Neurologisch-Psychiatrischen Universitätsklinik unter Müller-Hegemann 1963.

This study presents archival sources that shed light on a topic still being discussed by psychiatrists in East Germany: the death of two patients at the Leipzig Department that occurred in 1960 and 1962 under the directorship of Dietfried Müller-Hegemann. These fatalities were supposed to have been induced by obsolete psychotropic drugs and were associated with Ivan Pavlov's hypnotherapy. The incidents were investigated both by highest administrative bodies and the General State Prosecutor of the former GDR. Archival sources suggest that lower party organs and the ministerial administration tried to make use of the proceedings to bring about the downfall of the head of the Leipzig Department, who had become ideologically suspicious. However, the official General State Prosecutor's investigation ascertained that both Müller-Hegemann and Christa Kohler, head of the psychotherapeutic ward, were not to be held responsible. Although the SED Central Committee at first tried to influence the outcome on the basis of ideological reservations made by the university party organisation, it finally accepted and confirmed the judgment of the General State Prosecutor. Hence, in this case, the highest party bodies followed arguments that were the result of an independent investigation and were not influenced by an individual bias or ideological motives.

Melatonin restores the basal level of lipid peroxidation in rat tissues exposed to potassium bromate in vitro.

OBJECTIVE: Potassium bromate (KBrO3) is a prooxidant and carcinogen. Melatonin is a highly effective antioxidant. Indole-3-propionic acid (IPA; indole substance) and propylothiouracil (PTU; antithyroid drug) reveal some antioxidative effects. The aim of the study was to evaluate KBrO3-induced lipid peroxidation (LPO) in vitro in tissues collected from control or melatonin-treated rats, and to compare potential preventive effects of melatonin, IPA and PTU. MATERIALS AND METHODS: Kidney, liver and lung homogenates from either control or melatonin-pretreated rats (0.0645 mmol/kg b.w., i.p., twice daily, 10 days) were incubated in the presence of KBrO3 (0.1, 0.5, 1.0, 2.5, 5.0, 10.0 mM). Then, control lung homogenates were incubated with KBrO3 (10.0 mM) together with melatonin (0.01, 0.1, 0.5, 1.0, 5.0, 7.5 mM), or with IPA or with PTU. LPO products (malondialdehyde+4-hydroxyalkenals) were measured spectrophotometrically. RESULTS: Melatonin injections prevented KBrO3-induced LPO in lung homogenates. Melatonin, IPA and PTU, used in vitro, reduced KBrO3-induced LPO in control lungs. Unexpectedly, KBrO3 caused a concentration-dependent decrease in LPO in liver and kidney homogenates from control but not from melatonin-treated rats. CONCLUSIONS: Potassium bromate-induced LPO in the rat lung homogenates suggests that the lung may be the target for this carcinogen. An exposure of organisms to melatonin decreases tissue sensitivity to KBrO3-induced damage, possibly by restoring the oxidative balance.

Bromato de potássio em aditivos para panificação usados em padarias do III Distrito Sanitário do Recife, PE – 2006 / Potassium bromate in bread additives used in bakeries III Distrito Sanitário do Recife, PE - 2006

Bromato de Potássio é um agente oxidante utilizado a panificação, porém no Brasil, através da Lei 10.273, de 05/09/2001, é proibido em farinhas, aditivos para panificação e produtos para panificação, considerando seus efeitos tóxicos à saúde, sendo classificado como carcinogênico. O presente trabalho objetiva identificar o atendimento à Lei acima citada, bem como relacionar o valor comercial do pão com o uso do bromato de potássio. (...)

Bromato de potasio: un aditivo prohibido? / Potassium bromate: a banned additive?

El bromato de potasio es un aditivo que se agrega a la harina y actúa oxidando las proteínas del gluten, originando panes con mayor volúmen, mejor textura y estructura de la miga. Sin embargo, es altamente tóxico. En ratas y ratones produce tumores en riñón, tiroides y mesotelio peritoneal. Debido a ello la Unión Europea lo ha clasificado como tipo 2 (sospechoso cancerígeno para humanos). Durante el horneado de los panificados, el bromato se transforma en bromuro, inocuo. Pero ensayos realizados con métodos muy sensibles demuestran que, aún usado a niveles reconocidos como aceptables, queda siempre una parte sin modificar en el producto terminado. En éste país, la Resolución Nº 073/93 Mercosur-GMC incorporada al Código Alimentario Argentino estableció retirarlo de la Lista General Armonizada de Aditivos-Mercosur. Este trabajo se realizó con el objetivo de verificar el cumplimiento de la mencionada Resolución. Se analizaron 91 m

Toxic effects of potassium bromate and thioglycolate on vestibuloocular reflex systems of Guinea pigs and humans.

Potassium bromate (KBrO(3)) and thioglycolate are two components of hair curling solution. The neurotoxic effects of KBrO(3) and thioglycolate on the vestibuloocular reflex (VOR) system have not been elucidated. In this paper, we report the adverse effects of KBrO(3) and thioglycolate on the VOR system of Hartley-strain guinea pigs. The function of the VOR system was evaluated by caloric test coupled with the electronystagmographic recordings after subcutaneous injection of 20 or 50 mg/kg KBrO(3) or 15 mg/kg thioglycolate, either alone or in combination once daily for 14 consecutive days. The results showed that KBrO(3) produced abnormal caloric responses in a concentration-dependent manner and thioglycolate enhanced this abnormality. Our clinical patients, 10 female hairdressers exposed to the hair curling solution for 10-30 years revealed a similar dysfunction in the caloric test. The possible mechanism of this adverse effect was studied: the cerebellar-regulated functions such as motor equilibrium performance and spontaneous locomotor activity of guinea pigs were reduced, the enzymatic Na(+)/K(+)-ATPase and Ca(2+)-ATPase activities of cerebellar tissues were significantly decreased, and the loss of Purkinje cells as well as the derangement of the granular cell layer of the cerebellar cortex was revealed after treatment with KBrO(3) plus thioglycolate. These findings imply that KBrO(3) plus thioglycolate is toxic to the VOR system, mediated by, at least in part, the dysfunction of a higher cerebellar regulatory mechanism. We suggest that the caloric test is a noninvasive method for monitoring the consequences of hazardous exposure of hair curling solution in humans. Our clinical findings together with the animal study imply that clinicians should be alert to the risk of bromate exposure in hairdressers, especially those with vertigo, tinnitus, or hearing loss.

Requirement of glutathione and cysteine in guanine-specific oxidation of DNA by carcinogenic potassium bromate.

Potassium bromate (KBrO3), a food additive, induces renal-cell tumors in rats. KBrO3 induced 8-oxo-7, 8-dihydro-2'-deoxyguanosine (8-oxodG) formation in human leukemia cell line HL-60 as well as in its H2O2-resistant clone, HP100, suggesting no involvement of H2O2. Depletion of GSH by buthionine sulfoximine (BSO) had a little inhibitory effect on KBrO3-induced 8-oxodG formation. However, the amount of 8-oxodG was still significantly higher than that in control, suggesting that intracellular Cys can affect KBrO3 to oxidize DNA, when GSH decreased. KBrO3 caused 8-oxodG in isolated DNA in the presence of GSH (tripeptide; gamma-GluCysGly), gamma-GluCys, CysGly, or Cys. Methional completely inhibited 8-oxodG formation induced by KBrO3 plus GSH, but typical hydroxyl radical scavengers, SOD and catalase, had little or no inhibitory effects. When bromine solution (BrO(-)) was used instead of BrO3(-), similar scavenger effects were observed. Experiments with 32P-labeled DNA fragments obtained from the human p53 tumor suppressor gene and the c-Ha-ras-1 protooncogene suggested that KBrO3 induced 8-oxodG formation at 5'-site guanine of GG and GGG sequences of double-stranded DNA in the presence of GSH and that treatment of formamidopyrimidine-DNA glycosylase led to chain cleavages at the guanine residues. ESR spin-trapping studies showed that 1:2:2:1 quartet DMPO (5,5-dimethyl-1-pyrroline N-oxide) spectrum similar to DMPO/hydroxy radical (*OH) adduct, but the signals were not inhibited by ethanol. Therefore, the signal seemed not to be due to *OH but byproduct due to oxidation of DMPO by the reactive species. The signals were suppressed by the addition of dGMP, but not by other mononucleotides, suggesting the specific reactivity with guanine. On the basis of our results and previous literature, it is speculated that reduction of KBrO3 by SH compounds in renal proximal tubular cells yields bromine oxides and bromine radicals, which are the reactive species that cause guanine oxidation, leading to renal carcinogenesis of KBrO3.

Balancing the risks and benefits of drinking water disinfection: disability adjusted life-years on the scale.

To evaluate the applicability of disability adjusted life-years (DALYs) as a measure to compare positive and negative health effects of drinking water disinfection, we conducted a case study involving a hypothetical drinking water supply from surface water. This drinking water supply is typical in The Netherlands. We compared the reduction of the risk of infection with Cryptosporidium parvum by ozonation of water to the concomitant increase in risk of renal cell cancer arising from the production of bromate. We applied clinical, epidemiologic, and toxicologic data on morbidity and mortality to calculate the net health benefit in DALYs. We estimated the median risk of infection with C. parvum as 10(-3)/person-year. Ozonation reduces the median risk in the baseline approximately 7-fold, but bromate is produced in a concentration above current guideline levels. However, the health benefits of preventing gastroenteritis in the general population and premature death in patients with acquired immunodeficiency syndrome outweigh health losses by premature death from renal cell cancer by a factor of > 10. The net benefit is approximately 1 DALY/million person-years. The application of DALYs in principle allows us to more explicitly compare the public health risks and benefits of different management options. In practice, the application of DALYs may be hampered by the substantial degree of uncertainty, as is typical for risk assessment.

La prevención de las enfermedades alimentarias / The prevention of foodborne diseases

Introducción: Las gastroenteritis y otras enfermedades alimentarias son relativamente frecuentes en el país pero no se han efectuado hasta el presente diagnósticos de situación suficientemente específicos que permitan determinar las características de las mismas. Materiales y métodos: se estudiaron casos y brotes de enfermedad alimentaria, denunciados en el Departamento de Vigilancia Alimentaria, INAL-ANMAT, entre abril de 1993 y diciembre de 1995. La mayor parte de las denuncias correspondieron a la ciudad de Buenos Aires y al Gran Buenos Aires. Ocasionalmente informaron 9 provincias. Se determinaron agentes causales, tipos de alimentos involucrados, lugares de ingestión, deficiencias detectadas. Resultados: Se registraron en total 177 denuncias en las que 1298 personas enfermaron. El 38 por ciento de las veces se confirmó el agente causal en el laboratorio. Los agentes microbianos representaron el 70 por ciento del total y el 30 por ciento de los agentes químicos. Entre los primeros, los más frecuentes fueron Salmonella y Staphylococcus aureus. Las principales causas de enfermedad por agentes químicos fueron los bromatos en exceso y los zapallitos amargos. Conclusiones: El 63,5 por ciento del total de las personas se enfermó ingiriendo los alimentos fuera de su domicilio. Los alimentos más frecuentemente asociados fueron ensaladas y sandwiches con mayonesa, productos de confitería y golosinas, aguas envasadas, jugos y bebidas, productos cárnicos y lácteos. Los procedimientos de manipulación y la higiene incorrectos fueron las deficiencias más frecuentes. Se enfatiza la necesidad de intensificar las acciones iniciadas para el registro y prevención de estas enfermedades, y de promover actividades educativas. (AU)

La prevención de las enfermedades alimentarias / The prevention of foodborne diseases

Introducción: Las gastroenteritis y otras enfermedades alimentarias son relativamente frecuentes en el país pero no se han efectuado hasta el presente diagnósticos de situación suficientemente específicos que permitan determinar las características de las mismas. Materiales y métodos: se estudiaron casos y brotes de enfermedad alimentaria, denunciados en el Departamento de Vigilancia Alimentaria, INAL-ANMAT, entre abril de 1993 y diciembre de 1995. La mayor parte de las denuncias correspondieron a la ciudad de Buenos Aires y al Gran Buenos Aires. Ocasionalmente informaron 9 provincias. Se determinaron agentes causales, tipos de alimentos involucrados, lugares de ingestión, deficiencias detectadas. Resultados: Se registraron en total 177 denuncias en las que 1298 personas enfermaron. El 38 por ciento de las veces se confirmó el agente causal en el laboratorio. Los agentes microbianos representaron el 70 por ciento del total y el 30 por ciento de los agentes químicos. Entre los primeros, los más frecuentes fueron Salmonella y Staphylococcus aureus. Las principales causas de enfermedad por agentes químicos fueron los bromatos en exceso y los zapallitos amargos. Conclusiones: El 63,5 por ciento del total de las personas se enfermó ingiriendo los alimentos fuera de su domicilio. Los alimentos más frecuentemente asociados fueron ensaladas y sandwiches con mayonesa, productos de confitería y golosinas, aguas envasadas, jugos y bebidas, productos cárnicos y lácteos. Los procedimientos de manipulación y la higiene incorrectos fueron las deficiencias más frecuentes. Se enfatiza la necesidad de intensificar las acciones iniciadas para el registro y prevención de estas enfermedades, y de promover actividades educativas.

Organotropic formation and disappearance of 8-hydroxydeoxyguanosine in the kidney of Sprague-Dawley rats exposed to adriamycin and KBrO3.

A form of oxidative DNA damage, 8-hydroxydeoxyguanosine (8-OHdG), was comparatively determined for 48 h in the kidney and liver isolated from Sprague-Dawley rats i.p. treated with Adriamycin; potassium bromate (KBrO3), hydroquinone and vitamin A. HPLC-ECD analysis system showed that Adriamycin and KBrO3, renal carcinogens, induced higher levels of 8-OHdG in the target organ of kidney (12-13.8 residues/10(4) dG(deoxyguanosine)) compared to those in the liver (3.4-3.8 residues/10(4) dG) and showed highly persistent levels (8 residues, 10(4) dG) in the kidney. The data suggest that the organotropic persistence of 8-OHdG may provide a useful marker for identifying target organ systems in oxidative chemical carcinogenesis and screening free radical-generating carcinogens.

Toxicity and carcinogenicity of potassium bromate--a new renal carcinogen.

Potassium bromate (KBrO3) is an oxidizing agent that has been used as a food additive, mainly in the bread-making process. Although adverse effects are not evident in animals fed bread-based diets made from flour treated with KBrO3, the agent is carcinogenic in rats and nephrotoxic in both man and experimental animals when given orally. It has been demonstrated that KBrO3 induces renal cell tumors, mesotheliomas of the peritoneum, and follicular cell tumors of the thyroid. In addition, experiments aimed at elucidating the mode of carcinogenic action have revealed that KBrO3 is a complete carcinogen, possessing both initiating and promoting activities for rat renal tumorigenesis. However, the potential seems to be weak in mice and hamsters. In contrast to its weak mutagenic activity in microbial assays, KBrO3 showed relatively strong potential inducing chromosome aberrations both in vitro and in vivo. Glutathione and cysteine degrade KBrO3 in vitro; in turn, the KBrO3 has inhibitory effects on inducing lipid peroxidation in the rat kidney. Active oxygen radicals generated from KBrO3 were implicated in its toxic and carcinogenic effects, especially because KBrO3 produced 8-hydroxydeoxyguanosine in the rat kidney. A wide range of data from applications of various analytical methods are now available for risk assessment purposes.

New considerations on hydrogen peroxide and related substances as food additives in view of carcinogenicity.

The use of hydrogen peroxide as a labile and safe food preservative in fish cake and boiled noodles has recently been restricted by the Japanese government, since hyperplasia has been found in the duodenum of mice after long-term peroral study. The action of compounds with resembling mode of action, potassium bromate as an improving agent in bread, and sodium chlorate as a weed killer are discussed in this paper in view of developmental and environmental pharmacology.