Cancer incidence in an Austrian alpine valley 1983-2012 : A descriptive study.

After one of Austria's largest environmental scandals in 2014, which involved the release of hexachlorobenzene (HCB) in the Carinthian valley Görtschitztal, concerns about increased cancer rates have arísen in the affected local population. A descriptive study was conducted to examine the cancer incidence rates between 1983 and 2012. Data from the affected area (Görtschitztal, district St. Veit) were compared to data from the neighboring area within the same district and Carinthia excluding St. Veit, considering incidence rates of liver, lung, kidney, thyroid cancer and mesothelioma. Prostate cancer and carcinoma in situ were both included and excluded from overall cancer incidents in order to prevent potential bias due to screening programs. Considering the observed variability at an overall level, no conspicuous differences in cancer incidences could be found (Carinthia: 495, St. Veit West: 408, St. Veit East: 572 cases per 100,000 person-years in 2012). For some cancer types, e. g. liver, thyroid cancer and mesothelioma, the affected region showed a higher increase in rates than the neighboring area or Carinthia overall; however, these increased rates date back to a time prior to the HCB exposure, suggesting other carcinogenic influences, such as asbestos exposure from antecedent years.

Exposure to environmental concentrations of hexachlorobenzene induces alterations associated with endometriosis progression in a rat model.

Hexachlorobenzene (HCB) is a dioxin-like compound widely distributed and is a weak ligand of the aryl hydrocarbon receptor (AhR). Endometriosis is a disease characterized by growth of endometrial tissue in ectopic sites. Our aim was to investigate the impact of HCB on the endocrine, invasion and inflammatory parameters in a rat endometriosis model surgically induced. Female rats were exposed to HCB (1, 10 and 100 mg/kg b.w.) during 30 days. Results showed that HCB increases endometriotic like-lesions (L) volume in a dose-dependent manner. In L, HCB10 increases microvessel density (immunohistochemistry) and the vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2) and AhR levels (Western Blot), while HCB1 enhances aromatase expression (Western Blot). In addition, in eutopic endometrium (EU), HCB10/HCB100 augments microvessel density, VEGF and MMP-9 expression, while HCB1/HCB10 increases tumor necrosis factor-α (TNF-α) content in peritoneal fluid (ELISA). Interestingly, both L and EU from HCB-treated rats exhibited higher estrogen receptor α (ERα) (immunohistochemistry) and metalloproteases (MMP)-2 and -9 levels (Western Blot), as well as lower progesterone receptor (PR) expression (immunohistochemistry) than in control rats. Environmentally relevant concentrations of HCB could contribute to abnormal changes associated with endometriosis progression and development.

Organochlorine pesticides and prostate cancer, Is there an association? A meta-analysis of epidemiological evidence.

PURPOSE: The results of epidemiological studies about exposure to organochlorine pesticides (OCPs) and risk of prostate cancer (PC) are inconclusive. We conducted a meta-analysis to evaluate the association between exposure to specific OCPs and PC. METHODS: We searched PubMed, Scopus, and Web of science databases for case-control and cohort studies published till March 2015 that provided data about exposure to OCPs and PC. We also contacted authors and hand-searched references of the included articles. We calculated pooled estimates using random effects model and explored heterogeneity between studies. RESULTS: We systematically reviewed 15 articles and based our meta-analysis on 10 articles covering nine case-control studies and a large prospective cohort study. Pooled estimates of PC for highest versus lowest exposed category to p,p'-DDE was 1.02 (0.69-1.35), I (2) = 12.7 %, p = 0.333, trans-nonachlor, 0.88 (0.45-1.31), I (2) = 0.00 %, p = 0.892, oxychlordane, 0.91 (0.46-1.35), hexachlorobenzene, 0.88 (0.18-1.57), I (2) = 36.0 %, p = 0.210 from combining results of studies that applied serum OCPs measurements among the general population. For DDT, stratifying studies by exposed population revealed homogeneity, pooled estimate for serum level measurement for the highest exposed versus the lowest exposed of the general population was 0.81 (0.95-1.26), I (2) = 0.00 %, p = 0.400, and for occupational exposure 1.30 (0.94-1.67), I (2) = 13.4 %, p = 0.315. A positive but also insignificant association was obtained for pooling results for high exposure to lindane among farmers and pesticide applicators, 1.56 (0.82-2.29), I (2) = 41.7 %, p = 0.180. CONCLUSIONS: The existing epidemiological data do not support the hypothesis that exposure to specific OCPs is associated with an increased incidence of PC in the general population.

Environmental hexachlorobenzene exposure and human male reproductive function.

Hexachlorobenzene (HCB) is a persistent environmental fungicide that may disrupt androgen regulation. The aim of this study was to investigate associations between HCB levels and biomarkers of male reproductive function. 589 Spouses of pregnant women from Greenland, Poland and Ukraine were enrolled between 2002 and 2004. The men provided semen and blood samples and were interviewed. HCB was measured in serum by gas chromatography. The mean serum concentrations of HCB were higher in Ukraine (182.3ng/g lipid) and Greenland (79.0ng/g lipid) compared to Poland (14.2ng/g lipid). Sex hormone binding globulin (SHBG) and free androgen index (FAI) were associated with HCB in men from Ukraine and Poland. This study spanning large differences in environmental HCB exposure levels shows a positive association for SHBG and negative association for FAI with high serum levels of HCB in fertile men, but without major consequences for semen quality and the Inuit study population.

Association between serum levels of organochlorine pesticides and sex hormones in adults living in a heavily contaminated area in Brazil.

BACKGROUND: Several studies have investigated the effects of organochlorine (OC) pesticides on adverse reproductive outcomes. However, few previous studies explored their effects on sex hormones. OBJECTIVE: To examine the association between serum concentrations of OC pesticides and levels of sex hormones in adult population in a rural area in Brazil heavily contaminated with these pesticides. METHODS: A cross-sectional study with 304 men and 300 women was undertaken. Wet weight serum concentrations of 19 OC pesticides (dichloro-diphenyl-trichloroethane [DDT] and hexachlorocyclohexane [HCH], among others) were determined in all participants. Testosterone levels were obtained for men and estradiol, progesterone, prolactin, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) for women. Associations between OC pesticides and sex hormones were evaluated using linear regression models. RESULTS: Prevalence of women with non-physiological hyperprolactinemia was 4%. After adjusting for serum lipids and confounders, heptachlor and o,p'-DDT concentrations in men were associated with lower testosterone levels, while peri- and postmenopausal women (N=77) showed inverse associations between LH and hexachlorobenzene (HCB), p,p'-DDT, p,p'-DDD (dichloro-diphenyl-dichloroethane), endosulfan 1 and 2, aldrin and mirex, as well as between FSH and p,p'-DDD, endosulfan 1 and aldrin. Premenopausal women (N=210) did not show statistically significant associations between OC pesticides and sex hormones. CONCLUSIONS: Inverse associations between OC pesticide concentrations and testosterone in men and LH and FSH in peri-/postmenopausal women, together with the high proportion of women with elevated prolactin, suggest that these OC compounds may have triggered anti-androgenic effects in men and estrogenic effects in women in this population.

Effects of exposure to polychlorinated biphenyls and organochlorine pesticides on thyroid function during pregnancy.

In this study, the authors' objective was to determine whether serum concentrations of polychlorinated biphenyls (PCBs), hexachlorobenzene, p,p'-dichlorodiphenyl trichloroethane (DDT), o,p'-DDT, and p,p'-dichlorodiphenyl dichloroethylene (DDE) are associated with thyroid function during pregnancy. These compounds, as well as thyroid-stimulating hormone, total thyroxine, and free thyroxine, were measured in serum samples collected between October 1999 and October 2000 from 334 pregnant women living in the Salinas Valley, California. Data were analyzed by multivariate linear regression. After adjustment for covariates, seven of the 19 PCB congeners detected in more than 75% of participants and the sum of those congeners were negatively associated with free thyroxine concentrations. PCBs 44, 52, and 183 remained significant after the exclusion of two outliers. Hexachlorobenzene concentrations were negatively associated with both free thyroxine and total thyroxine. PCB and hexachlorobenzene concentrations were strongly correlated, which hampered the authors' ability to identify their independent associations with thyroid function. None of the exposures under study were associated with thyroid-stimulating hormone. Results suggest that exposure to PCBs and/or hexachlorobenzene at background levels may affect thyroid function during pregnancy. These findings are of particular significance, since thyroid hormones of maternal origin may play an essential role in fetal neurodevelopment.

Hepatic arachidonic acid metabolism is disrupted after hexachlorobenzene treatment.

Hexaclorobenzene (HCB), one of the most persistent environmental pollutants, can cause a wide range of toxic effects including cancer in animals, and hepatotoxicity and porphyria both in humans and animals. In the present study, liver microsomal cytochrome P450 (CYP)-dependent arachidonic acid (AA) metabolism, hepatic PGE production, and cytosolic phospholipase A2 (cPLA2) activity were investigated in an experimental model of porphyria cutanea tarda induced by HCB. Female Wistar rats were treated with a single daily dose of HCB (100 mg kg(-1) body weight) for 5 days and were sacrificed 3, 10, 17, and 52 days after the last dose. HCB treatment induced the accumulation of hepatic porphyrins from day 17 and increased the activities of liver ethoxyresorufin O-deethylase (EROD), methoxyresorufin O-demethylase (MROD), and aminopyrine N-demethylase (APND) from day 3 after the last dose. Liver microsomes from control and HCB-treated rats generated, in the presence of NADPH, hydroxyeicosatetraenoic acids (HETEs), epoxyeicosatrienoic acids (EETs), 11,12-Di HETE, and omega-OH/omega-1-OH AA. HCB treatment caused an increase in total NADPH CYP-dependent AA metabolism, with a higher response at 3 days after the last HCB dose than at the other time points studied. In addition, HCB treatment markedly enhanced PGE production and release in liver slices. This HCB effect was time dependent and reached its highest level after 10 days. At this time cPLA2 activity was shown to be increased. Unexpectedly, HCB produced a significant decrease in cPLA2 activity on the 17th and 52nd day. Our results demonstrated for the first time that HCB induces both the cyclooxygenase and CYP-dependent AA metabolism. The effects of HCB on AA metabolism were previous to the onset of a marked porphyria and might contribute to different aspects of HCB-induced liver toxicity such as alterations of membrane fluidity and membrane-bound protein function. Observations also suggested that a possible role of cPLA2 in the early increase of AA metabolism cannot be excluded. However, the existence of other pathway(s) for metabolizable AA generation different from cPLA2 activation is also proposed.

Disruption of androgen regulation in the prostate by the environmental contaminant hexachlorobenzene.

Hexachlorobenzene (HCB) is a persistent environmental contaminant that has the potential to interfere with steroid hormone regulation. The prostate requires precise control by androgens to regulate its growth and function. To determine if HCB impacts androgen action in the prostate, we used a number of methods. Our in vitro cell-culture-based assay used a firefly luciferase reporter gene driven by an androgen-responsive promoter. In the presence of dihydrotestosterone, low concentrations (0.5-5 nM) of HCB increased the androgen-responsive production of firefly luciferase and high concentrations of HCB (> 10 microM) suppressed this transcriptional activity. Results from a binding assay showed no evidence of affinity between HCB and the androgen receptor. We also tested HCB for in vivo effects using transgenic mice in which the transgene was a prostate-specific, androgen-responsive promoter upstream of a chloramphenicol acetyl transferase (CAT) reporter gene. In 4-week-old mice, the proportion of dilated prostate acini, a marker of sexual maturity, increased in the low HCB dose group and decreased in the high HCB dose mice. In the 8-week-old mice, there was a significant decrease in both CAT activity and prostate weight upon exposure to 20 mg/kg/day HCB. Therefore, in vitro and in vivo data suggest that HCB weakly agonizes androgen action, and consequently, low levels of HCB enhanced androgen action but high levels of HCB interfered. Environmental contaminants have been implicated in the rising incidence of prostate cancer, and insight into the mechanisms of endocrine disruption will help to clarify their role.

Breast cancer and serum organochlorine residues.

BACKGROUND: Controversy still exists about the breast carcinogenic properties in humans of environmental xenoestrogens (organochlorines), justifying new investigations. AIMS: To compare the blood levels of total dichlorodiphenyltrichloroethane (DDT) and hexachlorobenzene (HCB) in samples collected at the time of breast cancer discovery, in order to avoid the potential consequences of body weight change (after chemotherapy or radiotherapy) on the pesticide residue levels. METHODS: Blood levels of HCB and total DDT (we calculated total DDT concentrations by adding all DDT and DDE isomers) were compared in 159 women with breast cancer and 250 presumably healthy controls. Risk of breast cancer associated with organochlorine concentration was evaluated. RESULTS: Mean levels of total DDT and HCB were significantly higher for breast cancer patients than for controls. No differences in serum levels of total DDT or HCB were found between oestrogen receptor positive and oestrogen receptor negative patients with breast cancer. CONCLUSIONS: These results add to the growing evidence that certain persistent pollutants may occur in higher concentrations in blood samples from breast cancer patients than controls.

Association of hexachlorobenzene and other organochlorine compounds with anthropometric measures at birth.

The aim of the present study was to assess the association of prenatal exposure to hexachlorobenzene (HCB) and other organochlorine compounds with anthropometric measures at birth. A total of 98 mother-infant pairs (83% of all children born in a specific area polluted with HCB in the period 1997-1999) were recruited after giving written consent. Levels of organochlorine compounds were measured in 72 maternal serum samples at delivery and in 70 cord serum samples. Of the organochlorines measured in cord serum, median levels of HCB were higher than for the other compounds (median of HCB = 1.13 ng/mL, median of dichlorodiphenyl dichloroethylene = 0.85 ng/mL, and median of total polychlorinated biphenyls = 0.27 ng/mL). Premature newborns had higher concentrations of HCB [1.94 ng/mL among prematures versus 1.10 among nonprematures (p < 0.10)], dichlorodiphenyl dichloroethylene [2.40 versus 0.80 (p < 0.05)], and polychlorinated biphenyls in cord serum [0.70 versus 0.14 (p < 0.10)]. Those infants born with a small length for gestational age had higher levels of HCB in cord serum than those with an adequate length for gestational age [1.64 ng/mL versus 1.00 ng/mL (p < 0.05)]. In addition, HCB cord serum levels were negatively associated in a dose-response way with crown-heel length [for each doubling of the dose there was a decrease of 0.46 (SE = 0.22) cm] after adjusting for smoking, gestational age, and other organochlorine compounds. The associations of dichlorodiphenyl dichloroethylene and polychlorinated biphenyls with length were not significant. The results did not vary when stratified for prematurity. These data suggest that HCB reduces intrauterine physical linear growth.

Evaluation of urinary porphyrin excretion in neonates born to mothers exposed to airborne hexachlorobenzene.

The existence of a link between hexachlorobenzene (HCB) and porphyria cutanea tarda has been known for a long time. However, the epidemiologic data on effects on health caused by prenatal exposure have not provided convincing evidence that HCB alters porphyrin metabolism. Our objectives were to analyze urinary porphyrin excretion and HCB in maternal serum and fetal cord blood in neonates born in a village (Flix) near a chlorinated solvent factory, to detect possible adverse effects in urinary porphyrin excretion caused by prenatal exposure, and to assess their relationship with HCB blood levels. We conducted a cross-sectional study in the Porphyria Unit at a tertiary care facility in Barcelona, Spain, and the Pediatric Unit of the Móra d'Ebre Hospital, the reference hospital of the study area. We included in the study all neonates (n = 68) born in Móra d'Ebre Hospital 1997-1999 and their mothers. We obtained 68 urine specimens of singleton neonates on the third day after birth to test for urinary porphyrin excretion. We obtained 52 fetal cord blood and 56 maternal serum samples for HCB analysis. Total urinary porphyrins were quantified using spectrofluorometry. Porphyrin profile was determined by HPLC. Serum HCB was analyzed by gas chromatography coupled with electron capture detection. In total population, median HCB levels were 1.08 ng/mL in cord blood and 3.31 ng/mL in maternal serum. Total urinary porphyrin concentration was 37.87 micromol/mol creatinine. Coproporphyrin I and coproporphyrin III were the major porphyrins excreted. We found no positive relationship between urinary porphyrin excretion and HCB levels. However, we observed an association between maternal smoking and coproporphyrin excretion. Although high environmental levels of HCB are reported in the town of Flix, we found no alteration in urinary porphyrin excretion.

Proliferation and differentiation of murine haemopoietic progenitor cells in stroma-free culture in the presence of metabolites of chlorinated pesticides.

We have studied the influence of metabolites of chlorinated pesticides (lindane, pentachlorophenol, hexachlorobenzene) on proliferation and differentiation in two stroma-free murine bone marrow culture models, a multipotent progenitor cell line (FDCP-mix) and primary lineage-depleted bone marrow cells. Tetrachlorohydroquinone (Cl(4)pHQ), tetrachloro-p-benzoquinone (Cl(4p)BQ), but not their positional isomers, tetrachlorocatechol (Cl(4)oHQ) and tetrachloro-o-benzoquinone (Cl(4)oBQ), nor 2,4,6-trichlorophenol (2,4,6-Cl(3)P), were much more toxic to FDCP-mix cells cultured under conditions which lead to self-renewal than under conditions which lead to granulocyte-macrophage differentiation. Under the latter conditions, Cl(4)pHQ and Cl(4p)BQ even stimulated growth at intermediate concentration levels. In the primary cell cultures, pronounced differences were observed in the sensitivity between individual developmental pathways and between the different compounds. The percent of cells differentiating into the granulocytic lineage was increased at high concentration levels of each test compound. However, stimulatory effects on the macrophage lineage were observed at intermediate concentration levels of Cl(4)pHQ, Cl(4p)BQ and 2,4,6-Cl(3)P, and differentiation into erythrocytes was stimulated at low concentrations of 2,4,6-Cl(3)P. It is concluded that chlorinated monocyclic pesticides, after biotransformation to quinoid metabolites, may interact directly with haemopoietic progenitor cells with differential effects on self-renewal and differentiation. These mechanisms could lead to myeloplastic disorders.

Infections and atopic disorders in childhood and organochlorine exposure.

The authors investigated whether organochlorine exposure is associated with prevalence of otitis media, pneumonia, pertussis, asthma, and increased immunoglobulin E levels in children. Organochlorine concentrations and histories of infection and atopic manifestation were available for 343 children, and immunoglobulin E levels were available for 340 children. The authors applied logistic and linear regressions and controlled for confounders. In general, the prevalence of infections in children was not related to organochlorine exposure. However, for the combined effect of dichlorodiphenyldichloroethene with polychlorinated biphenyls or hexachlorobenzene, a significantly increased relative risk (odds ratios = 3.70 and 2.38, respectively) was found for otitis media. Exposure to dichlorodiphenyldichloroethene resulted in a significantly higher odds ratio for asthma (odds ratio = 3.71; 95% confidence interval = 1.10, 12.56) and in immunoglobulin E concentrations above 200 kU/l (odds ratio = 2.28; 95% confidence interval = 1.20, 4.31). This is the first study in which dichlorodiphenyldichloroethene has been identified as a substantial risk factor for asthma and for increased immunoglobulin E blood levels.

Porphyrin status in aluminum foundry workers exposed to hexachlorobenzene and octachlorostyrene.

The possible interference of hexachlorobenzene and octachlorostyrene (i.e., thermal byproducts from hexachloroethane in aluminum degassing) with porphyrin metabolism was investigated in exposed workers. Urine specimens from 9 male aluminum foundry workers (i.e., smelters) at 6 different companies and from 18 controls-matched for sex, age, residence, and socioeconomic status-were analyzed for total porphyrins and porphyrin isomers. Workers exposed to hexachlorobenzene and octachlorostyrene had a statistically significant increase in urinary total porphyrins, compared with controls (mean +/- standard deviation: 13.63 +/- 11.13 micromol/mol creatinine and 6.24 +/- 3.84 micromol/mol creatinine, respectively; p = .02). The authors attributed the results mainly to differences in excretion of coproporphyrins-notably coproporphyrin III. Erythrocyte uroporphyrinogen decarboxylase activity was similar in both groups. There was a high correlation between levels of hexachlorobenzene and octachlorostyrene, respectively, in plasma and urinary excretion of porphyrins; these findings, however, relied heavily on 1 subject for whom extreme values were obtained. The results indicated that occupational exposure to hexachlorobenzene and octachlorostyrene in aluminum degassing with hexachloroethane may affect porphyrin metabolism in a manner consistent with early secondary coproporphyrinuria-the first recognized step in the development of chronic hepatic porphyria. It was also noted that changes remained detectable some years after exposure ceased.

Environmental exposure to hexachlorobenzene (HCB) and risk of female breast cancer in Connecticut.

Earlier studies have provided inconclusive results relating hexachlorobenzene (HCB), an organochlorine fungicide, to female breast cancer risk. The current study, with a total of 304 breast cancer cases and 186 controls recruited in Connecticut between 1994 and 1997, examined the association by directly comparing breast adipose tissue levels of HCB between incident breast cancer cases and noncancer controls. The cases and controls were patients who had breast biopsies or surgery at the Yale-New Haven Hospital (New Haven, CT) and histologically diagnosed either as breast cancer or benign breast disease. Information on major known or suspected risk factors for breast cancer was obtained through in-person interview by trained interviewers. No significant difference in mean breast adipose tissue levels of HCB was observed between breast cancer patients (21.0 ppb) and controls (19.1 ppb) in this large case-control study. The risk also did not vary significantly by menopausal status, estrogen or progesterone receptor status of the breast cancer cases, breast cancer histology, stage of diagnosis, or type of benign breast disease. Among parous women who reported ever breast feeding, an odds ratio (OR) of 0.5 [95% confidence interval (CI), 0.2-1.4] was observed when the highest quartile was compared with the lowest quartile. However, no association was observed among parous women who reported never breast feeding (OR = 0.7; 95% CI, 0.3-1.7 for the fourth quartile). For nulliparous women, the adjusted OR was 2.1 (95% CI, 0.5-8.8) for the third tertile when compared with the lowest based on few subjects. Therefore, our study does not support a positive association between environmental exposure to HCB and risk of breast cancer.

Health effects of chronic high exposure to hexachlorobenzene in a general population sample.

Hexachlorobenzene, an organochlorine compound that accumulates in humans, is widespread throughout the environment. In this study, we describe the health status of inhabitants of a rural village that surrounds an electrochemical factory characterized by high levels of hexachlorobenzene in the air. During 1994, we conducted a cross-sectional study of 1 800 inhabitants in the south of Catalonia, Spain, who were older than 14 y of age. We obtained information on lifestyles and occupational and medical histories via questionnaire. Self-reported health outcomes were validated against clinical records and cancer registry data. Serum levels of hexachlorobenzene were very high in males who worked in the electrochemical factory (geometric mean = 54.6 ng/ml in randomized participants). Levels were lower among subjects who had never worked in the electrochemical factory (females, 14.9 ng/ml; males, 9.0 ng/ml). Levels of other organochlorine compounds (i.e., beta-hexachlorocy-clohexane, 2,2-bis[p-chlorophenyl]-1,1-dichloroethylene) were in the same range found in other communities. Perceived health, prevalence of self-reported common chronic conditions, and porphyria cutanea tarda, thyroid pathology, Parkinson's disease, cancer, and reproductive outcomes were within the ranges observed in other studies. Employment in the plant, however, was associated with having any of the a priori selected health outcomes that were potentially related to exposure to hexachlorobenzene (odds ratio for cancer prevalence = 1.9; 95% confidence interval = 0.5, 7.6). Our population of workers and nonworkers had the highest levels of hexachlorobenzene ever described. The results suggest that exposure to hexachlorobenzene did not affect the general health status of the this population, but it was associated with specific health effects of the most highly exposed subjects.

Case-control study on breast cancer and adipose tissue concentrations of congener specific polychlorinated biphenyls, DDE and hexachlorobenzene.

In a case-control study on 43 patients operated for invasive breast cancer (cases) and 35 patients operated for benign breast disease (controls) adipose tissue concentrations of polychlorinated biphenyls (PCBs), 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) and hexachlorobenzene (HCB) were investigated. Approximately 10 g of breast tissue free from tumour was taken and frozen until analysis. No significant difference for the sum of non co-planar PCBs or DDE was found between cases and controls. For postmenopausal women the odds ratio (OR) was increased for co-planar PCB #77 > 4.5 pg/g lipid (OR = 5.8, 95% confidence interval (CI) = 0.8-42), PCB #126 > 145 pg/g lipid (OR = 2.2, 95% CI = 0.2-18), PCB #169 > 90 pg/g lipid (OR = 7.8, 95% CI = 0.6-96), and for HCB > 40 ng/g lipid (OR = 1.9, 95% CI = 0.4-7.2) adjusted for age and parity. The risk increased further for postmenopausal women with oestrogen receptor positive tumours yielding for PCB #77 adjusted OR 33 (95% CI 1.8-588), PCB #126 OR not calculable (no unexposed cases), PCB #169 OR 8.6 (95% CI 0.5-136) and hexachlorobenzene OR 7.1 (95% CI 1.1-45). Also for the sum of PCB > 1230 ng/g lipid adjusted OR increased to 1.8 (95% CI 0.4-7.3) whereas the results were similar for DDE.

Experimental porphyria cutanea tarda and photosensitivity

FUNDAMENTOS - A porfiria cutânea tardia é uma doença metabólica da via porfirina-heme, resultante da deficiência da enzina uroporfirinogênio descarboxilase, que induz ao acúmulo de porfirinas, principalmente no fígado e na pele, responsáveis por lesöes cutâneas em áreas expostas ao sol. OBJETIVOS - Determinar a espécie animal que melhor corresponda ao modelo experimental da PCT, para o estudo de lesöes cutâneas relacionadas à fotossensibilidade. MÉTODO - Ratos, cobaias e camundongos foram submetidos a uma dieta contendo um dos fatores desencadeantes da PCT, o hexaclorobenzeno (HCB), na concentraçäo de 0,25 porcento. Após o surgimento da PCT, os animais foram expostos à radiaçäo ultravioleta, as porfirinas uninárias dosadas e as manifestaçöes cutâneas de fotossensibilidade anotadas, e, comparadas ao grupo controle. RESULTADOS - Somente os ratos apresentaram aumento da excreçäo de porfirinas urinárias, principalmente de uroporfirinas: 60,81ug/24h, comparados aos controles: 0,9ug/24h, neurotoxicidade e lesöes cutâneas em àreas fotoexpostas. CONCLUSÄO - Considerando-se as três espécies de animais estudadas, os ratos apresentaram quadro semelhante à PCT encontrada no homem. Em relaçäo às cobaias, sugere-se administrar dieta contendo menor concentraçäo de HCB e prolongar o tempo do experimento. Os camundongos näo se adequaram ao modelo experimental

Efectos de la intoxicación con haxaclorobenceno sobre la descarboxilación enzimatica de porfirinogenos hexa y penta-carboxilicos / Efects of the hexachlorobenzene intoxication over the enzimatic decarboxylation of the porphyrinogen hexa and penta carboxilase

La uroporfirinógeno decarboxilasa (URO-D) (porfinógeno carboxilasa E.C. 4.1.1.37) cataliza la descarboxilación del uroporfirinógeno lll a coproporfirinógeno lll. Este proceso tiene lugar a través de un camino preferencial en el senmtido de las agujas del reloj sobre la estructura del uroporfirinógeno lll (tanto en condiciones normales como patológicos). En mamíferos, la porfiria inducida por hexaclorobenceno (HCB), semejante a la porfiria cutánea tarda humana, esta asociada con daño hepático. Estos animales presentan disminución de URO-D hepática que coincide con la acumulación de porfirinas. Se utilizó como fuente de URO-D hígados de ratas de URO-D hígados de ratas Wistar hembras (150-180g) que recibieron diariamente HCB (1g/kg peso) por sonda gástrica (HCB) o no (N). Se estudió la descarboxilación de los porfirinógenos, ácidos carboxílicos libres, de las porfirinas sintetizadas en nuestro laboratorio, 1,3,8 trimetil-2,4,6,7- tetra-(2-metoxicarboniletil)-5-metoxi-carbonilmetil porfirina (pentageno abd) la 1,8-dimetil-2,4,6,7- tetra-(2-metoxicarboniletil)- porfirina (hexageno ad) por URO-D de hígados N y HCB en función de la concentración de ambos sustratos. El hexageno ad resultó el mejor sustrato por el criterio de Vmax/Km (Vmax/Km x 10 al cubo; hexageno ad (N): 560; (HCB): 37.5 y pentageno adb (N): 44.9; (HCB): 2.3). Experimentos con mezclas de hexageno ad y pentageno abd (a concentraciones totales finales de 1 a 2.5 uM y relaciones de hexageno ad: pentageno abd de 1:1 a 4:1 con URO-D (N) y (HCB) presentaron iguales proporciones de transformación de ambos porfirinógenos. Ni la concentración inicial ni las relaciones molares de ambos porfirinógenos en las mezclas, mostraron tener importancia en estos resultados, pese a los diferentes parámetros cinéticos encontrados cuando los porfirinógenos fueron sustratos únicos. Estos resultados indican que la presencia de ambos sustratos inducirían un reordenamiento conformacional en la URO-D que conduciría a iguales proporciones de descarboxilación de ambos porfirinógenos. El pentageno proveniente de la descarboxilación del hexageno permacería preferentemente unido a la estructura enzimática para mayor descarboxilación antes que ser liberado al medio

Modelo experimental de Porfiria Cutánea Tarda inducido por hexaclorobenceno en ratones Hairless / Experimental model of Porphyria Cutaneous Tarda by hexaclorobenceno in Hairless mice

En este trabajo se describe el efecto del HcB en ratones de la cepa hairless a fin de obtener un modelo experimental de PCT, lo que facilitaría el estudio de la fotosensibilización cutánea característica de la enfermedad y el ensayo de cremas dermatológicas. El HCB es un hidrocarburo polihalogenado que ha sido utilizado con éxito en ratones de las cepas Balb/C y C57BL. Los animales recibieron una única dosis de 200 mg HCB/Kg (vía i.p.). Dentro de los controles, un grupo no recibió ningún tratamiento y otro solo el pretratamiento con hierro. A distintos tiempos luego de comenzada la intoxicación, los animales fueron sacrificados y se determinó la relación porcentual peso hígado/peso corporal, se extrajeron y cuantificarón las porfirinas de piel, hígado, orina yheces; y se midió la actividad de la enzima Uro-D hepáica. Además se midieron los niveles de Cit-450 y LPO hepáticos y la concentración de glutation en hígado y piel, como indicadores del grado de intoxicación. Se observó en ambos sexos, un aumento del 40 por ciento en la relación porcentual peso hígado/ peso corporal tanto en los grupos intoxicados como en los control hierro. En hembras, los niveles de porfirinas aumentaron tanto en hígado como en piel, dicho aumento ocurrió luego de un descenso en los niveles de glutation. En cambio en machos , los niveles de prfirinas solo aumentarom en piel, registrándose una aumento en los niveles de glutation en ambos tejidos.