Human exposure to mercury and its hematological effects: a systematic review / Exposição humana ao mercúrio e seus efeitos hematológicos: uma revisão sistemática / Exposición humana al mercurio y sus efectos hematológicos: una revisión sistemática

Mercury is a metal found in the environment from natural and anthropogenic sources. It is highly toxic to ecosystems and living beings. Most human exposures come from ingestion of contaminated seafood, outgassing from dental amalgam or occupational exposure (e.g. gold mining), among other cases. Large populations are exposed to mercury, making it a very important issue from the public health perspective. Adverse health effects are commonly seen in the nervous system, but every organ is a potential target, such as the bone marrow. The main goal of this study was to assess the available evidence on human exposure to mercury and its hematological effects. A search strategy was constructed, including key terms (MeSH, text word and equivalents) for querying 2 repositories of master dissertation and PhD thesis (Fiocruz/ARCA and University of São Paulo) and 4 different electronic databases: BVS/LILACS, MEDLINE/PubMed, Scopus and TOXLINE/NIH, for articles published from 1950 to February 2018. There was no language restriction and a tool (EPHPP) was used to assess the quality of included studies. According to pre-established criteria, 80 studies were retrieved, all of them observational (48 case reports, 24 cross-sectional, 6 case series and 2 cohorts), comprising 9,284 people. Despite the fact that most exposed ones (6,012) had normal blood cell count and mercury hematological effects did not seem very usual (1,914 cases: 14 severe and 29 deaths), three studies reported association (β) for anemia, lymphopenia, neutrophilia and basophilia. We concluded that the gathered information pointed to mercury hematotoxic effects, some of them may be serious and even fatal.

O mercúrio é um metal que pode ser encontrado naturalmente no meio ambiente e através de fontes antropogênicas. É altamente tóxico para ecossistemas e seres vivos. A maior parte da exposição humana provém da ingestão de pescados contaminados, da liberação de gases da amálgama dentária ou da exposição ocupacional (p.ex.: extração de ouro). Vastas populações são expostas ao mercúrio, tornando-se uma questão de saúde pública muito importante. Efeitos adversos à saúde são comumente observados no sistema nervoso, mas todos os órgãos são alvos em potencial, como a medula óssea. O principal objetivo do estudo foi avaliar as evidências disponíveis sobre a exposição humana ao mercúrio e seus efeitos hematológicos. Uma estratégia de busca foi realizada, incluindo termos chave (palavras-chave, palavras do texto e equivalentes), para pesquisar dois repositórios de dissertações de mestrado e teses de doutorado (Fiocruz/ARCA e Universidade de São Paulo) e quatro bases de dados eletrônicas: BVS/LILACS, MEDLINE/PubMed, Scopus e TOXLINE/NIH (artigos publicados de 1950 até fevereiro de 2018). Não houve restrições de linguagem e uma ferramenta (EPHPP) foi utilizada para avaliar a qualidade dos estudos incluídos. De acordo com os critérios pré-estabelecidos, foram encontrados 80 estudos, todos observacionais (48 relatos de caso, 24 estudos transversais, 6 séries de casos e 2 coortes), que compreendiam 9.284 pessoas. Apesar do fato de que as pessoas mais expostas (6.012) tinham contagens de células sanguíneas normais, e os efeitos hematológicos do mercúrio não pareciam muito comuns (1.914 casos, 14 graves e 29 mortes), três estudos relataram a associação de (β) anemia, linfopenia, neutrofilia e basofilia. Concluímos que as informações coletadas indicam efeitos hematotóxicos do mercúrio, alguns dos quais podem ser muito graves e até fatais.

El mercurio es un metal que se puede encontrar de forma natural en el ambiente y mediante fuentes antropogénicas. Es altamente tóxico para los ecosistemas y seres vivos. Entre otras, la mayor parte de la exposición humana, proviene de la ingestión de pescado contaminado, liberación de gases de amalgamas dentales o exposición ocupacional (p.ej. extracción de oro). Vastas poblaciones están expuestas al mercurio, convirtiéndolo en un asunto muy importante desde la perspectiva de la salud pública. Los efectos adversos para la salud se observan comúnmente en el sistema nervioso, pero cada órgano es un objetivo potencial, como la médula ósea. El objetivo principal del estudio fue evaluar las evidencias disponibles sobre la exposición humana al mercurio y sus efectos hematológicos. Se realizó una estrategia de búsqueda, incluyendo términos clave (palabras-clave, palabras del texto y equivalentes), se consultaron 2 registros de trabajos finales de máster y tesis de doctorado (Fiocruz/ARCA y Universidad de São Paulo) y 4 bases de datos electrónicas diferentes: BVS/LILACS, MEDLINE/PubMed, Scopus y TOXLINE/NIH, para artículos publicados desde el año 1950, hasta febrero de 2018. No hubo restricciones de lengua y se usó la herramienta (EPHPP) para evaluar la calidad de los estudios incluidos. De acuerdo con los criterios preestablecidos, se recopilaron 80 estudios, todos observacionales (48 informes de casos, 24 estudios transversales, 6 series de casos, y 2 cohortes), que comprendieron a 9.284 personas. A pesar de que la mayoría de los expuestos (6.012) tenían un recuento normal de células sanguíneas y los efectos hematológicos del mercurio no parecían muy comunes (1.914 casos: 14 severos y 29 muertes), tres estudios informaron de la asociación (β) para anemia, linfopenia, neutrofilia y basofilia. Concluimos que la información recabada indicaba los efectos hematotóxicos del mercurio, algunos de los cuales pueden ser muy serios e incluso fatales.

Environmental exposure to benzene: evaluation of urinary S-PMmorphism (CYP2E1-129A and poly3G>C and NQO1 609C> T) in Campos Elíseos residents, Duque de Caxias, Rio de Janeiro State, Brazil / Exposição ambiental ao benzeno: avaliação do S-PMA urinário e de polimorfismos (CYP2E1-1293G>C e NQO1 609C> T) em residentes de Campos Elíseos, Duque de Caxias, Rio de Janeiro, Brasil / Exposición ambiental al benceno: análisis del S-PMA en la orina y polimorfismo (CYP2E1-1293G>C y NQO1 609C> T) en residentes de Campos Elíseos, Duque de Caxias, Río de Janeiro, Brasil

Benzene is one of the most important substances for assessment, due to its significant use, the environmental contamination resulting from its emission and the effects on human health. It is classified by the International Agency for Research on Cancer (IARC) as a known carcinogen to humans (group 1) and associated with the development of leukemia. In general, the population is exposed to this substance by inhaling contaminated air, which varies according to the location and intensity of its potential sources. The petrochemical industry is one of the most important sources of this compound. The municipality of Duque de Caxias, specifically the Campos Elíseos district, in Rio de Janeiro State, Brazil, houses the Industrial Complex of Campos Elíseos (PICE), a grouping of over 25 industries, which includes the second largest oil refinery in Brazil. Environmental contamination from the PICE has been recognized, but there is a lack of studies concerning its impact on the health of the surrounding population. S-phenylmercapturic acid (S-PMA) concentrations ranging from 0.80 to 8.01μg.g-1 creatinine were observed in the local population, apparently related to hematological changes also observed in exposed population. The quantifiable presence of urinary S-PMA from the benzene metabolism is associated with the fact that 60% of the participants present specific hematological changes, which may be due to the environmental benzene exposure. The allele and genotype frequencies of the CYP2E1 and NQO1 enzymes observed in the study population were similar to those reported in other studies. The presence of the variant allele in the NQO1 genotype may be a risk factor for the observed hematological changes.

O benzeno é uma das substâncias mais importantes para a biomonitorização, em função do uso disseminado, da contaminação ambiental que resulta da emissão e dos efeitos sobre a saúde humana. O benzeno é classificado pela Agência Internacional de Pesquisa em Câncer (IARC) como carcinógeno conhecido em seres humanos (grupo 1) e está associado ao desenvolvimento de leucemias. Em geral, a população fica exposta a essa substância através da inalação do ar contaminado, que varia de acordo com a localização e a intensidade das fontes potenciais. A indústria petroquímica é uma das fontes mais importantes desse composto. O Município de Duque de Caxias, especificamente o Distrito de Campos Elíseos, no Estado do Rio de Janeiro, Brasil, é sede do Polo Industrial de Campos Elíseos (PICE), um conjunto de mais de 25 indústrias que inclui a segunda maior refinaria de petróleo no Brasil. A contaminação ambiental produzida pelo PICE já é conhecida, mas faltam estudos sobre o impacto na saúde da população local. Foram observadas concentrações de ácido S-fenilmercaptúrico (S-PMA) entre 0,80 e 8,01μg.g-1 creatinina na população local, aparentemente implicadas nas alterações hematológicas também observadas na população exposta. A presença quantificável do S-PMA urinário do metabolismo do benzeno está associada ao fato de 60% dos participantes apresentarem alterações hematológicas específicas, o que pode ser devido à exposição ambiental ao benzeno. As frequências alélicas e genotípicas das enzimas CYP2E1 e NQO1, observadas na população do estudo, foram semelhantes àquelas relatadas em outros estudos. A presença da variante alélica do genótipo NQO1 pode ser um fator de risco para as alterações hematológicas observadas.

El benceno es una de las sustancias más importantes susceptibles de estudio, debido a su uso significativo, la contaminación ambiental resultante de sus emisiones y sus efectos sobre la salud humana. Está clasificado por el Centro Internacional de Investigaciones sobre el Cáncer (IARC) como un conocido carcinógeno para los humanos (grupo 1) y está asociado con el desarrollo de leucemias. En general, la población está expuesta a esta sustancia por inhalación de aire contaminado, que varía según el lugar y la intensidad de las emisiones. La industria petroquímica es un de las fuentes emisoras más importantes de este compuesto. La municipalidad de Duque de Caxias, específicamente el distrito de Campos Elíseos, en Río de Janeiro, Brasil, alberga el Complejo Industrial de Campos Elíseos (PICE), un conglomerado de más de 25 industrias, que incluye la segunda mayor refinería de petróleo en Brasil. La contaminación ambiental procedente del PICE ya ha sido reconocida, pero es notable la falta de estudios respecto a su impacto en la salud de la población circundante. Se observaron en la población local concentraciones de ácido s-fenilmercaptúrico (SPMA por sus siglas en inglés) que oscilan entre los 0,80 a 8,01μg.g-1 creatinina, aparentemente relacionadas con cambios hematológicos también hallados en la población expuesta. La presencia cuantificable de SPMA en la orina, procedente del metabolismo del benceno, está asociada con el hecho de que un 60% de los participantes presenta cambios específicos hematológicos, los cuales tal vez se deben a la exposición ambiental al benceno. Las frecuencias alélicas y genotípicas del CYP2E1 y enzimas NQO1 observadas en el estudio fueron similares a las reportadas en otros estudios. La presencia de la variante alélica en el genotipo NQO1 podría ser un factor de riesgo para los cambios hematológicos observados.

Association between IPTA Gene Polymorphisms and Hematological Abnormalities in Hepatitis C Virus-Infected Patients Receiving Combination Therapy

BACKGROUND/AIMS: Hematological abnormalities during hepatitis C virus (HCV) combination therapy with pegylated interferon alpha and ribavirin often necessitate dose reduction. Variants of the ITPA gene have been reported to protect against anemia during the early stages of HCV combination treatments but have also been associated with larger decreases in platelet counts. We aimed to identify the association between specific ITPA gene polymorphisms and hematological abnormalities in patients undergoing HCV combination therapy. METHODS: In this retrospective study, 175 patients treated with HCV combination therapy were enrolled at St. Martin De Porres Hospital in Taiwan between 2006 and 2012. Two single nucleotide polymorphisms (SNP) within or adjacent to the ITPA gene (rs1127354, rs6051702) were genotyped. We investigated the effect of ITPA gene variants on hematological abnormalities during the therapy. RESULTS: The ITPA rs1127354 minor variants were significantly associated with protection against anemia at week 4 (p=1.86 x 10(-6)) and with more severe decreases in platelet counts during HCV combination therapy. SNP rs6051702 was not associated with the hemoglobin decline to >3 g/dL at week 4 in our study (p=0.055). CONCLUSIONS: The ITPA SNP rs1127354 is a useful predictor of ribavirin-induced anemia in Taiwanese patients and may be related to more severe decreases in platelet counts during the early stage of HCV combination therapy.

Association between IPTA Gene Polymorphisms and Hematological Abnormalities in Hepatitis C Virus-Infected Patients Receiving Combination Therapy

BACKGROUND/AIMS: Hematological abnormalities during hepatitis C virus (HCV) combination therapy with pegylated interferon alpha and ribavirin often necessitate dose reduction. Variants of the ITPA gene have been reported to protect against anemia during the early stages of HCV combination treatments but have also been associated with larger decreases in platelet counts. We aimed to identify the association between specific ITPA gene polymorphisms and hematological abnormalities in patients undergoing HCV combination therapy. METHODS: In this retrospective study, 175 patients treated with HCV combination therapy were enrolled at St. Martin De Porres Hospital in Taiwan between 2006 and 2012. Two single nucleotide polymorphisms (SNP) within or adjacent to the ITPA gene (rs1127354, rs6051702) were genotyped. We investigated the effect of ITPA gene variants on hematological abnormalities during the therapy. RESULTS: The ITPA rs1127354 minor variants were significantly associated with protection against anemia at week 4 (p=1.86 x 10(-6)) and with more severe decreases in platelet counts during HCV combination therapy. SNP rs6051702 was not associated with the hemoglobin decline to >3 g/dL at week 4 in our study (p=0.055). CONCLUSIONS: The ITPA SNP rs1127354 is a useful predictor of ribavirin-induced anemia in Taiwanese patients and may be related to more severe decreases in platelet counts during the early stage of HCV combination therapy.

Adverse drug reactions associated with the use of disease-modifying anti-rheumatic drugs in patients with rheumatoid arthritis / Reacciones adversas a medicamentos asociadas con el uso de fármacos antirreumáticos modificadores de la enfermedad en pacientes con artritis reumatoide

This study describes the adverse drug reactions (ADRs) and their incidence in patients with rheumatoid arthritis who were treated in the Colombian health system. A retrospective cohort study was conducted using information from all patients who were diagnosed with rheumatoid arthritis and attended specialized health care centers in the cities of Bogotá, Cali, Manizales, Medellin, and Pereira between 1 December 2009 and 30 August 2013. The ADRs were obtained from medical records and the pharmacovigilance system registry and sorted by frequency and affected tissue according to World Health Organization Adverse Reaction Terminology (WHO-ART). A total of 949 reports of ADRs were obtained from 419 patients (32.8 ADRs per 100 patient-years); these patients were from a cohort of 1 364 patients being treated for rheumatoid arthritis and followed up for an average of 23.8 months (± 12.9). The cohort was mostly female (366, 87.4%) and had a mean age of 52.7 years (± 13.1). The highest numbers of ADRs were reported following the use of tocilizumab, rituximab, and infliximab (28.8, 23.1, and 13.3 reports per 100 patient-years respectively). The most frequently reported ADRs were elevated transaminase levels and dyspepsia. Overall, 87.7% of ADRs were classified as type A, 36.6% as mild, 40.7% as moderate, and 22.7% as severe. As a result, 73.2% of patients who experienced an ADR stopped taking their drugs. The occurrence of ADRs in patients treated for rheumatoid arthritis is common, especially in those associated with the use of biotechnologically produced anti-rheumatic drugs. This outcome should be studied in future research and monitoring is needed to reduce the risks in these patients.

Este estudio describe las reacciones adversas a medicamentos (RAM) y su incidencia en pacientes con artritis reumatoide y tratados en el sistema de salud colombiano. Se llevó a cabo un estudio retrospectivo de cohortes utilizando la información correspondiente a todos los pacientes con diagnóstico de artritis reumatoide que acudieron a centros especializados de atención de salud de las ciudades de Bogotá, Cali, Manizales, Medellín y Pereira entre el 1 de diciembre del 2009 y el 30 de agosto del 2013. Los casos de RAM se obtuvieron de las historias clínicas y del registro del sistema de farmacovigilancia, y se clasificaron por su frecuencia y el tejido afectado, según la Terminología de Reacciones Adversas de la Organización Mundial de la Salud ­ (WHO-ART). Se obtuvo un total de 949 informes de RAM en 419 pacientes (32,8 RAM por 100 pacientes-año); estos pacientes correspondían a una cohorte de 1 364 pacientes tratados por artritis reumatoide y seguidos durante un promedio de 23,8 meses (± 12,9). La cohorte estaba compuesta principalmente por mujeres (366, 87,4%) y la media de edad era de 52,7 años (± 13,1). El mayor número de casos de RAM se notificó tras el uso de tocilizumab, rituximab e infliximab (28,8, 23,1 y 13,3 notificaciones por 100 pacientes-año, respectivamente). Las RAM notificadas con mayor frecuencia fueron la elevación de los niveles de transaminasas y la dispepsia. En términos generales, 87,7% de las RAM se clasificaron como de tipo A, 36,6% como leves, 40,7% como moderadas y 22,7% como graves. Como consecuencia, 73,2% de los pacientes que presentaron una RAM dejaron de tomar sus medicamentos. La aparición de RAM en pacientes tratados por artritis reumatoide es frecuente, especialmente cuando se utilizan fármacos antirreumáticos de producción biotecnológica. Estos resultados deben ser objeto de estudio en futuras investigaciones y señalan la necesidad de actividades de vigilancia para reducir los riesgos en estos pacientes.

Compensation for Work-Related Hematologic, Liver, and Infectious Diseases

Occupational diseases may be defined only medically or scientifically, and even then, their definition is not simple. However, compensable occupational diseases involve the additional layer of legal systems and social welfare policies as well. Their multifaceted nature makes determining the work-relatedness of these diseases more complex. Korea has established standards for the recognition of occupational diseases in Schedule 5 of the Enforcement Decree of the Labor Standards Act, and specific criteria for the recognition of occupational diseases are listed in Schedule 3 of the Enforcement Decree of the Industrial Accident Compensation Insurance Act. The new list of compensable occupational diseases comprises 13 articles as an open-ended system. The newly added articles pertain to lymphohematopoietic (Article 5) and infectious diseases (Article 9), as well as diseases of other target organs. Furthermore, the article on liver diseases (Article 8) has been partially revised. The new act has been changed to clarify the meaning as it has been presented in recent research. It is necessary to achieve agreement among concerned parties, including experts from the legal, medical, and social domains to resolve the issues of work-relatedness, causation, notion of aggravation, and so on for preparing a list and a process that are more reasonable.

Experiencia clínica con el antipsicótico clozapina en niños y adolescentes menores de 18 años en Chile / Clinical experience in Chile with clozapine in child and adolescents under 18 years

Objective: Increase in severe psychopathology in adolescents who are resistant to common treatment creates a need to search new alternatives in pharmacological treatment. Background: To describe a sample 47 child and adolescent patients treated with clozapine between 1985 and 2010, indicating: age, gender, diagnoses, hospitalization, electroconvulsive therapy, dosing, adverse effects specially hematological ones. Methods: 47patients between the ages of 10 and 18 were treated with clozapine. Review of clinical charts, protocol investigation and Excel statistic analysis. Results: The sample consisted in: male: 40 percent, female: 60 percent, the youngest was 10 and the oldest 17years and 11 months old; the most frequent age was 15 years. The mean number of hospitalization was 1.5. Diagnosis Axis I,DSM IV: Affective disorders 64 percent, Schizophreniform disorder 23 percent. Electroconvulsive Therapy: 57 percent. Treatment indications: irreducible psychosis 23 percent, suicidability: 33 percent. Average dosing 200 mg. Adverse effects: sedation: 76 percent, hypersalivation: 68 percent, increase in weight: 66 percent. Neutropenia: not severe (more than 2000/ mm³): 17 percent; severe 1:15 percent, severe II: 2 percent, severe III: 2 percent. Conclusions: Clozapine appears as an effective drug, with moderate but frequent adverse effects. Hematologic adverse effects where transient; only one in 47 patients presented a severe neutropenia and require cancellation of treatment, which was reinstalled after three month without mayor side effects. There is a need for control studies with larger population and a longer period of time.

Introducción: El aumento de psicopatología severa en la clínica infanto-juvenil y la resistencia a los tratamientos habituales, lleva a los clínicos buscar nuevas alternativas farmacológicas. Surge entonces la clozapina como una alternativa útil, avalada por la literatura para tratamiento de estas patologías. Objetivos: Describir una muestra de 47 pacientes niños y adolescentes entre 10 y 18 años tratados con clozapina entre los años 1985 y 2010. Se indican: variables demográficas, diagnósticos, hospitalizaciones, dosis y efectos adversos, especialmente los hematológicos. Material y Método: Estudio descriptivo, retrospectivo consistente en revisión de fichas clínicas, protocolo de investigación y análisis estadístico con plantilla Excel. Resultados: Muestra de 47 pacientes; 40 por ciento hombres, 60 por ciento mujeres, el menor de 10 años y el mayor de 17 años y 11 meses; la edad más frecuente fue de 15 años. El 80 por ciento presentó al menos una hospitalización. Diagnósticos agrupados: Trastornos a predominio afectivo el 64 por ciento, Trastornos esquizomorfo el 23 por ciento y Trastornos a predominio del descontrol de los impulsos y agresión 9 por ciento. Un 57 por ciento recibió TEC. Causa de indicación: psicosis irreductible 36 por ciento, suicidalidad alta 33 por ciento, conducta heteroagrsiva 25 por ciento, efectos laterales con otros fármacos 23 por ciento. La dosis promedio de mantención fue de 200 mg. Los efectos adversos más frecuentes fueron: sedación 76 por ciento, salivación 68 por ciento, alza peso 66 por ciento. Baja inespecífica de neutrófilos: 17 por ciento, alarma 1:15 por ciento, alarma II: 2 por ciento, alarma III: 2 por ciento. Discusión: Clozapina aparece como fármaco útil, con efectos adversos frecuentes, pero en nuestra muestra fueron graves no y transitorios. Hubo un caso con alarma III que requirió de suspensión, pero se reinstaló 3 meses después; sin reincidir, ni presentar otros efectos adversos de gravedad...

Alteraciones hematológicas en trabajadores expuestos ocupacionalmente a mezcla de benceno- tolueno-xileno (BTX) en una fábrica de pinturas / Blood disorders among workers exposed to a mixture of benzene-toluene-xylene (BTX) in a paint factory

Objetivos. Evaluar las tres series celulares sanguíneas e identificar la presencia de hipocromía, macrocitosis, leucopenia, linfocitopenia y trombocitopenia en un grupo de trabajadores expuestos a la mezcla de benceno-tolueno-xileno (BTX). Materiales y métodos. Estudio transversal donde se incluyó a 97 trabajadores de una empresa de pinturas de México a los que se les realizó una biometría hemática convencional y les fue estimada la exposición a través de la dosis diaria potencial acumulada para vapores de BTX. Resultados. Del total de trabajadores, 19,6%, mostró macrocitosis, 18,6%, linfocitopenia, 10,3% hipocromía, 7,2% trombocitopenia y 5,2% leucopenia. La asociación cruda de macrocitosis con exposición a dosis alta de mezcla de BTX fue la única significativa (OR:3,6; IC95%: 1,08 - 13,9; p=0,02) y en la que se estructuró un modelo de regresión logística (OR:6,7; IC95%: 1,33 - 13,55; p:0,02) ajustada por edad, consumo de alcohol y tabaquismo. Conclusiones. Todos los componentes citohemáticos analizados mostraron cambios leves; que podrían estar asociados con la exposición a la mezcla de BTX. De ellos, la macrocitosis podría constituirse en una manifestación precoz que merece ser vigilada.

Objectives. Evaluate the three blood cell series and identify the presence of hypochromia, macrocytosis, leucopenia, lymphopenia, and thrombocytopenia in a group of workers exposed to the mixture of benzene-toluene-xylene (BTX). Materials and methods. A cross-sectional study which included 97 workers from a paint factory in Mexico. The participants underwent conventional blood count and tests for potential cumulative daily dose of BTX fumes, to estimate exposure. Results. From the total of workers, 19.6% showed macrocytosis, 18.6%, lymphopenia, hypochromia 10.3%, 7.2% and 5.2% thrombocytopenia leukopenia. The crude association of macrocytosis with exposure to high doses of BTX mixture was the only with statistical significance (OR: 3.6, 95% CI 1.08 to 13.9, P = 0.02), and the base for a logistic regression model (OR: 6.7, 95% CI 1.33 to 13.55, P = 0.02) adjusted for age, alcohol consumption, and smoking. Conclusions. All blood cytological components analyzed demonstrated mild changes, potentially associated with exposure to the mixture of BTX. Macrocytosis could constitute an early manifestation worthy for surveillance.

Polymorphisms in genes involved in innate immunity and susceptibility to benzene-induced hematotoxicity

Benzene, a recognized hematotoxicant and carcinogen, can damage the human immune system. We studied the association between single nucleotide polymorphisms (SNPs) in genes involved in innate immunity and benzene hematotoxicity in a cross-sectional study of workers exposed to benzene (250 workers and 140 controls). A total of 1,236 tag SNPs in 149 gene regions of six pathways were included in the analysis. Six gene regions were significant for their association with white blood cell (WBC) counts (MBP, VCAM1, ALOX5, MPO, RAC2, and CRP) based on gene-region (P < 0.05) and SNP analyses (FDR < 0.05). VCAM1 rs3176867, ALOX5 rs7099684, and MPO rs2071409 were the three most significant SNPs. They showed similar effects on WBC subtypes, especially granulocytes, lymphocytes, and monocytes. A 3-SNP block in ALOXE3 (rs7215658, rs9892383, and rs3027208) showed a global association (omnibus P = 0.0008) with WBCs even though the three SNPs were not significant individually. Our study suggests that polymorphisms in innate immunity genes may play a role in benzene-induced hematotoxicity; however, independent replication is necessary.

Tratamiento neoadyuvante del cáncer de mama localmente avanzado: comparación de dos esquemas a base de docetaxel-epirrubicina versus 5-fluoraciloepirrubicina-ciclofosfamida / Neoadjuvant treatment for locally advanced breast cancer: comparison of two schemes based on docetaxel-epirubicin vs. 5-fluorouracil-epirubicin-cyclophosphamide

BACKGROUND: Breast cancer is the most common type of cancer in women worldwide. In Mexico, >34% of patients are in locally advanced stages at the time of diagnosis. Neoadjuvant chemotherapy is administered to control local disease, make surgical resection possible and increase the possibility of breast tissue conservation. METHODS: We performed a double-blind, randomized clinical trial in patients with locally advanced breast cancer (stages IIB and IIIA) with two therapy schemes; 5-fluorouracil-epirubicin-cyclophosphamide (control group) vs. docetaxel-epirubicin (study group). Both were indicated in three preoperative cycles, and patients were submitted afterwards to surgery. Pathological response was measured. RESULTS: Forty one patients were included in our study. They were distributed in two homogeneous groups: 21 in the control group and 20 in the study group. Dimensional pathological response was higher in the study group than in the control one (p <0.05). Five patients in the control group and ten patients of the study group experienced complete pathological response (p <0.05). The most common secondary events were leucopenia, neutropenia and fever. Morbidity, number of lymph nodes, disease-free survival and general survival did not show significant differences between groups. No mortality was reported during a minimum follow-up of 28 months. CONCLUSIONS: Our results confirm the effectiveness of docetaxel-epirubicin to obtain complete pathological response. Neoadjuvant therapy has been shown to increase the pathological response when a taxane is added to an anthracycline. This combination presented more secondary events, but they can be effectively managed medically. Neoadjuvant docetaxel-epirubicin followed by surgery is an appropriate regimen for patients with locally advanced breast cancer.

A comparative study on hematological effects of carboplatin plus cyclophosphamide and carboplatin plus paclitaxel chemotherapy for the first line treatment of epithelial ovarian cancer.

OBJECTIVE: To compare the hematological effects of carboplatin plus cyclophosphamide, and carboplatin plus paclitaxel chemotherapy for first line treatment of epithelial ovarian cancer (EOC). MATERIAL AND METHOD: A retrospective study was conducted between January 2003 and May 2006 on 29 patients who received 145 cycles of carboplatin, area under the curve (AUC) 6 plus cyclophosphamide 600 mg/mm2 (CC) intravenous and on 11 patients who received 65 cycles of carboplatin AUC 5 plus paclitaxel 175 mg/mm2 (CP) intravenous chemotherapy for the first line treatment of epithelial ovarian cancer. They had no history of hematologic disease and complete blood count (CBC), renal function and liver function tests were normal. RESULTS: Both groups were similar regarding age, body mass index, performance status and stage of cancer. Hematological effects were found in 61 of 145 cycles (42.1%) in CC group and 33 of 65 cycles (50.8%) in CP group (p = 0.05). Twenty patients received all 6 cycles of chemotherapy in the CC group and 10 patients in the CP group. Fifteen of 20 patients (75%) and 8 of 10 patients (80%) had hematologic effect of at least one cycle found in the CC and the CP groups, respectively (p = 0.05). There were no treatment-related deaths in both arms. CONCLUSION: Hematological effects did not differ in carboplatin AUC 6 plus cyclophosphamide 600 mg/mm2 regimen and carboplatin AUC 5 plus paclitaxel 175 mg/mm2 regimen and both regimens were accepted adverse effect in the first line treatment of EOC.

Biochemical toxicity of benzene.

Human exposure to benzene in work environment is a global occupational health problem. After inhalation or absorption, benzene targets organs viz. liver, kidney, lung, heart and brain etc. It is metabolized mainly in the liver by cytochrome P450 multifunctional oxygenase system. Benzene causes haematotoxicity through its phenolic metabolites that act in concert to produce DNA strand breaks, chromosomal damage, sister chromatid exchange, inhibition of topoisomerase II and damage to mitotic spindle. The carcinogenic and myelotoxic effects of benzene are associated with free radical formation either as benzene metabolites or lipid peroxidation products. Benzene oxide and phenol have been considered as proheptons. Liver microsomes play an important role in biotransformation of benzene whereas in kidney, it produces degenerative intracellular changes. Cohort studies made in different countries suggest that benzene induces multiple myeloma in petrochemical workers. Though extensive studies have been performed on its toxicity, endocrinal disruption caused by benzene remains poorly known. Transgenic cytochrome P450 IIE1 mice may help in understanding further toxic manifestations of benzene.

Adverse affects of paclitaxel and carboplatin combination chemotherapy in epithelial gynecologic cancer.

OBJECTIVE: To evaluate the adverse affects of paclitaxel and carboplatin combination chemotherapy. DESIGN: Descriptive cross sectional study MATERIAL AND METHOD: Patients with epithelial cancer of the ovary, fallopian tube and peritoneum treated with paclitaxel and carboplatin combination chemotherapy at Chiang Mai University Hospital between August 2003 and August 2004. RESULTS: Of 224 evaluable cycles in 63 patients treated with paclitaxel (175 mg/m2) and carboplatin (AUC 5), grade 3 and 4 neutropenia occurred in 37.1% or 41.3% of patients. 4.8% of patients experienced febrile neutropenia. Grade 3 and 4 leukopenia occurred in 8.6% of courses and 12.6% of patients. Grade 3 anemia occurred in 5.2% of courses and 9.5% of patients. Grade 3 thrombocytopenia occurred in 2.8% of courses and 9.6% of patients. The nonhematologic adverse affects were rare, however, some adverse events may be potentially life threatening. CONCLUSION: Adverse affects of paclitaxel and carboplatin combination chemotherapy are acceptable and manageable in the majority of patients.

Benzenismo no Complexo Petroquímico de Camaçari, Bahia / Benzenism in the Camaçari Petrochemical Complex, Bahia

O presente trabalho constitui-se em um estudo de prevalência, realizado a partir de dados hematimétricos referentes a 7.356 trabalhadores de nove empresas do Complexo Petroquímico de Camaçari, Bahia. Do total de trabalhadores avaliados, 216 (2,9 por cento) apresentaram valores leucocitários abaixo de 4.000 e/ou número de neutrófilos abaixo de 2.000. Para estes últimos, caracterizou-se evidente exposição ocupacional ao benzeno, sendo que todos foram afastados da exposição e encaminhados para investigação hematológica mais aprofundada. O presente estudo permitiu evidenciar o valor do método de vigilância epidemiológica na inspeção trabalhista dos ambientes de trabalho

Current role of chemotherapy protectors in cancer treatment

The administration of full doses of chemotherapy according to an established schedule improves the response rate and duration of response in cancer patients. However, frequently there are delays in therapy due to dose-limiting side effects and chemotherapy could affect permanently normal tissues. This has led to the development of chemotherapy protectors and of rescue agents in the past years. We will discuss some of these new agents and their use in cancer treatment. Some of these agents include amifostine (Ethyol), dexrazoxane (Zinecard), mesna (Mesnex), leucovorin, G-CSF, GM CSF, recombinant erythropoietin and thrombopoietin. Oncologists must learn the adequate use of different strategies in reducing chemotherapy toxicity in order to improve both the quality and quantity of life of cancer patients

Alteraçöes hematológicas em pacientes expostos cronicamente ao benzeno / Hematological abnormalities in patients chronically exposed to benzene

Foram apresentadas as alteraçöes hematológicas do sangue periférico e da medula óssea em pacientes expostos cronicamente ao benzeno. Foram descritos a biotransformaçäo metabólica e os possíveis mecanismos envolvidos neste tipo de toxicidade. Os dados hematológicos do sangue periférico säo mostrados e avaliados em sua importância, sendo a macrocitose e a linfocitopenia sinais precoces de toxicidade ao benzeno. As alteraçöes da medula óssea observadas säo demonstradas pelos métodos complementares citológico e histológico. A anormalidade histológica de maior importância foi a hipocelularidade global devida, principalmente, ao setor granulocítico. Foi observado também aumento do percentual de eosinófilos, de mastócitos e de atipias no setor megacariocítico. Foram observadas alteraçöes de caráter inflamatório e ressaltada a presença de sinais de dismielopoiese. Foram enfatizadas a necessidade da valorizaçäo das alteraçöes hematológicas do sangue periférico e a visäo crítica e global desse importante problema de saúde pública

Toxicidad hematológica por Anfotericina B en el tratamiento de Leishmaniasis mucocutánea

Se analizan en forma prospectiva las alteraciones hematológicas en 20 pacientes con Leishmaniais mucocutánea (refractarios al tratamiento con antímoniales pentavalentes) que recibieron tratamiento con anfotericina B. El medicamento se administró en dosis de 50mg endovenosos hasta completar 1500 mg de dosis total acumulado (150 mg por semana). El 95 por ciento de pacientes presentó algún tipo de complicación hematológica, siendo las más frecuentes anemía (95 por ciento) y retículocitopenia (90 por ciento). La anemia fue de tipo normocíticanormocrómica con pobre respuesta medular, intensidad leve en la mayoría, y reversible. La disminución del hematocrito fue temprana y con una dosis acumulada relativamente pequeña (250 - 550 mg), luego de la cual el hematocrito se estabilizó. Se encontró correlación entre la caída del hematocrito y la dosis acumulada. El principal mecanismo para el desarrollo de la anemia seria una disminución de la producción de los globulos rojos por supresión de la médula ósea como consecuencia de un bloqueo en la producción de eritropoyetina, más un efecto tóxico directo sobre la médula ósea. Las alteraciones en el número de eosinófilos son difíciles de interpretar, pues al parecer tanto la enfermedad de fondo como la anfotericina B causarían alteraciones en esta línea celular. Se encontró leucopenia y linfopenia en 5 por ciento de pacientes, estos hallazgos se relacionaron a la presencia de citofagocitosis medular. No se encontró ningún caso de trombocítopenia, pero si una disminución significativa temprana del número de plaquetas, probablemente asociado a depresión medular de la serie megacariocítica