Cancerogenic effect of long-term benzene exposure. Occurrence at the same work place of a plasmacytoma and two solid carcinomas

A report is given on three different malignomas appearing after high inhalative exposure to benzene for many years at the same working place in a cable plant. The exposure to benzene amounted to 22 years in a 50 year old man with oesophagus carcinoma, 17 years in a 61 year old man with plasmocytoma and 10 years in a 45 year old man with embryonal carcinoma of the testicles. The malignomas appeared 5-7 years after the end of the exposure. The carcinogenity of benzene is discussed on the basis of a survey of medical literature on epidemiological studies, casuistic contributions and experimental investigations in animals. A direct and indirect mechanism of benzene inducing carcinogenity is discussed: Activation of normal cellular oncogenes in DNA molecules by changes directly caused by benzene and; Damage of the lymphatic cell particularly susceptible to benzene followed by a disturbance of immunological monitoring and defence reactions against tumour cells.     

The number needed to treat: a clinically useful measure of treatment effect.

The relative benefit of an active treatment over a control is usually expressed as the relative risk, the relative risk reduction, or the odds ratio. These measures are used extensively in both clinical and epidemiological investigations. For clinical decision making, however, it is more meaningful to use the measure "number needed to treat." This measure is calculated on the inverse of the absolute risk reduction. It has the advantage that it conveys both statistical and clinical significance to the doctor. Furthermore, it can be used to extrapolate published findings to a patient at an arbitrary specified baseline risk when the relative risk reduction associated with treatment is constant for all levels of risk.     

Exposition of humans to low doses and low dose rate irradiation: an urgent need for new markers and new models

In human radiation protection, the shape of the dose effects curve for low doses irradiation (LDI) is assumed to be linear, extrapolated from the clinical consequences of Hiroshima and Nagasaki nuclear explosions. This extrapolation probably overestimates the risk below 200 mSv. In many circumstances, the living species and cells can develop some mechanisms of adaptation. Classical epidemiological studies will not be able to answer the question and there is a need to assess more sensitive biological markers of the effects of LDI. The researches should be focused on DNA effects (strand breaks), radioinduced expression of new genes and proteins involved in the response to oxidative stress and DNA repair mechanisms. New experimental biomolecular techniques should be developed in parallel with more conventional ones. Such studies would permit to assess new biological markers of radiosensitivity, which could be of great interest in radiation protection and radio-oncology.     

Serum pneumoproteins and biomarkers of exposure to urban air pollution: a cross-sectional comparison of policemen and foresters.

Very few biomarkers are available for the non-invasive detection of effects of urban air pollution on the respiratory tract. The objective was to evaluate whether Clara cell protein (CC16) and surfactant-associated protein-A (SP-A), two pulmonary secretory proteins, were useful in the detection of effects of urban air pollutants on the pulmonary epithelium. These proteins were determined in the serum of 53 policemen working in Brussels, Belgium, and a control group of 59 foresters working in the countryside. Except for ozone (O(3)), annual concentrations of the main air pollutants (PM(10), NO(2), CO, SO(2) and benzene) were significantly higher in Brussels than in the country. The proportion of smokers was lower in urban policemen compared with foresters, but they smoked on average a similar number of cigarettes per day as confirmed by their urinary excretion of cotinine. Muconic acid, a marker of benzene exposure, was significantly higher in urban policemen than in foresters, in both smokers and non-smokers. Multiple regression analysis showed that the type of work, smoking habits and time spent outdoors and in a car were significant determinants of benzene uptake. Tobacco smoking impaired lung function to a similar extent in urban policemen and foresters. The serum levels of SP-A were significantly increased in smokers but were not different between policemen and foresters. Serum CC16 was significantly reduced by tobacco smoking and slightly decreased in policemen compared with foresters. Interestingly, the reduction of serum CC16 was more pronounced in the subgroup of traffic compared with survey policemen, the latter being also less exposed to benzene. The results suggest that serum pneumoproteins and especially serum CC16 could be useful in the detection of chronic effects of urban air pollutants on the respiratory epithelium of populations particularly at risk.     

Serum pneumoproteins and biomarkers of exposure to urban air pollution: a cross-sectional comparison of policemen and foresters

Very few biomarkers are available for the non-invasive detection of effects of urban air pollution on the respiratory tract. The objective was to evaluate whether Clara cell protein (CC16) and surfactant-associated protein-A (SP-A), two pulmonary secretory proteins, were useful in the detection of effects of urban air pollutants on the pulmonary epithelium. These proteins were determined in the serum of 53 policemen working in Brussels, Belgium, and a control group of 59 foresters working in the countryside. Except for ozone (O₃), annual concentrations of the main air pollutants (PM₁₀, NO₂, CO, SO₂ and benzene) were significantly higher in Brussels than in the country. The proportion of smokers was lower in urban policemen compared with foresters, but they smoked on average a similar number of cigarettes per day as confirmed by their urinary excretion of cotinine. Muconic acid, a marker of benzene exposure, was significantly higher in urban policemen than in foresters, in both smokers and non-smokers. Multiple regression analysis showed that the type of work, smoking habits and time spent outdoors and in a car were significant determinants of benzene uptake. Tobacco smoking impaired lung function to a similar extent in urban policemen and foresters. The serum levels of SP-A were significantly increased in smokers but were not different between policemen and foresters. Serum CC16 was significantly reduced by tobacco smoking and slightly decreased in policemen compared with foresters. Interestingly, the reduction of serum CC16 was more pronounced in the subgroup of traffic compared with survey policemen, the latter being also less exposed to benzene. The results suggest that serum pneumoproteins and especially serum CC16 could be useful in the detection of chronic effects of urban air pollutants on the respiratory epithelium of populations particularly at risk.     

Investigation of outbreaks of salmonella in hospitals.

In a two year prospective survey of outbreaks of salmonella infection in hospitals in England and Wales 55 outbreaks were identified. Reports of investigation of these outbreaks were reviewed for evidence of food borne infection and cross infection. Food borne infection probably accounted for only six outbreaks, but these made up 40% of the 15 outbreaks in which there were more than five patients and staff with symptoms. Person to person transmission was the probable mode of spread in most outbreaks. It is recommended that in addition to bacteriological investigations clinical and epidemiological data should be collected to implicate food or other possible common vehicles of infection. Bacteriological screening of patients and staff who do not have symptoms may be unrewarding in the absence of epidemiological data to define groups at risk of infection.     

Serum pneumoproteins and biomarkers of exposure to urban air pollution: a cross-sectional comparison of policemen and foresters

Very few biomarkers are available for the non-invasive detection of effects of urban air pollution on the respiratory tract. The objective was to evaluate whether Clara cell protein (CC16) and surfactant-associated protein-A (SP-A), two pulmonary secretory proteins, were useful in the detection of effects of urban air pollutants on the pulmonary epithelium. These proteins were determined in the serum of 53 policemen working in Brussels, Belgium, and a control group of 59 foresters working in the countryside. Except for ozone (O₃), annual concentrations of the main air pollutants (PM₁₀, NO₂, CO, SO₂ and benzene) were significantly higher in Brussels than in the country. The proportion of smokers was lower in urban policemen compared with foresters, but they smoked on average a similar number of cigarettes per day as confirmed by their urinary excretion of cotinine. Muconic acid, a marker of benzene exposure, was significantly higher in urban policemen than in foresters, in both smokers and non-smokers. Multiple regression analysis showed that the type of work, smoking habits and time spent outdoors and in a car were significant determinants of benzene uptake. Tobacco smoking impaired lung function to a similar extent in urban policemen and foresters. The serum levels of SP-A were significantly increased in smokers but were not different between policemen and foresters. Serum CC16 was significantly reduced by tobacco smoking and slightly decreased in policemen compared with foresters. Interestingly, the reduction of serum CC16 was more pronounced in the subgroup of traffic compared with survey policemen, the latter being also less exposed to benzene. The results suggest that serum pneumoproteins and especially serum CC16 could be useful in the detection of chronic effects of urban air pollutants on the respiratory epithelium of populations particularly at risk.     

Radiation Hormesis and Cancer

Despite the long history of radiation hormesis and the public health concerns with low-level exposures to ionizing radiation, there has been surprisingly little formal evaluation of whether hormetic effects are displayed with respect to radiation exposure and cancer incidence (i.e., reduced cancer risk at low radiation doses compared to controls, enhanced cancer risk at higher doses) until relatively recently. This paper reviews data relevant to the question of radiation hormesis and cancer with particular emphasis on experimental studies in animal models exposed to low levels of ionizing radiation. Data exist that provide evidence both consistent with and/or supportive of radiation hormesis. Other biomedical research provides potentially important mechanistic insight: low dose exposures have the capacity to activate immune function to prevent the occurrence of tumor development and metastasis; low doses of radiation have been shown to reduce mutagenic responses and induce endogenous antioxidant responses. These findings are consistent with epidemiological data suggesting an inverse relationship between background radiation and cancer incidence and with occupational epidemiological investigations in which low-dose exposure groups display markedly lower standardized mortality rates than the referent or control group.     

The threshold for radiation stochastic effects: arguments "pro" and "contra". Applied realization

This study represents the analysis of the data available in the literature and the author's findings concerning the issue of a shape of the dose stochastic effect curve in the range of low levels of radiation (LLR). The data obtained from radioepidemiological and experimental investigations are used. Also considered are the arguments "pro" and "contra" regarding approximation of these curves by means of a linear function (linear non-threshold conception) or as a quasi-plateau (threshold conception). The above analysis allows us to conclude that the threshold conception is more reliable than the non-threshold one from the standpoint of the analysis of postulate bases, theoretical paradigms, the mechanisms for radiobiological effects, epidemiological and experimental data. It is suggested that a separate radiogenic cancer risk estimation should be used in case of LLR and high level radiation instead of one overall estimation by means of the linear non-threshold model.     

Environmental Tobacco Smoke Exposure and Heart Disease: A Critique of the Claims of Glantz and Parmley

Background—A review by Glantz and Parmley published in 1995 and subsequently widely cited claims to demonstrate that passive smoke exposure increases the risk of heart disease. We have critically examined this claim in the light of the published evidence which they cite and of more recent publications. Methods and results—An updated review of the epidemiological evidence reveals no association between heart disease and ETS exposure in the workplace. Claims of an association with spousal smoking are weakened by the existence of various forms of bias in the studies. They are also undermined by recent reports from three large studies without evident major weaknesses which find essentially no association with spousal smoking. Interpretation of the experimental clinical studies is problematic because it is not possible to expose humans to ETS without their knowledge. For several reasons, short-term effects of exposure to unrealistically high concentrations of ETS throw no useful light on risk of coronary atherogenesis from long-term realistic exposure. In particular, the fact that humans can adapt to reduced ambient oxygen availability needs to be allowed for. Effects of counts of anuclear endothelial cell carcasses in circulating blood after ETS exposure are uninterpretable without basic information on the significance of this endpoint. The need for a realistic animal model for coronary atherosclerosis is not fulfilled by short-term studies in rats, rabbits, hamsters, birds or dogs in which aortic atheromatous plaque formation is used as a surrogate endpoint. Stress from confinement within cages, from the noise of fans and from irritation from high ETS concentrations needs to be controlled for, particularly in experiments on rabbits and birds. This has not been done and there is generally a serious dearth of information on the non-specific or specific effects of other environmental chemicals on many of the endpoints that have been used. Studies on the possible role of platelets in the aetiology of coronary heart disease are difficult to interpret because of confusion between their possible long-term role in atherogenesis and their putative involvement in thrombus formation which results in myocardial infarction. Evidence from an inadequately designed one-day study involving persons exposed to unmeasured amounts of ETS in a hospital corridor provides no insight into mechanisms involved in coronary atherogenesis. A study of the effect of exposure to ETS on the diameter of the brachial artery diameter is open to criticism because of the way in which subjects were recruited and failure to control for potentially important confounders. Conclusion — The available experimental and epidemiological evidence does not justify a conclusion that ETS exposure increases the risk of heart disease.     

Environmental genotoxicants/carcinogens and childhood cancer: bridgeable gaps in scientific knowledge

Cancer in children is a major concern in many countries. An important question is whether these childhood cancers are caused by something, or are just tragic random events. Causation of at least some children's cancers is suggested by direct and indirect evidence, including epidemiological data, and animal studies that predict early life sensitivity of humans to carcinogenic effects. Candidate risk factors include genotoxic agents (chemicals and radiation), but also diet/nutrition, and infectious agents/immune responses. With regard to likelihood of risks posed by genotoxicants, there are pros and cons. The biological properties of fetuses and infants are consistent with sensitivity to preneoplastic genotoxic damage. Recent studies of genetic polymorphisms in carcinogen-metabolizing enzymes confirm a role for chemicals. On the other hand, in numerous epidemiological studies, associations between childhood cancers and exposure to genotoxicants, including tobacco smoke, have been weak and hard to reproduce. Possibly, sensitive genetic or ontogenetic subpopulations, and/or co-exposure situations need to be discovered to allow identification of susceptible individuals and their risk factors. Among the critical knowledge gaps needing to be bridged to aid in this effort include detailed tissue and cellular ontogeny of carcinogen metabolism and DNA repair enzymes, and associations of polymorphisms in DNA repair enzymes with childhood cancers. Perinatal bioassays in animals of specific environmental candidates, for example, benzene, could help guide epidemiology. Genetically engineered animal models could be useful for identification of chemical effects on specific genes. Investigations of interactions between factors may be key to understanding risk. Finally, fathers and newborn infants should receive more attention as especially sensitive targets.     

Comparison of Toxicity of Benzene Metabolite Hydroquinone in Hematopoietic Stem Cells Derived from Murine Embryonic Yolk Sac and Adult Bone Marrow

Benzene is an occupational toxicant and an environmental pollutant that potentially causes hematotoxicity and leukemia in exposed populations. Epidemiological studies suggest an association between an increased incidence of childhood leukemia and benzene exposure during the early stages of pregnancy. However, experimental evidence supporting the association is lacking at the present time. It is believed that benzene and its metabolites target hematopoietic stem cells (HSCs) to cause toxicity and cancer in the hematopoietic system. In the current study, we compared the effects of hydroquinone (HQ), a major metabolite of benzene in humans and animals, on mouse embryonic yolk sac hematopoietic stem cells (YS-HSCs) and adult bone marrow hematopoietic stem cells (BM-HSCs). YS-HSCs and BM-HSCs were isolated and enriched, and were exposed to HQ at increasing concentrations. HQ reduced the proliferation and the differentiation and colony formation, but increased the apoptosis of both YS-HSCs and BM-HSCs. However, the cytotoxic and apoptotic effects of HQ were more apparent and reduction of colony formation by HQ was more severe in YS-HSCs than in BM-HSCs. Differences in gene expression profiles were observed in HQ-treated YS-HSCs and BM-HSCs. Cyp4f18 was induced by HQ both in YS-HSCs and BM-HSCs, whereas DNA-PKcs was induced in BM-HSCs only. The results revealed differential effects of benzene metabolites on embryonic and adult HSCs. The study established an experimental system for comparison of the hematopoietic toxicity and leukemogenicity of benzene and metabolites during mouse embryonic development and adulthood.     

Teratogen update: inorganic arsenic

BACKGROUND: Inorganic arsenic has been used by many laboratories to study the pathogenesis of exencephaly in rodents. These studies, which used predominantly injection exposures, coupled with the paucity of epidemiology data, resulted in the erroneous inference that inorganic arsenic should be considered a human teratogen. METHODS: This study assembles and assesses literature analyses of older human and animal investigations together with the results of new experimental studies. These recent studies were performed according to modern regulatory guidelines, and relevant exposure routes (inhalation and ingestion) were used to evaluate the potential risk of developmental effects in humans. RESULTS: The existing epidemiological data are inadequate to support risk assessment because of the failure to confirm or measure arsenic exposure during early gestation and the deficiencies in accounting for potential confounding factors. The animal data revealed that inorganic arsenic caused malformations in offspring only when it was injected into the veins or peritoneal cavity of pregnant animals during early gestation. Exposure via inhalation or oral ingestion, even at concentrations that were nearly fatal to pregnant females, caused no arsenic-related malformations. CONCLUSIONS: Inorganic arsenic poses virtually no danger to developing offspring when maternal exposure occurs by relevant routes (oral and inhalation) at concentrations that are likely to be experienced in the environment or in the workplace.     

Enhanced anaerobic degradation of benzene by enrichment of mixed microbial culture and optimization of the culture medium

A heterogeneous mixed culture, originally collected from two different sources, namely cow-drug and sludge from the mineral medium containing 1% glucose and then adapted on benzene as the carbon and energy source. Under anaerobic conditions benzene was degraded via benzoic acid as a major intermediate in the benzene degradation pathway. The degradation rate of benzene was improved stepwise by the number of enrichments and optimization of the culture medium. The effects of microaerobic conditions and/or physicochemical treatment with H₂O₂ prior to anaerobic degradation were studied with respect to variations in benzene degradation rate, growth of biomass and gas produced is less than the theoretical value expected and the percentage of methane in the product gas was very small (3%–3.5%). The reason for this is not well understood but it is presumed that the major group of benzene-degrading bacteria present in the culture medium are sulphate reducers and the mixed consortium is unable to degrade certain complex aromatic intermediates in the benzene degradation pathway under the experimental conditions. For an actual explanation of the situation arising in this study, further investigations must be carrie out. However, the mixed culture is capable of oxidizing benzene more rapidly to intermediate compounds and also partly into gas under the culture conditions, compared to the published data for the anaerobic degradation of benzene.     

The renaissance of lipoprotein(a): Brave new world for preventive cardiology?

Lipoprotein(a) [Lp(a)] is a highly heritable cardiovascular risk factor. Although discovered more than 50 years ago, Lp(a) has recently re-emerged as a major focus in the fields of lipidology and preventive cardiology owing to findings from genetic studies and the possibility of lowering elevated plasma concentrations with new antisense therapy. Data from genetic, epidemiological and clinical studies have provided compelling evidence establishing Lp(a) as a causal risk factor for atherosclerotic cardiovascular disease. Nevertheless, major gaps in knowledge remain and the identification of the mechanistic processes governing both Lp(a) pathobiology and metabolism are an ongoing challenge. Furthermore, the complex structure of Lp(a) presents a major obstacle to the accurate quantification of plasma concentrations, and a universally accepted and standardized approach for measuring Lp(a) is required. Significant progress has been made in the development of novel therapeutics for selectively lowering Lp(a). However, before these therapies can be widely implemented further investigations are required to assess their efficacy, safety, and cost-efficiency in the prevention of cardiovascular events. We review recent advances in molecular and biochemical aspects, epidemiology, and pathobiology of Lp(a), and provide a contemporary update on the significance of Lp(a) in clinical medicine.“Progress lies not in enhancing what is, but in advancing toward what will be.” (Khalil Gibran)     

Increased hair selenium concentration in hyperlipidemic patients

Selenium is an essential trace element with potential anti‐atherogenic and antioxidant effects. Experimental data suggest that selenium might be beneficial in the prevention of atherosclerosis and its complications, whereas human epidemiological studies have yielded conflicting results. Data on hair selenium status in hyperlipidemic patients are still lacking. Therefore, we analysed selenium concentrations by X‐ray fluorescence in the hair of 81 statin‐naïve patients with newly diagnosed Fredrickson‐type IIa and IIb hyperlipoproteinemia and compared their data with 43 healthy volunteers. We also assessed the frequency of other classical risk factors of atherosclerosis. Hair selenium levels were found to be significantly higher in hyperlipidemic patients compared with volunteers with normal lipid levels. Also, a significantly increased number of traditional atherosclerosis risk factors were observed in hyperlipidemic patients with hair selenium concentrations above the median in contrast to those with below. Our results suggest that high hair selenium status might be associated with adverse blood lipid profile together with an increased number of traditional risk factors in a selenium‐deplete population. These findings warrant further investigations to study the impact of selenium supplementation on the incidence of cardiovascular events.     

Environmental exposure to benzene, micronucleus formation and polymorphisms in DNA-repair genes: a pilot study

This report is part of a biomarker study conducted in an Italian population with exposure to environmental benzene ranging from 1.43 to 31.41 μg/m3 (values from personal sampling). DNA damage induced by benzene is the crucial mechanism of its genotoxicity, which leads to chronic benzene poisoning, haematotoxicity and leukaemia. Therefore, genetic variation in DNA-repair genes may modulate susceptibility to benzene-induced DNA damage. In light of this, the effects of polymorphisms in DNA-repair genes (APEX1, hOGG1, NBS1, XPD, XRCC1, and XRCC3) on micronucleus (MN) formation as a biomarker of early biological effects were evaluated. A significantly higher median MN frequency was recorded in traffic wardens than in controls. However, none of the analysed polymorphisms was significantly associated with the median MN frequency. A gene-gender interaction was observed for the APEX1 genotype. The APEX1 variant genotype was associated with significantly lower median MN frequency in men, not in women. Statistical analysis did not reveal any association between the score of the protective alleles - hypothetically pushing the pathway towards optimal DNA-damage repair - and MN. Even though there are some limitations in the study, our results indicate that the general population may be exposed to benzene concentrations higher than the threshold level for air-quality standards in the European Union of 10 μg/m3. Furthermore, urban traffic wardens are exposed to significantly higher levels of benzene than individuals spending most of the time indoors. This higher exposure may contribute to DNA damage, suggesting that benzene might be implicated both as an environmental and occupational risk factor in leukaemia and other haematological diseases. In conclusion, this study suggest the need for (i) regular monitoring of traffic wardens for possible exposure to benzene, as a precautionary step to reduce the associated health risks, and (ii) more comprehensive studies in order to better elucidate the involvement of APEX1 genotypes in benzene genotoxicity.     

个体化补充维生素D与多发性硬化疾病治疗的探讨

维生素D不仅在骨骼代谢及钙平衡中发挥着重要作用,而且具有免疫调节、抗炎及神经细胞保护功能等。这提示我们,VD在自身免疫性疾病如多发性硬化中可能发挥着重要的作用。流行病学调查及临床数据显示,低VD水平或VD代谢失调是诱发多发性硬化的危险因素之一。另有研究报道,VD血清浓度与多发性硬化的疾病活动和进展呈反相关。但是,这些数据并不是没有争议的,VD在多发性硬化治疗和预防中的作用还有着很多需要回答的问题。现有的以VD补充作为治疗MS措施的临床干预研究中得到的临床数据并不具备得出结论的能力,并且有些数据之间甚至是相互矛盾。     

Review and meta-analysis of epidemiological associations between low/moderate doses of ionizing radiation and circulatory disease risks, and their possible mechanisms

Although the link between high doses of ionizing radiation and damage to the heart and coronary arteries has been well established for some time, the association between lower-dose exposures and late occurring cardiovascular disease has only recently begun to emerge, and is still controversial. In this paper, we extend an earlier systematic review by Little et al. on the epidemiological evidence for associations between low and moderate doses of ionizing radiation exposure and late occurring blood circulatory system disease. Excess relative risks per unit dose in epidemiological studies vary over at least two orders of magnitude, possibly a result of confounding and effect modification by well-known (but unobserved) risk factors, and there is statistically significant (p < 0.00001) heterogeneity between the risks. This heterogeneity is reduced, but remains significant, if adjustments are made for the effects of fractionated delivery or if there is stratification by endpoint (cardiovascular disease vs. stroke, morbidity vs. mortality). One possible biological mechanism is damage to endothelial cells and subsequent induction of an inflammatory response, although it seems unlikely that this would extend to low-dose and low-dose-rate exposure. A recent paper of Little et al. proposed an arguably more plausible mechanism for fractionated low-dose effects, based on monocyte cell killing in the intima. Although the predictions of the model are consistent with the epidemiological data, the experimental predictions made have yet to be tested. Further epidemiological and biological evidence will allow a firmer conclusion to be drawn.     

Benzene hematotoxicity and leukemogenesis

Benzene is ubiquitous and accepted as a human carcinogen by regulatory agencies. Proposed regulations assume without proof that the carcinogenic response to benzene exposure is "one hit" implying a linear with no threshold. There is no solid experimental proof for this concept. This research involves exposure of CBA/Ca male mice to benzene vapor in varying concentrations. Exposure to 300 ppm 6 hrs/day, 5 days/week, for 16 weeks is highly leukemogenic. Exposure for the same time to 100 ppm is also leukemogenic. Concentrations from 25 ppm to 400 ppm 6 hrs/day, 5 days/week, for 10 exposures produce an increasing lymphopenia. Exposure to 100 ppm for the same exposure time produces anemia, decrease in stem cell content of marrow, and marrow cellularity. Further dose-effect studies are required to test the "one hit hypothesis" and to determine whether the same integral dose of benzene administered over variable exposure has the same or different biological responses. It is of concern that biologic effects are observed at 25 ppm only 2.5 times the present permissible time-weighted average exposure during a working day and research by others (see Discussion) has demonstrated an effect (noncarcinogenic) at 10 ppm.