Evaluating the mutagenic potential of chemicals the minimal battery and extrapolation problems

During the past ten years growing concern about damage to DNA as an important cause of human ill-health has resulted in an explosive development of the field of genetic toxicology. Adequate regulations to restrict exposure to chemical mutagens require recognition and evaluation of mutagenic activity. For this purpose a qualitative and an extrapolation phase can be distinguished. For the qualitative phase, the minimal battery should consist of at least three tests, that is: (1) tests for gene- or point mutations in bacteria (Salmonella or E. coli) with and without metabolic activation; (2) two tests for point mutations in eukaryotes, or (3) one such test and a test for the detection of chromosome aberrations in mammalian cells in vitro. Depending on experience and facilities, a choice of two can be made out of the following four test systems: (1) Tests for point mutations in mammalian cells in vitro, with and without metabolic activation (deficiency for HGPRT, or TK); (2) the sex-linked recessive lethal test with Drosophila melanogaster; (3) tests with yeast, Saccharomyces cerevisiae, for point mutations, with and without metabolic activation; (4) tests for chromosome aberrations in mammalian cells in vitro, with and without metabolic activation. Two different metabolic activation systems should be employed. For further selection of more sensitive test systems, studies on comparative mutagenesis are considered important. A mammalian test for chromosome aberrations in vivo is not included in this minimal battery. Since under in vivo conditions considerably lower concentrations have to be employed than in vitro, it seems unlikely that positive results will be obtained with an in vivo mammalian cytogenetic assay, following negative results in an in vitro cytogenetic assay or in two different tests for point mutations. The finding that the effective concentration for the production of chromosome breakage events differs from that required to induce point mutations (the two-level effect) will be briefly discussed. When mutagenic compounds are indispensible or, in the case of ubiquitous exposure, a quantification of risks becomes necessary and here one is confronted with many difficulties. Information on damage that is hard to measure directly can be obtained in an indirect way by comparison with end-points that can be determined experimentally, such as alkylation per nucleotide. Names of chemical substances tested: hydroxylamine; diepoxybutane; N-ethyl-N-nitrosourea; methylmethanesulfonate (MMS); DEN; Mitomycin C; Procarbazine; atrazine; benz(a)pyrene; EMS; pyrolitic products; flavonoids; mycotoxins; nitrosamines; TEMGiven at the International Conference Mutagenicity Testing of Pharmaceuticals: Present Status, Paris, 12–14 March, 1980, sponsored by the Fondation de l'Industrie Pharmaceutique pour la Recherche     

Programming a predictive rormula for angina and other risk factors in patients with cardiac diseases undergoing noncardiac operations

We programmed a formula which predicts the incidence of either myocardial infarction or cardiac death during the postoperative period. The original formula was proposed by Shah et al, based on their own data and analysis. The program is simple and is written in a language called Quick Basic. The use of this program is also simple. Such a program has improved the use of this analysis substantially. The program has been posted on to a few Computer network services as a free software.(Suwa K, Ogura S: Programming a predictive formula for angina and other risk factors in patients with cardiac diseases undergoing non-cardiac operations. J Anesth 6: 241–242, 1992)     

体力活动与乳腺癌发生的关系

目的:评估体力活动是否可降低中国妇女乳腺癌发生。材料与方法:本文利用1998年至2001年在上海市区开展的一项以人群为基础的乳腺癌病例对照研究数据,分析妇女既往不同年龄段(13～19岁青春期和近10年成年期)各种体力活动与乳腺癌的关系。在上海市共招收1 495名合格的乳腺癌病例和1 573名年龄频数匹配的全人群随机对照,应答率分别为95.1％和87.7％,在研究对象家中进行结构式问卷调查。结果:对可能的混杂因素校正后,发现青春期和成年期体育锻炼活动均能降低乳腺癌发生,每周运动量在75％分位数以上的妇女OR值分别为0.83(0.66～1.03)和0.64(0.46～0.87),趋势性检验的P值分别为0.040和0.002。两个年龄段做家务、骑自行车和成年期步行均与乳腺癌无关,但青春期较多步行可减少乳腺癌发生。另外未发现职业体力活动与乳腺癌有明显联系。最后对体育锻炼和日常生活体力活动的综合分析发现,只有成年期的体力活动具有独立的保护作用。结论:较多体力活动可降低中国妇女乳腺癌的发生,但仅成年期体力活动具有独立作用。     

Bladder Cancer and Arsenic Exposure： Differences in the Two Populations Enrolled in A Study in Southwest Taiwan

Objective Analyses of bladder cancer mortality in the Black Foot Disease (BFD) endemic area of southwest Taiwan conducted by Morales et al. showed a discontinuity in risk at 400 μg/L arsenic in the drinking water in a stratified analysis and no discontinuity in a continuous analysis.     

Kinetic versus thermodynamic factors in calcium renal lithiasis

Calcium renal lithiasis formation depends on the balance between thermodynamic (supersaturation) and kinetic (inhibitors, nucleants)factors. In this paper, the importance of both groups was evaluated using(a) the complete urine analysis data obtained from 32 healthy volunteers and 141 active stone-formers, and (b) a comprehensive computer model to calculate the supersaturation values of calcium oxalate monohydrate,hydroxyapatite and brushite in each urine sample. The results of this evaluation were used to assess the possible effectiveness of a given pharmacological treatment. This revised version was published online in August 2006 with corrections to the Cover Date.     

某钢铁企业肿瘤发病及危险因素研究

[目的]探讨某钢铁企业肿瘤的发病情况及其相关的危险因素.[方法]在某钢铁企业近10年新发生119例肿瘤作为病例组,另选取同性别、同年龄(上下不超过3岁)的同一工作场所和不同工作场所的健康人各119例作对照,共计238例,进行1:2配对对照研究.[结果]肿瘤的发病率为109.40/10万,以肺癌、上消化道癌为主.多因素条件Logistic分析表明接触毒害物质、吸烟、使用煤炉、肿瘤家族史、精神创伤、喜食烫的食物为肺癌、上消化道癌发病的主要危险因素,食新鲜蔬菜、新鲜水果有保护作用.[结论]该钢铁企业肿瘤发病呈较高水平,以肺癌、上消化道癌占多数.其危险因素与公认的肿瘤危险因素一致,应采取改善环境等综合预防措施.     

Cigarette tar yield and risk of upper digestive tract cancers: case-control studies from Italy and Switzerland.

BACKGROUND: Tobacco smoking is one of the main risk factors for oral, pharyngeal and oesophageal cancers in developed countries. Information on the role of the tar yield of cigarettes in upper digestive tract carcinogenesis is sparse and needs to be updated because the tar yield of cigarettes has steadily decreased over the last few decades. PATIENTS AND METHODS: We analysed two case-control studies, from Italy and Switzerland, conducted between 1992 and 1999, involving 749 cases of oral and pharyngeal cancer and 1770 controls, and 395 cases of squamous-cell oesophageal carcinoma and 1066 matched controls. Odds ratios (ORs) were estimated by unconditional multiple logistic regression models, including terms for age, sex, study centre, education and alcohol consumption. RESULTS: Based on the brand of cigarettes smoked for the longest time, the multivariate ORs for current smokers compared with never smokers were 6.1 for <20 mg and 9.8 for >or=20 mg tar for oral and pharyngeal neoplasms, and 4.8 and 5.4 for oesophageal cancer, respectively. For the cigarette brand smoked in the previous six months, the ORs for >or=10 mg compared with <10 mg were 1.9 for cancer of the oral cavity and pharynx and 1.8 for oesophageal cancer, after allowance for number of cigarettes and duration of smoking. CONCLUSIONS: The present study confirms the direct relationship between the tar yield of cigarettes and upper digestive tract neoplasms, and provides innovative information on lower tar cigarettes, which imply reduced risks compared with higher tar ones. However, significant excess risks were observed even in the lower tar category, thus giving unequivocal indications for stopping smoking as a priority for prevention of upper digestive tract neoplasms.     

A Competency-based Model of Child Depression: A Longitudinal Study of Peer, Parent, Teacher, and Self-evaluations

In a two-wave longitudinal study of third and sixth graders ( N = 617), we obtained self-reports of depression and peer, teacher, parent, and self-reports of competence in five domains: academic, social, attractiveness, conduct, and athletic. Competency evaluations by others predicted change in self-perceived competence over time for girls, but not for boys. Depression predicted change in self-perceived competence over time for boys but not for girls. Among girls, the relative importance of parent, teacher, and peer appraisals shifted from third to sixth grade. For both boys and girls, self-perceptions of competence predicted change in depression scores over time. Furthermore, self-perceived competencies mediated the relation between competency appraisals by others and children's self-reported depression. Results are interpreted in light of a competency-based model of child depression.     

Interactions between maternal smoking and other prenatal risk factors for sudden infant death syndrome (SIDS)

Abstract In numerous investigations, maternal smoking increases the risk of sudden infant death syndrome (SIDS). In the present study we investigated whether prenatal risk factors for SIDS modify the effect of maternal smoking on SIDS mortality. We analysed data from a population-based cohort study (222 cases, 260,604 infants at risk) within the Westphalian Perinatal Inquiry in Germany between 1990 and 1994. In the stratified analysis, smoking was classified into non-smoking, moderate (1–10 cigarettes/d) and heavy smoking (> 10 cigarettes/d). Multiplicative interactions between smoking and other prenatal risk factors were assessed in a logistic regression model. The relative risk (RR) for maternal smoking was 2.4 (95% confidence interval 1.7-5.4) for moderate and 7.2 (5.3, 9.7) for heavy smokers. Previous established risk factors for SIDS, such as preterm birth, low birthweight, and number of prenatal visits did not increase the risk of SIDS among non-smokers, but became important risk factors among smokers. In preterm infants (< 37 weeks) of heavy smokers, the RR was 19.6 (10.4, 36.8) compared to term infants of non-smokers. Low birthweight infants (< 2500 g) of heavy smokers had a RR of 16.3 (8.4, 31.2) compared to normal weighted infants of non-smokers. Adjustment for occupational status did not change the crude estimates. The RR of < 6 prenatal visits in the heavy smoking subgroup was 14.8 (7.2, 29.6) compared to > 9 prenatal visits in the nonsmoking strata. Heavy smoking potentiates other prenatal risk factors for SIDS suggesting an increased susceptibility towards the adverse effects of tobacco smoke in utero. In infants born to non-smoking mothers, prenatal risk factors are absent and postnatal factors may be of major importance.