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The effect of cholesterol on the microsomal membrane components and the induction of drug–metabolizing enzymes was studied in rats after feeding with a two per cent cholesterol diet and administration of phenobarbitone or 3–methylcholanthrene intraperitoneally. The results revealed that cholesterol affected both the amount and the binding properties of protein, phospholipid and cholesterol in microsomes. Cholesterol also modified the effects of phenobarbitone and 3–methylcholanthrene on microsomal membranes. The administration of inducers increased the liver–body weight ratio significantly. Phenobarbitone enhanced NADPH cytochrome c reductase activity in native microsomes by about 2–fold. The aryl hydrocarbon hydroxylase activity was increased markedly by both phenobarbitone and 3–methylcholanthrene. The UDPglucuronosyltrans–ferase activity was also enhanced by both inducers. After trypsin digestion of microsomes UDPglucuronosyltransferase activity was significantly higher in rats on a high cholesterol diet than in those on standard diet. After treating the microsomes in vitro by various membrane perturbants it was found that 3–methylcholanthrene made the enzyme proteins less soluble than phenobarbitone. The results support the idea that cholesterol affects the activities of drug metabolizing enzymes, due to changes in the structure of microsomal membranes.

An inhalation exposure of male rats to 300 p.p.m. of a commercial turpentine 6 hrs daily 5 days a week for 8 weeks enhanced the activities of drug biotransformation enzymes of liver microsomes considerably. The activities of NADPH cytochrome c reductase and 7-ethoxycoumarin deethylase, and microsomal content of cytochrome P-450 were increased 35-60% during the first weeks of the experiment, but had a tendency to return towards the control values later on. A similar enhancement of activities was also found in liver microsomal epoxide hydratase and UDP glucuronosyltransferase, but these enzyme activities tended to adapt less during the experiment. The turpentine treatment increased the affinity of liver microsomal cytochrome P-450 to alpha-pinene (the main component of the turpentine). The present data suggests that exposure to turpentine is able to modify considerably the biotransformation of drugs.

The sorption behaviour of a polymer-supported sulphonic acid catalyst, Smopex-101, was studied in different solvent mixtures at 60 and 70 °C. The physical characteristics of the catalyst were investigated. Six catalysts with activities, ranging from 2.1 to 3.6 mmol/g, various degrees of cross-linking, 0%, 0.5%, 2% and 4% divinylbenzene as well as dimensions (lengths and diameters) were studied. The analyses of the liquid phase were carried out by using a densitometer. Catalyst swelling was studied with pure solvents as well as in acetic acid–ethyl acetate mixtures. The sorption phenomenon was found to be a complex one depending on the catalyst swelling.

Low alcohol consumption seems to decrease total mortality and to have beneficial properties on cardiovascular disease; data for cancer are still inconclusive. There is evidence that wine consumption decreases the risk of cancer at several sites, including cancer of upper digestive tract, lung, colon, basal cell carcinoma, and non-Hodgkin lymphoma. The presence of resveratrol, a polyphenol specifically present in red wine, may contribute to these cancer preventive effects. Resveratrol in fact inhibits the metabolic activation of carcinogens, has antioxidant and anti-inflammatory properties, decreases cell proliferation and induces apoptosis. Data on the availability of resveratrol in vivo are however still lacking. Although regular consumption of one or two glasses of wine seems reasonably safe from the health point of view, a recommendation to the general population for low wine consumption is not justified.

The kinetics of hydrogenation of xylose to xylitol on a sponge nickel catalyst (commonly referred to as Raney Ni catalyst) and of catalyst deactivation were studied. Plausible explanations for the decrease in catalytic activity by means of surface studies, nitrogen adsorption and thermogravimetric analyses of the fresh and spent catalysts are presented. The kinetic parameters of the process were estimated by the use of a semi-competitive model, which allows full competition between the organic species and the hydrogen atoms for the adsorption sites on the catalyst surface (competitive case). In the model, a competitiveness factor (alpha) is introduced to take into account that even after complete coverage of the surface by the organic species, interstitial sites remain for the adsorption of the hydrogen atoms.

Esterification kinetics of propanoic acid with methanol in the presence of a fibrous polymer-supported sulphonic acid catalyst as well as a conventional resin catalyst was studied. Kinetic experiments were carried out in a laboratory-scale batch reactor operating isothermally at 55, 60 and 63 °C and with different initial molar ratios of propanoic acid and methanol (1:1, 2:3 and 3:2). The fibre catalyst was active and stable in all the experiments. A reference experiment with the conventional catalyst, Amberlyst 15 was carried out at 60 °C, with the initial molar ratio 1:1. The reaction rate was higher with the fibre catalyst than with the Amberlyst 15. The apparent second-order rate constant for the fibre catalyst was 1.82×10 −3 dm 9 /(mol 2 g min) at 60 °C with the initial molar ratio 1:1 and 7.03×10 −4 dm 9 /(mol 2 g min) for the conventional catalyst under comparable conditions. The fibre catalyst was re-used in four experiments to explore its durability. After four successive experiments, the catalyst activity and capacity remained on the initial level, indicating good stability. A new kinetic model comprising the adsorptive interaction of propanoic acid and water with the sulphonic acid groups on the catalyst surface was developed and tested with the experimental data. The new rate equation gave a good fit to the data and was able to describe the behaviour of the system at various initial molar ratios of propanoic acid and methanol.

The activity of a Mo-promoted Raney nickel catalyst was studied in the hydrogenation of xylose to xylitol. Kinetic measurements carried out in a laboratory scale pressurised slurry reactor (40–70 bar H2 and 80–130°C) with recycled catalysts revealed that the catalyst deactivates during the use, but an asymptotic activity level is finally attained. Water and water–ethanol mixtures were used as solvents. The formation kinetics of the main product, xylitol as well as the by-products, xylulose, d -arabinitol, furfural and xylonic acid were registered quantitatively in the experiments. Catalyst characterisation studies carried out with nitrogen adsorption, XRD, ESCA-XPS and gravimetric reduction with hydrogen suggested that the main reasons for the deactivation is the decay of accessible active sites through collapse of the pore structure and leaching of the promoter metal, Mo and alumina. Also, accumulation of organic species in the pores may slightly contribute to the deactivation process. Catalyst deactivation was more rapid in aqueous milieu than in water–ethanol solutions. The deactivation rate was retarded, if the catalyst was treated with ethanol at elevated hydrogen pressure and temperature between the hydrogenation experiments. A rate model based on plausible surface reaction mechanisms was proposed for the generation of the main and by-products. The rate equations were based on a semi-competitive adsorption model for hydrogen and organic species. The catalyst deactivation kinetics was described with a reversible semi-empirical model, which lumped the physical and chemical reasons for deactivation to a simple two-parameter system. The deactivation model was combined with the rate equations and the model of the slurry reactor. The kinetic and deactivation parameters were determined with a sequential technique, by using non-linear regression analysis. The model was able to reproduce the hydrogenation behaviour of Raney nickel very well: it predicted the product distribution and the catalyst deactivation within a wide range of process parameters.

Good evidence indicates that the regular consumption of aspirin reduces the risk of colorectal cancer by up to 50%. This paper discusses mechanisms for this protection and considers carcinogen activation, cell proliferation, apoptosis and immune surveillance. It is not clear, however, whether these mechanisms are dose related. This question will remain to be answered until the optimum dose and duration of aspirin required for protection against colorectal cancer is established.

The in vitro cytotoxicity and the induction of micronuclei of two ultrafine titanium dioxide (TiO(2)) samples was assessed in a rat liver epithelial cell (RLE) assay. Pigmentary TiO(2) was used as a control particle, and mitomycin C, a potent inducer of chromosome damage, was used as a positive control agent in the micronucleus experiments. Since photoexcitation of TiO(2) particles has been reported to increase the cell-killing effect of the dust, a duplicate series of experiments was carried out by irradiating the TiO(2) exposed cells with near-UV light. Neither of the ultrafine TiO(2) samples was toxic to the cells at the concentration range of 5-200 mug/cm(2). The UV treatment had no significant effect on the results. The induction of micronuclei was tested in three concentrations (5, 10 and 20 mug/cm(2)). None of the TiO(2) samples, either ultrafine or pigmentary, increased the numbers of micronuclei in the RLE cells. By contrast, all three samples had a slight decreasing effect on the frequency of micronuclei at the lowest treatment concentration of 5 mug/cm(2), both in the absence and in the presence of UV irradiation. The results suggest that ultrafine particles, similar to pigmentary TiO(2), have no direct clastogenic potential.

The 12th meeting of the Scientific Group on Methodologies for the Safety Evaluation of Chemicals (SGOMSEC) considered the topic of methodologies for determining human and ecosystem susceptibility to environmental hazards. The report prepared at the meeting describes measurement of susceptibility through the use of biological markers of exposure, biological markers of effect, and biomarkers directly indicative of susceptibility of humans or of ecosystems. The utility and validity of these biological markers for the study of susceptibility are evaluated, as are opportunities for developing newer approaches for the study of humans or of ecosystems. For the first time a SGOMSEC workshop also formally considered the issue of ethics in relation to methodology, an issue of particular concern for studies of susceptibility.

Background Humans vary in their ability to metabolize endogenous and exogenous compounds. Glutathione S-transferases (GSTs) and N-acetyltransferases (NATs) are enzymes involved in the detoxification of hazardous agents. The GSTM1 and GSTT1 genes exhibit null (i.e., deletion) polymorphisms; in specific individuals, homozygous deletion (i.e., both copies lost) of these genes can be detected. Polymorphism of the NAT2 gene results in slow and fast acetylators of potentially toxic substances. The GSTM1-null and the NAT2 slow-acetylator genotypes have been associated with increased risks for the development of environmentally induced cancers. Purpose We assessed whether homozygous GSTM1-null or GSTT1-null genotypes or the NAT2 slow-acetylator genotype were associated with increased risks for the development of malignant and nonmalignant asbestos-related pulmonary disorders in a cohort of Finnish construction workers. Methods The study population consisted of 145 asbestos insulators who were classified as having been exposed to high levels of asbestos; 69 of these individuals had no pulmonary disorders (control subjects), and 76 had either malignant mesothelioma (n = 24) or nonmalignant pulmonary disorders, such as asbestosis and/or pleural plaques (n = 52). Lymphocyte DNA and the polymerase chain reaction were used to determine the GSTM1, GSTT1, and NAT2 genotypes of the study subjects. Odds ratios (ORs) and 95% confidence intervals (CIs) estimating the relative risks of disease associated with specific genotypes were calculated from 2 x 2 tables by use of Fisher's exact method. Results Risks for the development of asbestos-related pulmonary disorders were not affected significantly by homozygous deletion of the GSTM1 or GSTT1 genes. However, the risk of developing both malignant and nonmalignant pulmonary disorders for individuals with a NAT2 slow-acetylator genotype was more than twice that observed for those with a NAT2 fast-acetylator genotype (OR = 2.3; 95% CI = 1.1-4.7); the risk of developing malignant mesothelioma for NAT2 slow acetylators was increased almost fourfold (OR = 3.8; 95% CI = 1.2-14.3). Individuals who lacked the GSTM1 gene and possessed a NAT2 slow-acetylator genotype had a risk of developing malignant and nonmalignant pulmonary disorders that was approximately fivefold greater than that observed for those who had the GSTM1 gene and a NAT2 fast-acetylator genotype (OR = 5.1; 95% CI = 1.6-17.6); these individuals had a fourfold increased risk of developing nonmalignant pulmonary disorders (OR = 4.1; 95% CI = 1.1-17.2) and an eightfold increased risk of developing malignant mesothelioma (OR = 7.8; 95% CI = 1.4-78.7) when compared with the same reference group. Conclusions Individuals with homozygous deletion of the GSTM1 gene and a NAT2 slow-acetylator genotype who are exposed to high levels of asbestos appear to have enhanced susceptibility to asbestos-related pulmonary disorders.

We investigated point mutational DraI and RsaI restriction fragment length polymorphisms (RFLPs) in the CYP2E1 gene in 101 lung cancer patients, 40 patients with other pulmonary diseases and 121 healthy control subjects. In the DraI RFLP analysis of the 121 healthy control subjects, 96 had the DD genotype, 24 the CD genotype and one the CC genotype. Genotypic distribution in the patients with other pulmonary disease showed a similar trend (P = 0.50), though the group was considerably smaller. The distribution of DraI genotypes in the lung cancer patients was not significantly different from that of the healthy controls (P = 0.44). We were not able to reproduce the results of a Japanese report describing a statistically significant association between the rare DraI RFLP genotype CC and predisposition to lung cancer. Furthermore, this genotype was much less frequent in our study populations than in the Japanese study. The other point mutation studied, which results in RsaI restriction site polymorphism in the 5'-flanking region of the CYP2E1 gene, was almost absent in our study groups. These findings on our Finnish lung cancer population suggest that the CYP2E1 gene polymorphisms studied do not have an important role in susceptibility to lung cancer.

Almost 200 pharmaceutical chemicals and groups of drugs have been evaluated for their carcinogenic properties by working groups convened by the International Agency for the Research on Cancer. Therapeutic agents are exceptional environmental carcinogens in that humans are exposed to relatively pure substances at well-defined dosages. Of those evaluated, 20 are conclusively carcinogenic to humans and 52 are probably or possibly carcinogenic. The human tissues most often affected are bone marrow, skin, urinary bladder, liver, lymphatic tissue and endometrium. In cases in which there is sufficient evidence for carcinogenicity from both epidemiological and experimental studies, the similarity between humans and animals with regard to the target organs involved is close (85%). Since data on carcinogenicity exist for several groups of pharmaceuticals, risk versus benefit evaluations should be made carefully in relation to possible clinical applications. Carcinogenesis

The global incidence of cancer is soaring due to the rapidly aging populations in most countries. In 2000, there were ten million new cancer cases, six million cancer deaths, and 22 million people living with cancer (Parkin 2001). By the year 2020, there will be an estimated 20 million new cancer patients each year. Almost three quarters of them will be living in countries that between them have less than 5% of the resources of cancer control (Sikora 1999).

Preface.- 1. Cancer Causes and Opportunities for Prevention.- 2. Genetic and Environmental Factors in Carcinogenesis.- 3. Genetic Pathways to Human Cancer.- 4. Signalling Pathways as Targets in Cancer Prevention.- 5. TP53 in Carcinogenesis and Cancer Prevention.- 6. Apoptosis.- 7. Deficient DNA Mismatch Repair in Carcinogenesis.- 8. Epigenetic Changes, Altered DNA Methylation and Cancer.- 9. Hormonal Carcinogenesis.- 10. Angiogenesis: A Promising Target for Cancer Prevention.- 11. Arachidonic Acid Pathway in Cancer Prevention.- 12. Infections, Inflammation and Cancer: Roles of Reactive Oxygen and Nitrogen Species.- 13. Infections and the Etiology of Human Cancer. Epidemiological Evidence and Opportunities for Prevention.- 14. Xenobiotic Metabolism and Cancer Susceptibility.- 15. Animal Models for Mechanistic Cancer Research.- 16. New Promising Chemopreventive Agents and Mechanisms.- 17. Molecular Epidemiology in Cancer Prevention.

The systematic development and application of biomarkers in environmental health risk assessment is a relatively new field. At first, the major interest was in biomarkers of exposure, borrowing concepts from pharmacology, then it moved from the external estimates of exposure to internal measures of dose, and ultimately, to markers of target dose. While these markers provide evidence of exposures, they do not provide evidence of that toxicological damage has occurred. For this reason, measurements of DNA adducts and protein adducts are of interest, since they may provide bridges between exposures and disease end-points. In parallel, more quantitative and more sensitive end-points for diseases have been sought. Again, with advancing techniques in cytogenetics, extensive studies were conducted on such markers as chromosomal aberrations, micronuclei and other changes deemed to represent genomic damage. However, these types of end-points are quite unspecific for application to new hazards of uncertain human toxic (carcinogenic) potential. Recent work focusing on more specific early-effect markers such as certain oncogenes and tumour-suppressor genes have substantial promise as shown by work with aflatoxins and vinyl chloride. Such studies have also enhanced mechanistic insight. The advances in molecular genetics have led to an upsurge in interest in most susceptibility factors, and identification of polymorphisms of various enzymes has become possible. Ongoing search for "ultra-high risk" individuals may be fruitful, but probably only relevant to a small segment of potentially exposed populations. Factors associated with a small differential risk, however theoretically or mechanistically important, offer only little practical use.

Viruses play a major role in the etiology of a number of malignancies, including hepatocellular carcinoma (HCC) and cervical cancer, which are common in many parts of the world. In 1991, an ad hoc advisory group was convened by the International Agency for Research on Cancer (IARC) to consider whether viruses and other biological agents should be included in the IARC Programme for the preparation of Monographs on the Evaluation of Carcinogenic Risks to Humans. The group agreed unanimously that the carcinogenic risks of biological agents should be evaluated by expert groups such as those that have been convened by IARC over the past 20 years to discuss chemicals, physical agents, industries and cultural habits. A list of biological agents to be evaluated was drawn up, and the priority of each was designated by consensus on the basis of considerations regarding both their importance to public health and the status of the available epidemiological and biological evidence. On 8-15 June 1993, IARC convened a Working Group consisting of experts in epidemiology, experimental carcinogenicity, internal medicine, pathology, communicable diseases and molecular biology (see list of participants) to discuss 3 viruses given high priority by the ad hoc advisory group, i.e., hepatitis B virus (HBV), hepatitis C virus (HBC) and hepatitis D virus (HDV, or the delta agent). These 3 viruses all cause a similar acute illness involving the liver, but they are very different in structure and biology. Their common feature is that the liver disease they cause may have a chronic course; they differ in that way from hepatitis A and hepatitis E viruses, for which no association with chronic liver infection has been recognized. Furthermore, no indication is available to suggest that hepatitis A virus leads to HCC or any other cancer, and no studies have been reported on hepatitis E virus. The considerations of the Working Group were thus limited to HBV, HCV and HDV.

To investigate the association between alcoholism and risk of male breast cancer.We conducted a retrospective population-based cohort study in Sweden of men diagnosed with alcoholism between 1965 and 1995. The cohort was followed up through interlinkages with nationwide registries (the national cancer registry, immigration registry, causes of death registry, and population registry), using the national registration numbers. Standardized incidence ratios (SIRs), calculated using the Swedish national cancer incidence rate as reference, were used as estimates of relative risks.A total of 145,811 men were enrolled into the cohort, contributing 1,499,504 person-years of follow-up. Sixteen incident breast cancer cases were identified, and the mean age at diagnosis was 68 years. We excluded the first year of follow-up (cases and person-years) from the analysis to avoid detection bias. The overall SIR (excluding the first year of follow-up) was 1.1 (95% CI 0.6-2.0). Although based on small numbers we found no indication of a differential SIR according to duration of follow-up, age at cohort enrolment, or age at follow-up (attained age or age at cancer diagnosis).The observed associations are not compatible with an increase in breast cancer risk among male alcoholics.

Diisocyanates are the most common low molecular weight chemicals to cause occupational asthma. However, only some 5-10% of exposed workers develop asthma, which suggests an underlying genetic susceptibility. Diisocyanates and their metabolites may be conjugated with glutathione by glutathione S-transferases (GSTs). We examined whether polymorphisms in the GSTM1, GSTM3, GSTP1 and GSTT1 genes modify allergic responses to diisocyanate exposure. The study population consisted of 182 diisocyanate exposed workers, 109 diagnosed with diisocyanate-induced asthma and 73 without asthma. Lack of the GSTM1 gene (null genotype) was associated with a 1.89-fold risk of diisocyanate-induced asthma [95% confidence interval (CI) 1.01-3.52]. Moreover, among the asthma patients, the GSTM1 null genotype was associated with lack of diisocyanate-specific immunoglobulin (Ig)E antibodies [odds ratio (OR) 0.18, 95% CI 0.05-0.61] and with late reaction in the specific bronchial provocation test (OR 2.82, 95% CI 1.15-6.88). Similarly, GSTM3 AA genotype was related to late reaction in the specific bronchial provocation test (OR 3.75, 95% CI 1.26-11.2). The GSTP1 Val/Val genotype, on the other hand, was related to high total IgE levels (OR 5.46, 95% CI 1.15-26.0). The most remarkable effect was seen for the combination of GSTM1 null and the GSTM3 AA genotype which was strongly associated with lack of diisocyanate-specific IgE antibodies (OR 0.09, 95% CI 0.01-0.73) and with late reaction in the bronchial provocation test (OR 11.0, 95% CI 2.19-55.3). The results suggest, for the first time, that the polymorphic GSTs, especially the mu class GSTs, play an important role in inception of ill effects related to occupational exposure to diisocyanates.

Provocative findings have been published suggesting that the use of sunscreens may promote skin cancer. A recent meeting of international experts on the use of sunscreens and skin cancer was held at the International Agency for Research on Cancer in Lyon. The workshop concluded that the topical use of sunscreens reduces the risk of sunburn and that sunscreens probably prevent squamous-cell carcinoma of the skin when used mainly during unintentional sun exposure. No conclusion could be drawn about the cancer-preventive activity of topical sunscreens against basal-cell carcinoma and cutaneous melanoma. The use of sunscreens can extend the duration of intentional sun exposure, such as sunbathing. Such an extension may increase the risk for cutaneous melanoma. The workshop warned against relying solely on sunscreens for protection from ultraviolet radiation.

Aspirin and other NSAIDs are showing promise in the chemoprevention of colorectal cancer. Ongoing trials will eventually provide still lacking information about the optimum dose and treatment duration. NSAIDs may also help to lower the risk of cancer in other organs such as the oesophagus, and possibly breast, stomach, and lung. The chemoprevention by NSAIDs should be seen not as the sole method of prevention, but as an additional tool which will be accompanied by other approaches such as stopping smoking, limiting alcohol consumption, and eating more fruits and vegetables. The chemoprevention by NSAIDs needs also to be balanced against the risks of toxicity (particularly in the stomach) and the other beneficial effects such as prevention of cardiovascular morbidity and mortality. Some of the NSAID induced gastric ulceration and bleeding will most likely be avoided by adopting the use of cyclooxygenase-2 (COX-2) selective NSAIDs, which will selectively inhibit COX-2 while sparing COX-1.

We have reviewed the potential cancer-preventive and other relevant properties of Panax ginseng C. A. Meyer, which has been traditionally used as a natural tonic in Oriental countries. DATA IDENTIFICATION AND STUDY SELECTION: Publications on Panax ginseng and its relation to cancer were obtained from the Medline database (1983-1998) and by checking reference lists to find earlier reports. The reports cover experimental models and human studies on cancer-preventive activity, carcinogenicity and other beneficial or adverse effects. In addition, possible mechanisms of chemoprevention by ginseng were considered.Published results from a cohort and two case-control studies in Korea suggest that the intake of ginseng may reduce the risk of several types of cancer. When ginseng was tested in animal models, a reduction in cancer incidence and multiplicity at various sites was noted. Panax ginseng and its chemical constituents have been tested for their inhibiting effect on putative carcinogenesis mechanisms (e.g., cell proliferation and apoptosis, immunosurveillance, angiogenesis); in most experiments inhibitory effects were found.While Panax ginseng C. A. Meyer has shown cancer-preventive effects both in experimental models and in epidemiological studies, the evidence is currently not conclusive as to its cancer-preventive activity in humans. The available evidence warrants further research into the possible role of ginseng in the prevention of human cancer and carcinogenesis.

Some 3-10% of Caucasians are deficient in CYP2D6 metabolism (poor metabolizers), due to inheritance of two defective alleles, whereas amplification of the CYP2D6 gene results in ultrarapid metabolism in 1-2% of Caucasian populations. To examine the possible association between CYP2D6 polymorphism and individual smoking behaviour, we analysed the prevalence of CYP2D6 genotypes among 292 long-term heavy smokers, 382 individuals with more variable smoking histories, and 302 never-smokers. The prevalence of ultrarapid metabolizers in heavy smokers (7.9%) was twofold compared to individuals with variable smoking habits (3.7%; odds ratio 2.3, 95% confidence interval 1.2-4.4), and fourfold compared with never-smokers (2.0%) (odds ratio 4.2, 95% confidence interval 1.8-9.8). The frequency of poor metabolizer genotype was approximately 2%, in each smoker group. However, when men and women were studied separately, the prevalence of poor metabolizer genotype was higher in male never-smokers (3.6%) than in variable smokers (2.7%) and heavy smokers (2.2%). Moreover, a trend test, adjusted by age, gender and cancer status, revealed a significant trend for the increased tobacco usage with increased metabolic capacity. Our results are in agreement with the assumption that increased CYP2D6 activity may contribute to the probability of being addicted to smoking.

Publisher Summary Xylitol is a commonly used sweetening agent with anti-carries properties and no insulin requirement. Batchwise, three-phase hydrogenation of xylose to xylitol over Raney nickel and anomeric equilibria of xylose is studied in this chapter. Raney Ni catalyst was active but deactivated relatively rapidly. Kinetic measurements, carried out with recycled catalysts revealed that the catalyst deactivates during the use, but an asymptotic activity level is finally attained. Catalyst characterization studies (nitrogen adsorption, XRD, ESCA-XPS and gravimetric reduction) suggested that the main reasons for the deactivation is the decay of accessible active sites through collapse of the pore structure and leaching of the promoter metal (Mo) as well as alumina.

Epidemiological studies indicate that the use of aspirin decreases incidence of and mortality from gastrointestinal cancers. A major target of aspirin and other nonsteroid anti-inflammatory drugs is cyclooxygenase (Cox), the rate-limiting enzyme in the conversion of arachidonic acid to prostanoids. Two Cox genes have been cloned (Cox-1 and Cox-2), of which Cox-2 has recently been found to be expressed in several human carcinomas. We have now studied the expression of Cox-2 mRNA and protein in human lung adenocarcinoma, squamous cell carcinoma, and small cell lung cancer. Cox-2 mRNA steady-state levels were high in well-differentiated adenocarcinoma samples, but low in poorly differentiated adenocarcinoma, squamous cell carcinoma, and small cell lung cancer, as detected by Northern blot analysis. Immunohistochemistry showed Cox-2 staining in 19 of 21 adenocarcinomas. However, well-differentiated adenocarcinomas contained more Cox-2 staining than the poorly differentiated ones. Expression of the Cox-2 protein was also seen in all 11 squamous cell carcinomas studied, although the level of staining seemed to be less than that in the adenocarcinomas. Small cell lung cancer specimens (n = 4) stained with a relatively weak intensity. Interestingly, atypical alveolar epithelium, which associates with asbestosis and idiopathic fibrosing alveolitis and is considered to be a precursor lesion for lung cancer, expressed the Cox-2 protein. Our data, thus, suggest that Cox-2 is expressed in human lung carcinomas and in precursor lesions leading to this malignancy.

The IARC convened a Working Group of experts in December 1997 to evaluate the cancer-preventive potential of carotenoids and to compile the second volume of the IARC Handbooks of Cancer Prevention. In observational epidemiological studies, beta-carotene is associated with reduced risks for cancer at many but not all sites. It is unclear, however, to what extent beta-carotene itself is responsible for the decreased risks observed. Three large, randomized, placebo-controlled clinical trials indicate, however, that, in substantial doses, supplementation with beta-carotene not only does not prevent lung cancer but may actually increase the risk among individuals initially at high risk of lung cancer. These trials do not provide clear evidence concerning cancers at other specific sites. Thus, the Working Group considered that there is evidence suggesting a lack of cancer-preventive activity for beta-carotene when it is used as a supplement at high doses. At usual dietary levels of beta-carotene, the evidence for cancer-preventive activity was considered inadequate. However, there is sufficient evidence that beta-carotene has cancer-preventive activity in experimental animals, based on models of skin carcinogenesis in mice and buccal pouch carcinogenesis in hamsters. The observational epidemiological data on alpha-carotene, lycopene, and lutein are much less extensive than those for beta-carotene. For canthaxanthin, there are no published data regarding associations with cancer risk. These carotenoids have not been studied in human trials for cancer prevention. In animal models, there is sufficient evidence for canthaxanthin and limited evidence for alpha-carotene, lycopene, and lutein of cancer-preventive activity. Pending further research, supplemental beta-carotene, canthaxanthin, alpha-carotene, lutein, and lycopene should not be recommended for cancer prevention in the general population.

Glutathione S-transferases (GSTs) are known to take part in detoxification of many potentially carcinogenic compounds. Therefore, polymorphisms of the GST genes have been considered as potentially important modifiers of individual risk of environmentally induced cancers. The association between lack of glutathione S-transferase M1 gene (GSTM1 null genotype) and susceptibility to smoking-related lung cancer has been actively studied, with contradictory results. In contrast, little is known about the more recently found polymorphisms in GSTM3, GSTP1 and GSTT1 genes with respect to individual responses to environmental exposures. In this study, we determined the genotype distribution of all these genes, and their combinations, among 208 Finnish lung cancer patients and 294 population controls. None of the genotypes studied had a statistically significant effect on lung cancer risk, when studied separately. However, a significant association was observed for concurrent lack of the GSTM1 and GSTT1 genes and susceptibility to squamous cell carcinoma. For that cell type, the risk was more than 2-fold when compared with that of individuals having other genotype combinations (OR = 2.3; 95% CI = 1.0-5.3; p = 0.05). Moreover, the risk was mostly attributable to patients with smoking history of 40 pack-years or less (OR = 2.9; 95% CI = 1.1-7.7; p = 0.03). In contrast, this genotype combination did not affect the risk for other histological types of lung cancer, and the other genotype combinations had no effects on individual susceptibility to this malignancy. The overall role of GST polymorphisms in modifying the lung cancer risk may therefore be more limited than has been so far anticipated.

Cytochrome P4501A1 (CYP1A1) is involved in the bioactivation of polycyclic aromatic hydrocarbons into their reactive epoxide metabolites. CYP1A1 is considered to be important with regard to individual susceptibility to lung cancer since phenotypic and genotypic polymorphisms of CYP1A1 have been associated with an increased risk of lung cancer in a number of studies. We examined here the expression and localization of CYP1A1 mRNA in human lung tissue using in situ hybridization with a CYP1A1-specific RNA probe. A centrilobular expression of CYP1A1 mRNA was observed in the peripheral lung. The expression was intense in bronchiolar epithelium of peripheral lung, especially in terminal cuboidal epithelium. Type II alveolar epithelial cells were also intensely labelled. Type I alveolar epithelial cells and vascular epithelium exhibited binding but the hybridization signals were less intense. Our results are in good agreement with our previous work on immunohistochemical localization of CYP1A protein, in which we used the 1-7-1 MAb that recognizes both CYP1A1 and CYP1A2. In serial sections analyzed with in situ hybridization and immunohistochemistry, a similar distribution of CYP1A1 mRNA and CYP1A protein was observed. CYP1A1 mRNA is thus expressed in human lungs and the expression is particularly intense in the cell types involved in the development of peripheral lung cancers.

We performed a comparative genomic hybridization study on 25 samples of adenocarcinoma and 19 samples of squamous cell carcinoma of the lung to detect recurrent changes in the genetic material. DNA copy number changes were found in 16 squamous cell carcinoma samples and 17 adenocarcinoma samples. The most common changes were gains of DNA sequences in 3q (43%), 1q (34%), 8q (32%), 5p, (30%), 7p (25%), and 12p (25%). Of the squamous cell carcinoma samples with DNA copy number changes, 94% (15/16) had a gain in 3q (minimal common region of overlap q24-qter), whereas only 24% (4/17) of the adenocarcinoma samples with DNA copy number changes showed a gain in 3q (q22-qter) (P0.001). Six high-level amplifications in 3q (q26.2-q26.3) were detected in the squamous cell carcinoma samples but none were observed in the adenocarcinoma samples. Our results suggest that amplification of genes in 3q may be important in the tumorigenesis of squamous cell carcinoma but not necessarily of adenocarcinoma.

The ADI as a tool for risk management and regulation of food additives and pesticide residues is not readily applicable to inherent food plant toxicants: The margin between actual intake and potentially toxic levels is often small; application of the default uncertainty factors used to derive ADI values, particularly when extrapolating from animal data, would prohibit the utilisation of the food, which may have an overall beneficial health effect. Levels of inherent toxicants are difficult to control; their complete removal is not always wanted, due to their function for the plant or for human health. The health impact of the inherent toxicant is often modified by factors in the food, e.g. the bioavailability from the matrix and interaction with other inherent constituents. Risk-benefit analysis should be made for different consumption scenarios, without the use of uncertainty factors. Crucial in this approach is analysis of the toxicity of the whole foodstuff. The relationship between the whole foodstuff and the pure toxicant is expressed in the `product correction factor' (PCF). Investigations in humans are essential so that biomarkers of exposure and for effect can be used to analyse the difference between animals and humans and between the food and the pure toxicant. A grid of the variables characterising toxicity is proposed, showing their inter-relationships. A flow diagram for risk estimate is provided, using both toxicological and epidemiological studies.

People differ in their susceptibility to particular cancers and in their sensitivity to certain carcinogens. Differences in sensitivity to environmental carcinogens are determined by variations in genetic background--genetic polymorphism. Susceptibility or sensitivity factors can act at any stage in the multistage process of carcinogenesis, from exposure to carcinogens to the clinical appearance of cancer. This paper addresses the use and limitations of studies on human polymorphism for carcinogen metabolizing enzymes and their relevance for cancer control. The practical use of susceptibility and sensitivity markers in cancer control is not yet clear. Some of the potential dangers of their use are job discrimination and genetic exculpation--the 'blame the victim' attitude. Furthermore, an imprudent focus on genetic predisposition could shift the attention from carcinogens in the environment to biological 'defects' in the individual. Although carcinogens act in predisposed subjects, this should not overshadow the fact that most cancers are due to environmental factors, in both susceptible and unsusceptible individuals, and are therefore preventable. Even if individuals differ in their sensitivity to carcinogens, the primary option in cancer control must be to reduce exposure in order to include and protect the most sensitive fraction of the population.

Occupational exposure to gasoline has been identified in several studies as a risk factor for renal-cell cancer. Cases of renal-cell cancer with and without work-related exposure to gasoline or gasoline and diesel fuel were studied for the presence of mutations in the tumour-suppressor gene p53 (n = 23 exposed and 30 non-exposed cases studied) and ras oncogene (n = 30 exposed and 36 non-exposed cases studied). An average cumulative exposure was estimated at 10 ppm-years benzene among the exposed. Three p53 mutations were detected by denaturing-gradient gel electrophoresis (DGGE) among the 23 exposed cases (3/23, 13%). Of the non-exposed referent cases, 4 had a mutation (4/30, 13%). All but one of the cases with a p53 mutation had smoked. A ras gene (K-ras or N-ras) mutation was found in 3 (3/66, 4.5%) cases, all of whom were smoker referents. We conclude that p53 and ras mutations are infrequent in renal-cell cancer associated with occupational exposure to gasoline. However, the majority of the mutations (6/7 for p53, and 3/3 for ras genes) were seen in smokers.

1. Cytochrome P450 isozymes from Asian (31 Chinese subjects) and Caucasian (14 Finnish subjects) livers were examined for their roles in the metabolism of toluene (rates of benzyl alcohol, o- and p-cresol formation) and styrene (rates of styrene glycol formation). 2. For toluene, the overall rate of metabolism was higher in samples from Finnish than from Chinese subjects. At 0-20 mM toluene, the rate of o-cresol formation was significantly higher in Finnish microsomes than in Chinese ones. The formation rates of benzyl alcohol and p-cresol in Finnish samples were also higher than those of Chinese samples, but only at a high substrate concentration (5.0 mM). For styrene metabolism, the Chinese liver microsomes showed higher metabolic rates than the Finnish ones at 0.085 mM styrene, but not at the higher substrate concentration. 3. Mean expression levels of immunochemically detected CYP1A2/1 and CYP2B6 were almost 3-fold higher in Finnish microsomes, whereas CYP2E1 was 1.7-fold higher in Chinese samples. 4. Correlation analysis showed that CYP2E1 (benzyl alcohol formation) and CYP1A2/1 (o-cresol formation) contributed to the metabolism of toluene at the low substrate concentration, whereas CYP2C8 was the form more actively involved at the higher toluene concentrations. At the higher concentration (1.8 mM) of styrene, CYP2B6 was most active isozyme to catalyse the formation of styrene oxide from styrene. 5. These results suggest that CYP2E1 and CYP1A2/1 are the main isoforms responsible for the metabolism of toluene at low substrate concentrations in human liver microsomes, CYP2E1 at low styrene concentration, and CYP2C8 and CYP2B6 at high concentrations of toluene and styrene respectively.

Molecular epidemiology supplies information on various stages of the multistep process of carcinogenesis and allows identification of biological markers that may indicate an increased risk of cancer. These markers have an established position in occupational and environmental epidemiology.

In this study, we found an unexpected association (crude odds ratio = 2.8; 95% confidence interval = 0.9-8.4) between definite work-related exposure to asbestos and carcinoma of the urinary bladder in a small group of patients (n = 28) initially recruited as referents for an epidemiological feasibility study on the occupational causes of lung cancer. We extended the study by using molecular methods to examine mutations in the p53 tumor suppressor gene in the same cases of bladder cancers. The same number of archival samples of transitional cell carcinoma, mainly of grade 3, were added to the analysis. We failed to show any association between occupational exposure to asbestos and p53 mutations among bladder cancer patients. We observed an increasing occurrence of p53 mutations in nonsmokers (5 of 17, 29%), former smokers (8 of 21, 38%), and current smokers (9 of 16, 56%) in that order; however, this was not statistically significant. The most prevalent type of mutation was G:C to A:T transition. Tumor grade was not associated with the frequency of mutations, but the higher stage (T3-T4) tumors appeared to have mutations more frequently than did the less invasive tumors (T1-T2).

For more than twenty years, the IARC has been evaluating the carcinogenic risk to humans of chemicals, groups of chemicals, complex mixtures, occupational exposures, behavioral and life-style exposures, biological agents, such as bacteria and viruses, and physical agents, such as radiation, on the basis of published studies of carcinogenicity in humans and laboratory animals. This paper includes the list established by IARC of substances carcinogenic to humans.

The inactivation of the p53 suppressor gene and the activation of the ras proto-oncogenes are frequent events in non-small cell lung cancer as well as in many other solid neoplasms in man. Somatic mutations in exons 5-8 of the p53 gene were detected in 59% (30/51) of the squamous cell carcinoma and in 38% (14/37) of the adenocarcinoma tumors using GC-clamped, non-radioactive denaturing gradient gel electrophoresis (DGGE). The mutations in the exons 5 and 8 represented larger proportion of the alterations in squamous cell carcinoma tumors (p=0.04; Fisher's exact test, two-tailed); in the adenocarcinoma tumors, mutations were most common in the exon 7 of p53. Most of the identified mutations (25/39; 64%) are predicted to cause an amino acid substitution. Mutations leading to the premature termination of translation were more frequent in adenocarcinoma (6/14) than in squamous cell carcinoma (3/30) tumors (p=0.02). In adenocarcinoma, also base substitutions in the K-ras gene were detected more often (18/37; 49%) than in squamous cell carcinoma (p

Cancer incidence during 1953 to 1991 in 811 Finnish silicotic patients diagnosed between 1936 and 1977 was evaluated. In comparison with the general population, excesses were observed for all cancers (standardized incidence ratio, 1.7 [95% confidence interval, 1.4 to 1.9]), all lung cancers (2.9 [2.4 to 3.5]), squamous cell lung cancers (3.3 [2.3 to 4.5]), and skin cancers: melanoma (3.0 [0.8 to 7.6]) and nonmelanoma (2.9 [1.2 to 6.1]). Confounding by tobacco smoking did not explain the lung cancer increment. The consistency of the association between silicosis and lung cancer across a large number of studies suggests that silicosis represents a direct or indirect lung cancer hazard. The skin cancer excess, a relatively novel finding, may be explained either by carcinogens in foundries, or silica-induced lowering of immunocompetence, which would lead to a more pronounced effect of solar ultraviolet radiation.