Importance of hazard identification and exposure monitoring in primary prevention of cancer.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
H Vainio
Publications and source records attributed to H Vainio.
Styrene revisited--exposure assessment and risk estimation in reinforced plastics industry.
A survey performed in 32 workshops in reinforced plastics industry showed the mean TWA 8 h concentration of styrene in personal air to be 43 ppm (range 5-182 ppm) among laminators and 11 ppm (range 1-133 ppm) among other workers. The biological measurement of urinary mandelic acid + phenylglyoxylic acid showed mean values of 2.4 mmol/l among laminators without respirators and 1.3 mmol/l when respirators were used. No effects of work related exposure were detected in the cytogenetic parameters, chromosome aberrations, sister chromatid exchanges or micronuclei analyzed in peripheral blood lymphocytes. Grading of the exposure on the basis of lamination method, years of exposure, daily laminating time, air styrene concentration and urinary mandelic acid among laminators, neither revealed any dose dependency.
Air Pollutants, Occupational↗
Use of exposure information and animal cancer data in the prevention of environmental and occupational cancer.
In order to prevent cancer, a hazard should optimally be identified before humans are exposed to it. Therefore, valid procedures should be available for predicting human risks on the basis of experimental results. The adequacy of experimental data for identifying potential human health risks have been the subject of scientific question and debate. Use of such results and of data on exposure in setting priorities for cancer prevention should, in principle, be feasible in view of the relatively good correlation between animal and human data. Studies have also revealed a reasonable quantitative relationship between carcinogenic potencies of several chemicals in laboratory rodents and humans. The ranking of cancer hazards on the basis of experimental data requires estimates of both the extent of human exposure and of the size of the exposed population. Occupational exposures can result in high individual exposures, whereas the general population is usually exposed to lower levels. Action for cancer prevention can be taken at both levels.
Animals↗
Monoclonal antibody-directed characterization of benzene, ethoxyresorufin and pentoxyresorufin metabolism in rat liver microsomes.
The contribution of cytochrome P450IA, P450IIB, P450IICII and P450IIEI to the oxidative metabolism of benzene, 7-ethoxyresorufin and 7-pentoxyresorufin was investigated using monoclonal antibodies (MAb) in liver microsomes from fed, one-day fasted, phenobarbital (PB)-, 3-methylcholanthrene (MC)- and ethanol-treated rats. Overall catalytic activity varied with different pretreatments and thereby the contribution of different P450s. MAb 1-91-3 against P450IIE1 did not influence alkoxyresorufin dealkylation but inhibited benzene aromatic hydroxylase (BAH) in relation to its increasing inducibility as follows: MC, PB (less than or equal to 48%) less than fed (less than or equal to 59%) less than fasted (less than or equal to 70%) less than ethanol (less than or equal to 91%). MAbs 2-66-3, 4-7-1 and 4-29-5, all against P450IIB, had no effect on 7-ethoxyresorufin O-deethylase (EROD) but inhibited the activities of high-Km BAH (greater than or equal to 58%) and 7-pentoxyresorufin O-depentylase (PROD) (greater than or equal to 96%) in PB-treated microsomes. MAb 1-7-1 against P450IA inhibited EROD (79%), PROD (50%) and high-Km BAH (42%) activities in MC-microsomes. MAb 1-68-11 against P450IIC11 inhibited EROD, PROD and high-Km BAH activities. Thus, P450IIE1 contributed to benzene metabolism as a low-Km BAH but not to alkoxyresorufin metabolism. P450IIB was responsible besides for the major part of 7-pentoxyresorufin metabolism also, selectively, for benzene hydroxylation at high benzene concentrations. P450IA contributed primarily to 7-ethoxyresorufin metabolism and only slightly to PROD and high-Km BAH activities. P450IIC11 contributed slightly to high-Km BAH and to alkoxyresorufin metabolism.
Animals↗
Human biomonitoring in exposure to environmental genotoxicants.
Explore the source record for details and available documents.
Carcinogens, Environmental↗
Pulmonary toxicity of inhaled styrene in acetone-, phenobarbital- and 3-methylcholanthrene-treated rats.
Pulmonary changes in glutathione (GSH) indicated by the concentration of non-protein sulphydryls showed a decrease of 43% in rats exposed for 5 h per day three times to 500 cm3/m3 (2100 mg/m3) styrene vapour. In these rats, only a marginal decrease was observed in the pulmonary cytochrome P450 oxidative metabolism. Following a single 24-h inhalation exposure to 500 cm3/m3 styrene, the decreases in GSH were 66% in lung but only 16% in liver. On the other hand, a multifold increase in the disposition of thioether compounds was found in urine. Pulmonary cytochrome P450-dependent metabolism was decreased, shown by low residual activities of 7-ethoxyresorufin (less than 20%), 7-ethoxycoumarin (53%) and 7-pentoxyresorufin O-dealkylases (76%). Epoxide hydrolase and GSH S-transferase enzyme activities which catalyze styrene detoxification were not decreased. Styrene exposure (24 h) of acetone-, phenobarbital- or 3-methylcholanthrene-pretreated rats resulted in pulmonary effects different from each other and from those of styrene alone. Acetone potentiated the lung effect and elevated 1.5-fold urine thioether output. Inducer pretreatment seemed to be a factor aggravating styrene toxicity; in effect this was clearest in acetone-induced rats. In general, GSH depletion accompanied by inhibition of cytochrome P450-dependent oxidative drug metabolism were the earliest biochemical lesions manifested in styrene-exposed lung.
Acetone↗
[Chlorinated dioxins and dibenzofurans--threat to the national health?].
Explore the source record for details and available documents.
Abnormalities, Drug-Induced↗
Epidemiological and experimental applications to occupational cancer prevention.
At present, there is a whole array of risk factors, such as industrial chemicals, drugs, pesticides, complex chemical mixtures, physical and biological agents, for which there is a proven causal relationship with human cancer. The epidemiological studies are essential in providing proof for a causal relationship in humans. However, the epidemiological approach to the identification of the etiology of cancer is limited for two main reasons: only relatively high risks can be detected; and, secondly, the epidemiological surveys are based on observations of the effects as a consequence of an exposure that took place many years before. It can be estimated that epidemiological cancer research on common types of tumours is able to detect risk levels ranging from 5 x 10(-2) to 10(-3). This is, of course, far from commonly defined "acceptable risk" of 10(-5) - 10(-6). Frequently, negative epidemiological studies are thought to provide evidence of non-carcinogenicity, even though the exposure levels were so low that no such effect could even be expected. While the epidemiological studies have their greatest limitation in not being able to detect a low risk, that is to produce "false negative" results, carcinogenicity tests in experimental animals have been criticized in producing "false positive" results, i.e., in picking up cancer risks at very high exposure levels. Some investigators hold that the relatively high exposure levels given to experimental animals often results in carcinogenicity because of compensatory cell proliferation from toxic effects of the chemical, and accordingly, they have questioned the use of the Maximum Tolerated Dose (MTD). However, most of the chemicals determined to be carcinogenic would exhibit carcinogenic effects at exposure levels below the level of target organ toxicity. All epidemiologically proven human carcinogens which have been adequately studied, are also carcinogenic in laboratory animals. This does not necessarily mean that all animal carcinogens are human carcinogens. A more comprehensive evaluation of interspecies correlation between humans and rodents is limited by the lack of known human non-carcinogens. Nevertheless, the high interspecies correlation shown between rats and mice supports the view that extrapolation of carcinogenicity outcomes to other species, including humans, is appropriate. There is now a range of short-term laboratory tests which have been used to predict the results of long-term tests of carcinogenicity in mammalian species. Prediction is not entirely accurate, mainly because a fraction of carcinogens is active via a mechanism not employed by the short-term tests.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Effects of commercial chlorophenolate, 2,3,7,8-TCDD, and pure phenoxyacetic acids on hepatic peroxisome proliferation, xenobiotic metabolism and sister chromatid exchange in the rat.
The induction of hepatic peroxisome proliferation and drug metabolizing enzymes and of sister chromatid exchange (SCE) in lymphocytes was studied in male Han/Wistar rats after exposing them for 2 weeks to a commercial chlorophenolate formulation (Ky-5) (100 mg/kg/day), to 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD; 0.05-5 micrograms/kg/wk) and to the pure phenoxyacetic acids, 2,4-dichlorophenoxyacetic acid (2,4-D; 100 mg/kg/day) and 2-chloro-4-methylphenoxyacetic acid (MCPA; 100 mg/kg/day). The chlorophenolate formulation and pure 2,4-D and MCPA caused significant increases in the number of peroxisomes in liver cells, although the average size of peroxisomes was not affected, whereas the effect of even the highest dose of 2,3,7,8-TCDD remained small. This finding indicates that dioxin impurities do not account for the peroxisome proliferation induced by chlorophenolate. The relative weight of the liver increased significantly in rats treated with the chlorophenolate formulation and with 2,3,7,8-TCDD (5.0 and 0.5 micrograms/kg). The pattern of induction of xenobiotic metabolizing enzymes showed some differences between chlorophenolate treatment and 2,3,7,8-TCDD treatment. Furthermore, the effects of pure phenoxyacetic acids were different from that seen with chlorophenolate and 2,3,7,8-TCDD. The highest dose of 2,3,7,8-TCDD increased the frequency of SCE in circulating lymphocytes slightly, but significantly.
Animals↗
Cytogenetic effects of tobacco smoke exposure among involuntary smokers.
Tobacco smoke is highly genotoxic and produces chromosomal damage in several experimental systems. Active smokers have been shown to have an increased prevalence of somatic chromosome damage in their peripheral blood lymphocytes: this is seen in most cases as an increased sister-chromatid exchange (SCE) frequency and often also as increased structural chromosome aberrations (CAs). Among passive smokers, in association with exposure to environmental tobacco smoke, no such induction of chromosomal damage has been documented. In the present paper we report negative results on induction of chromosomal damage in 2 separate groups of intensive involuntary exposure to tobacco smoke, non-smoking restaurant personnel and newborn children of smoking mothers. While significant exposure in these groups is clearly seen in biochemical intake markers, e.g. cotinine and thiocyanate values in plasma, the conventional cytogenetic parameters, structural chromosome aberrations and sister-chromatid exchanges, are unable to detect the low exposures of involuntary smokers.
Cells, Cultured↗
Population burden of lung cancer due to environmental tobacco smoke.
The population burden of lung cancer due to environmental tobacco smoke is significant because a large fraction of the population is exposed. The risks are, of course, lower than those to smokers themselves; but smoking is self-inflicted, passive smoking is involuntary. Making various assumptions, the proportion of lung cancer cases among non-smokers that could reasonably be attributed to environmental tobacco smoke can be calculated to be about 20-30% in western countries. Thus, non-smokers in the society could benefit considerably from diminishing exposures to other people's smoke.
Humans↗
Immunochemical characterization of cytochrome P-450 isozymes responsible for benzene oxidation in the rat liver.
The contribution of cytochrome P-450 isozymes to benzene metabolism in liver microsomes from fed, fasted, pyrazole-, phenobarbital (PB)- and ethanol-treated rats and in respective isocaloric controls was investigated using monoclonal antibodies (mAbs). Clone 1-7-1 mAb did not inhibit benzene metabolism, whereas clone 2-66-3 inhibited only in PB-induced microsomes at a high concentration of benzene (6.26 mM), and clone 1-91-3 mAb inhibited benzene metabolism in all cases. The degree of inhibition was as follows: fed congruent to isocaloric control congruent to PB less than fasted less than pyrazole congruent to ethanol. The pattern of inhibition was similar with clone 1-91-3 for low (0.23 mM) and high concentrations of benzene, except in PB-induced microsomes. Western blot analysis showed that clone 1-7-1 mAb did not bind any liver microsomal protein in the region of cytochrome P-450s, whereas with clone 2-66-3 a clear-cut band was seen only in liver microsomes from PB-treated rats, with clone 1-98-1, a band was detected in microsomes from all treated groups, in the following order: PB = isocaloric control less than fed less than fasted less than pyrazole less than ethanol. These results indicate that (i) cytochromes P-450b,e and P-450j contribute to benzene metabolism in rat liver; (ii) the former has a low affinity to benzene and is induced by PB; and (iii) P-450j has a high affinity to benzene and is induced by 1-day fasting, pyrazole and ethanol, but decreased by PB treatment.
Animals↗
Chlorinated dioxins and dibenzofurans in the environment--a hazard to public health?
Polychlorinated dibenzodioxins (PCDD) and polychlorinated dibenzofurans (PCDF) are globally distributed, are persistent in the environment, and tend to accumulate in human tissues. Several 2,3,7,8-substituted PCDD and PCDF have been found at parts-per-trillion levels in human milk and adipose tissue. Food is the major source for the general population. Above-average exposures may be caused by the incineration of various wastes, certain industries (eg, metal and paper and pulp), and traffic exhaust. PCDD and PCDF have been of great public concern because one of the congeners, 2,3,7,8-tetrachlorodibenzodioxin, is an extremely potent carcinogen and teratogen in rodents. Although epidemiologic studies on cancer are too few for conclusions, animal studies and documented human exposure suggest that humans may be at increased risk. Human exposure is generally low when compared with the effective levels for rodents. However, part of the population can be more exposed and, consequently, also be potentially at higher risk.
Air Pollutants↗
Carcinogenesis and teratogenesis may have common mechanisms.
The specific mechanisms of carcinogenesis and teratogenesis are poorly understood. There are, however, some known or potential common mechanisms, such as gene or chromosome mutations, interference with gene expression, altered membrane properties, or altered intracellular homeostasis. Carcinogenesis is generally regarded as a multistage process, and a carcinogen can act at one or several stages. Agents acting in the early stages of the neoplastic process are DNA-reactive, mutagenic compounds which enable cells to be transformed to malignancy. These agents can also, if acting during critical periods of ontogenesis, induce abnormal development of the embryo. Agents which block gap junctional intercellular communication may act both as tumor-promoting agents and ans teratogens in the developing embryo. Hormones are essential in the control of development and differentiation. Modulation of the intracellular hormone receptors may lead to changes in homeostasis with abnormal cellular proliferation and development as a consequence.
Animals↗
Occupational cancer prevention.
Studies of occupational cancer are particularly significant for primary prevention of cancer. Firstly, most cancers, once identified, can be prevented by reasonably simple means, without impinging on personal freedom. Secondly, the prevention of occupational cancers represents a saving of lives and the elimination of illness during the most active period of the lifespan. A third reason for investigating occupational cancers is that, in some cases, workers represent a particularly heavily exposed subgroup, and the occupational setting thus serves as a laboratory for the general environment. The protection of human health in the workplace should not depend solely on the epidemiological demonstration of existing risks; it is essential that results of predictive toxicology from long- and short-term laboratory studies also be used in the identification of possible carcinogenic risk factors.
Carcinogens↗
Is passive smoking increasing cancer risk?
Although the amounts of environmental tobacco smoke absorbed by passive smokers are small in comparison to those absorbed by active smokers, the fact that (almost) everybody in modern society is exposed makes it an important public health problem. The many published epidemiologic studies are all consistent with a 30% increase in the risk of lung cancer. This increase is plausible in relation to the exposure levels derived from various biological dose indicators. The risks of passive smokers are, of course, smaller than those of active smokers, but it is generally accepted that involuntary risks should be much smaller than those that are self-inflicted. Even a relative risk for lung cancer of 1.3 due to passive smoking would constitute an increase on the order of 1 in 1,000 in the lifetime risk. Normally, this level would be considered "unacceptable," and preventive measures should be taken.
Humans↗
Metabolic host factors as modifiers of reactive intermediates possibly involved in human cancer.
Explore the source record for details and available documents.
Animals↗
Response of experimental animals to human carcinogens: an analysis based upon the IARC Monographs programme.
Only the results of epidemiological studies can be used to establish a causal relationship between an exposure to an agent and human cancer; however, such studies often cannot be carried out due to limitations of population or latent period or to the presence of mixed exposures. It is essential, therefore, that the validity be established of extrapolating to humans the results obtained from long-term carcinogenicity tests in animals. The responses of experimental animals to known and suspected human carcinogens, as evaluated in the IARC Monographs series, were analysed as an indication of the sensitivity of animal tests for predicting human carcinogens. Although the response was high - 84% - it would have been even higher had all the compounds been adequately tested experimentally. An additional finding was that for many exposures causally related to human cancer, there is a target organ in common between humans and at least one animal species, despite many inherent physiological differences. These findings show clearly the importance of experimental carcinogenicity studies in the primary prevention of cancer.
Animals↗