Cytochrome P4501A2: enzyme induction and genetic control in determining 4-aminobiphenyl-hemoglobin adduct levels.

Cytochrome P4501A2 (CYP1A2) activity may be related to bladder cancer risk through metabolic activation of aromatic amines, such as 4-aminobiphenyl (ABP), to reactive intermediates that can form DNA and hemoglobin (Hb) adducts. In the context of a study on smoking and bladder cancer risk, 97 healthy male volunteers were investigated. CYP1A2-dependent N-oxidation activity was measured using a molar ratio of urinary caffeine metabolites [(paraxanthine + 1,7-dimethyluric acid)/caffeine] obtained between the fourth and fifth h after drinking a standardized cup of coffee. N-Oxidation activity was induced by blond tobacco smoke, meat consumption the dinner before the test, or more than four cups of coffee a day. The regular use of medication appeared associated with a decrease in N-oxidation levels. Age and alcohol consumption were not related with CYP1A2 activity. A polymorphic distribution of the CYP1A2 and N-acetyltransferase-2 (determined by the caffeine metabolite ratio 5-acetylamino-6-formylamino-3-methyluracil:1-methylxanthine) phenotypes was examined in relation to susceptibility to ABP-Hb adduct formation. Rapid oxidizers and subjects with the combined slow acetylator-rapid oxidizer phenotype showed the highest ABP-Hb adduct levels at a low smoking dose. Blond tobacco smokers exhibited higher adduct levels compared with black tobacco smokers, after adjustment for the quantity of cigarettes smoked. At the highest levels of smoking exposure, no major difference in ABP-Hb adduct levels was found among the different combinations of CYP1A2 and N-acetyltransferase-2 phenotypes. In a subset of only 45 available samples, no association was seen between the ABP-Hb adduct levels and the glutathione S-transferase M1 genotype.

The Seveso studies on early and long-term effects of dioxin exposure: a review.

The industrial accident that occurred in the town of Seveso, Italy, in 1976 exposed a large population to substantial amounts of relatively pure 2,3,7,8-tetrachlorodibenzo-p-dioxin. Extensive monitoring of soil levels and measurements of a limited number of human blood samples allowed classification of the exposed population into three categories, A (highest exposure), B (median exposure), and R (lowest exposure). Early health investigations including liver function, immune function, neurologic impairment, and reproductive effects yielded inconclusive results. Chloracne (nearly 200 cases with a definite exposure dependence) was the only effect established with certainty. Long-term studies were conducted using the large population living in the surrounding noncontaminated territory as reference. An excess mortality from cardiovascular and respiratory diseases was uncovered, possibly related to the psychosocial consequences of the accident in addition to the chemical contamination. An excess of diabetes cases was also found. Results of cancer incidence and mortality follow-up showed an increased occurrence of cancer of the gastrointestinal sites and of the lymphatic and hematopoietic tissue. Experimental and epidemiologic data as well as mechanistic knowledge support the hypothesis that the observed cancer excesses are associated with dioxin exposure. Results cannot be viewed as conclusive. The study is continuing in an attempt to overcome the existing limitations (few individual exposure data, short latency period, and small population size for certain cancer types) and to explore new research paths (e.g., differences in individual susceptibility).

[Bis-chloromethyl ether and carcinogenesis of alkylating agents]. / Bis-Cloro-Metil-Etere e cancerogenicità da sostanze alchilanti.

Bis-Chloro-Methyl-Ether is an alkylating agent and a recognised carcinogen. It can form spontaneously from the reaction of chloridric acid with formaldehyde. In the past it was extensively used as a chemical intermediate in organic synthesis, particularly as a crosslinking agent in the manufacture of ion-exchange resins. Recently, since its carcinogenicity has been proved in animal studies and confirmed in epidemiological studies of occupationally exposed cohorts, its use has been consistently reduced. A characteristic association has been observed between BCME exposure and a peculiar lung cancer histotype (oat cell carcinoma). In spite of these data, little information is available on the molecular alterations related to BCME exposure and possibly to its carcinogenic activity. Some suggestions can reasonably be obtained considering how the class of alkylating agents acts. They form adducts, binding different positions of DNA bases. The reaction that seems more relevant for mutagenesis and carcinogenesis is the alkylation at the atom O6 of guanine in DNA, which is followed by mis-coding and GC-->AT transition mutation. This kind of alteration determines the activation of a group of enzyme like DNA repair, mismatch repair, excision repair and a specific one, methyl guanine methyl transferase (MGMT). This last repair protein transfers alkyl groups from the O6 position of guanine to an internal cysteine residue, inactivating itself. Thus, the possibility for the cell to eliminate alkylated DNA bases depends strictly upon the cellular content of MGMT. In this view reduced or absent levels of the enzyme are associated with an increased number of adducts and hence increased risk of DNA mutations and cancer. At the moment no molecular studies in vivo have been performed to verify this hypothesis. The peculiar association BCME-oat cell carcinoma, the most chemosensitive tumor, need further investigation.

[IARC multicenter study on neoplastic disease caused by man-made vitreous mineral fibers (MMVF)]. / Studio multicentrico IARC sulla patologia neoplastica da fibre minerali artificiali vetrose (MMVF).

Man-made vitreous fibres (MMVF) showed carcinogenic potential in experimental animals. Epidemiological data suggested an increased mortality from lung cancer among production workers, but the interpretation is still a matter of controversy. A European study encompassing 13 plants in 7 countries pointed towards a moderate excess of lung cancer among workers employed longer than 1 year in the production of rock/slag wool (SMR = 1.34, 95% CI = 1.08-1.63) and glass wool (SMR = 1.27, 95% CI = 1.07-1.50); the latter increase was not confirmed after applying local rates to calculate expected deaths. The elevated risk among rock/slag wool producers was present even in comparison with local rates, and was associated with increasing time from first exposure, and duration of exposure. Glass wool results exhibited a less definite pattern. Smoking was excluded, although indirectly, as a sufficient alternative explanation of the increased lung cancer risk. In a few plants, exposure to asbestos had occurred in limited periods for some workers, and might have contributed to the findings. Case-control studies are under way to thoroughly investigate the relative and possibly combined role of the different exposures, either occupational or not. Cohort studies in the USA produced results closely consistent with those of the European study.

Mortality study in an Italian oil refinery: extension of the follow-up.

This article present the results of the extension of the follow-up of a cohort of workers employed in an Italian oil refinery. 1,583 workers employed in 1949-1982 in a northern Italy oil refinery plant were followed-up for mortality as of May 31, 1991. Environmental measurements documented potential exposure to benzene. Standardized mortality ratios (SMR) and their 95% confidence intervals (95% CI) were calculated using as references national (1949-1968) and regional mortality rates (1969-1991). Elevated mortality from lymphoma (seven deaths, SMR 190, 95% CI 76-391) and leukemia (eight deaths, SMR 225, 95% CI 97-443) was observed. No consistent trends by length of employment or time since first exposure were apparent. Nonetheless, the excess risk was particularly and significantly increased among workers with 15 or more years of employment, and 30 or more years since first employment. The findings of elevated mortality from leukemia and lymphoma are in agreement with those of other oil refinery studies. Chance, confounding, or other biases might have played a marginal, if any, role in determining the results. Exposure to benzene is a biologically plausible explanation.