Exposures to carcinogens and consequences of listing of carcinogens in the Swedish working environment.
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Biomedical subjects
Publications and source records attributed to B Holmberg.
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Dioxane, perchloroethylene, and trichloroethylene were investigated as rat liver altered foci promoters in an initiation/promotion protocol. Animals were initiated with diethylnitrosamine, 30 mg/kg, injected i.p. 24 h after 2/3 partial hepatectomy. The chemical under study was administered by gavage once a day, 5 times a week for 7 weeks. Ten days after the last administration the animals were killed. Liver sections were stained for gamma-glutamyl-transpeptidase (GGT) and the number and total volume of GGT-positive foci was studied. Dioxane (1000 mg/kg) significantly increased the number and total volume of foci while a marginal effect was noted for the high dose of trichloroethylene (1100 mg/kg). A high dose of perchloroethylene (1100 mg/kg) had no effect.
Exposure to combustion engine exhaust and its effect on crews of roll-on roll-off ships and car ferries and on bus garage staff were studied. The peak concentrations recorded for some of the substances studied were as follows: total particulates (diesel only) 1.0 mg/m3, benzene (diesel) 0.3 mg/m3, formaldehyde (gasoline and diesel) 0.8 mg/m3, and nitrogen dioxide (diesel) 1.2 mg/m3. The highest observed concentration of benzo(a)pyrene was 30 ng/m3 from gasoline and diesel exhaust. In an experimental study volunteers were exposed to diesel exhaust diluted with air to achieve a nitrogen dioxide concentration of 3.8 mg/m3. Pulmonary function was affected during a workday of occupational exposure to engine emissions, but it normalized after a few days with no exposure. The impairment of pulmonary function was judged to have no appreciable, adverse, short-term impact on individual work capacity. In the experimental exposure study, no effect on pulmonary function was observed. Analyses of urinary mutagenicity and thioether excretion showed no sign of exposure to genotoxic compounds among the occupationally exposed workers or among the subjects in the experimental study.
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The concentration from inhalation of trichloroethylene (TCE) in venous blood from female rats was studied. Exposure consisted of 200, 400 and 500 ppm for 6 hrs, or 50 and 100 ppm for 2 hrs. In each experiment, 1 rat was exposed at a constant concentration of TCE. Blood samples were obtained from an indwelling jugular cannula throughout the experiment. Combination effects with chloral hydrate (0.2 g/kg), ethanol (0.8 ml/kg), isopropanol (0.8 ml/kg), pyrazole (0.2 g/kg), tetraethylthiuram disulfide (TETD; 0.2 g/kg) or tetrachloroethylene (TTCE; 1 g/kg) given orally were observed. The experimental data on the uptake of TCE in blood were fitted, by use of nonlinear regression analysis, to a simple toxicokinetic model. TETD caused the greatest increase in the steady state concentration of TCE (3.7 X), compared to TCE alone at 200 ppm. Isopropanol, pyrazole and TTCE also produced pronounced effects, but chloral hydrate treatment resulted in no significant change. At 50 and 100 ppm TCE exposure for 2 hrs, a significant increase (almost 3 X) in the steady state concentration of TCE from both ethanol and isopropanol was observed.
The mortality and incidence of cancer was studied among 8,734 workers from two Swedish rubber manufacturing companies. Mortality was investigated from 1952 to 1981 and cancer incidence from 1959 to 1980. The expected numbers of deaths were calculated from national statistics. No significant risk excesses were detected when the cohort was analyzed without consideration of employment time or latency period. However, the mortality from coronary heart disease and the incidence of lung cancer were increased when the study period was limited to greater than or equal 40 years since first employment. The standardized mortality ratio for coronary heart disease correlated positively with employment duration. The mortality from asthma, bronchitis, and emphysema was nonsignificantly increased. The incidence of bladder cancer was increased among individuals with heavy and long-term exposure in the weighing and mixing departments. Twenty-five percent of the individuals in the cohort were not Swedish citizens at the time of employment, and an analysis of the mortality and cancer incidence in this group showed a markedly increased lung cancer incidence for certain immigrant groups, probably mainly due to ethnic factors. The results indicate that ethnic factors must be considered in the analysis of occupational groups when a high proportion of the workers are immigrants.
The national occupational standard values for benzene are 10 ppm for Australia, 10 ppm for Denmark, 10 ppm for Finland, 10 ppm for Japan, 10 ppm for The Netherlands, 10 ppm for the United States, and 5 ppm for Sweden; in the Federal Republic of Germany the technical guideline value is 8 ppm. Crude mineral oil contains benzene as a natural constituent of approximately 0.1%. Gasoline in Sweden may contain 4-5% benzene by volume. The 8-hour time-weighted average (TWA) exposure levels of Swedish petroleum refinery workers vary between 0.1 to 1 mg benzene/m3 in air. The exposures of benzene in various other occupations were measured and described. Other environmental exposures to benzene may have their origin in pyrolysis, such as tobacco smoking and burning of substances such as polyvinylchloride.
Female mice were exposed to 500 ppm vinyl chloride (VC) for 6 h/day 5 days/week for 1-8 weeks. Groups of mice were killed at different times during this period. DNA damage, expressed as single-strand breaks (SSB), was studied in liver, kidneys, lungs, spleen and brain. The level of SSB increased in liver, kidneys, spleen and lungs with time of exposure and reached a plateau for kidneys and lungs after 80 and 120 h of exposure. In spleen there was only a slight increase in the SSB, and in brain no detectable increase was found.
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The irritating aldehyde acrolein was injected intraperitoneally into mice. A single injection at 4 mg/kg gave rise to a 5-fold increase in plasma total lactate dehydrogenase (LDH) activity, with the peak after approximately 10 h. The pattern of LDH isoenzymes was not altered. Repeated injections (daily or weekly) caused a progressively less pronounced effect on the LDH activity. Experiments with formaldehyde and crotonaldehyde gave essentially the same results. The LD50 for acrolein i.p. in mice was increased from a level of 7 mg/kg to a level of 12 mg/kg by pretreatment with sublethal doses of 4 mg/kg/day for 5 days. Thus, the response to repeated acrolein injections, in terms of LDH and LD50, indicates an acquired tolerance against the irritant. Likewise, pretreatment with formaldehyde or crotonaldehyde could induce tolerance, in terms of LDH activity, towards a subsequent injection of acrolein. Histopathological examination revealed that spleen, adrenals and thymus were affected. The thymus markedly decreased in size after repeated injections of acrolein, crotonaldehyde or formaldehyde. Adrenalectomized mice given acrolein showed no thymus atrophy. A single injection of aldehyde caused an increased level of the adrenal hormone corticosterone in blood plasma. Adrenalectomized mice still showed a certain tolerance, in terms of LDH activity, after repeated injections of acrolein, but the increase in plasma LDH activity was smaller than for normal animals. Treatment with acrolein for six days did not change the level of reduced glutathione or the glutathione S-transferase activity in liver cytosol, but the rate of glutathione synthesis was increased. It is concluded that adrenalectomy does not completely prevent the development of tolerance in mice. It is possible that an increased metabolism can partially explain the acquired tolerance.
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A cohort of 13,114 workers employed during 1930-1975 in two Swedish plants producing tires and industrial rubber goods was investigated with regard to cancer mortality and cancer incidence. Separate analyses were performed on the following subgroups of the cohort: mixers/weighers, other production workers, and white-collar employees. For all causes of death no increase of risk was observed in the population as a whole. Mixers/weighers showed however an increased overall standardized mortality ratio. The pattern of causes of death was not changed in the total cohort. An increased risk to die from liver cancer (risk ratio 4.12) and pancreatic cancer (risk ratio 2.70) was, however, observed for the category other production workers. An increased risk of death from tumors of the respiratory organs was also observed for the categories other production workers (risk ratio 1.89) and white-collar employees (risk ratio 2.63). For tumors in the urinary bladder (risk ratio 2.50) and for ischemic heart diseases (risk ratio 1.27) the death risk was elevated for the category other production workers. The cancer morbidity pattern showed an increase in malignant melanomas (risk ratio 2.50) for the category other production workers and for lung cancer (risk ratio 2.09), as well as for tumors in the nervous system (risk ratio 3.18) for white-collar employees.
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Personnel lists from four PVC-processing industries were collected on production of employees with at least three months of employment at the beginning of 1945 and the last day of employment December 31, 1974. Of 2073 persons, 103 could not be followed up, because they had moved abroad. The remaining persons comprise the cohort of 1970 individuals who were analyzed and compared with the national population with respect to mortality from various diseases and cancer morbidity. The death risk from myocardial infarction is elevated in the cohort. This elevation is most clearly apparent in the subcohort which had at least two years of exposure time and where the analysis was directed at circumstances chronologically close to the time of exposure. The myocardial infarction risk related to vinyl chloride exposure is discussed in relation to earlier studies on the vascular effects of vinyl chloride. An indication of an elevated risk of morbidity and mortality from tumors in the digestive organs is also present. However, this is not statistically confirmed. A few future follow-ups of the present study are necessary in order to clarify any possible elevated risk of tumors in the PVC-processing industry.
1,1,1,-Trichloroethane, benzene, trichloroethylene, tetrachloroethylene, dibromoethane, 1,2-dichloroethane, and 1,1,2,2-tetrachloroethane were applied to the skin of guinea-pigs for histopathological studies. Biopsies taken at different times of exposure showed the presence of karyopyknosis for all solvents tested; 1,1,1-trichloroethane, benzene, trichloroethylene, and tetrachloroethylene showed karyolysis; 1,1,1-trichloroethane, benzene, trichloroethylene, tetrachloroethylene, and dichloroethane induced spongiosis. All solvents, except 1,1,2,2-tetrachloroethane, produced junctional separation. Pseudoeosinophilic infiltration occurred for all solvents, except for 1,2-dichloroethane. The results are discussed in terms of occupational hazards and in relation to parallel studies on blood uptake and systemic toxicity at epicutaneous administration.
Disulfiram (DS) was administered perorally once a day to rats for 30 days to investigate the effects on cytochrome P-450 content and benzo(a)pyrene (BP) monooxygenase activity in microsomes isolated from the small intestinal mucosa. 50 mg or 100 mg DS/kg body weight caused a dose-related increase in BP monooxygenase activity, whereas the content of cytochrome P-450 was increased at the higher dose only. Similar absorption characteristics of cytochrome P-450 and turnover rates for BP on the basis o f cytochrome P-450 was observed among the different microsomal preparations. The addition of DS or diethyldithiocarbamate (DDTC) to incubates of intestinal microsomes inhibited BP monooxygenase activity. Microsomes isolated from DS-treated rats were however less sensitive to in vitro inhibition by DS.