Cancer risk in patients hospitalised for Graves' disease: a population-based cohort study in Sweden.

BACKGROUND: The possibility of an association of Graves' disease (GD) with subsequent cancers raised by certain studies. METHODS: Using a database on 18 156 hospitalised GD patients, subsequent cancers were ascertained. RESULTS: Increased risks of thyroid and parathyroid tumours were limited to the early follow-up period, which is probably a surveillance bias. Cancer sites with observed excess included the mouth and breast, in contrast to decreased risks of colon cancer, melanoma and non-Hodgkin's lymphoma. CONCLUSION: Increased subsequent cancers in GD patients appeared to be balanced by decreased risks at other sites; chance cannot be excluded.

An evaluation of styrene genotoxicity using several biomarkers in a 3-year follow-up study of hand-lamination workers.

A study employing several biomarkers of styrene exposure and genotoxicity was carried out in a group of lamination (reinforced plastic) workers and controls, who had been repeatedly sampled during a 3-year period. Special attention will be paid to the last sampling (S.VI), reported here for the first time. Styrene concentration in the breathing zone, monitored by personal dosimeters, and urinary mandelic acid (MA) were measured as indicators of external exposure. Blood samples were assayed for styrene-specific O6-guanine adducts in DNA, N-terminal valine adducts of styrene in haemoglobin, DNA single-strand breaks (SSB), determined by use of the single cell gel electrophoresis (Comet) assay), and hypoxanthine guanine phosphoribosyl transferase (HPRT) mutant frequencies (MF) in T-lymphocytes. O6-styrene guanine adduct levels were significantly higher in the exposed group (5.9 +/- 4.9 adducts/10(8) dNp) as compared to laboratory controls (0.7 +/- 0.8 adducts/10(8) dNp; P = 0.001). DNA adduct levels significantly correlated with haemoglobin adducts, SSB parameters and years of employment. Styrene-induced N-terminal valine adducts were detected in the lamination workers (1.7 +/- 1.1 pmol/g globin), but not in the control group (detection limit 0.1 pmol/g globin). N-terminal valine adducts correlated strongly with external exposure indicators, DNA adducts and HPRT MF. No significant correlation was found with SSB parameters. A statistically significant difference in HPRT MF was observed between the laminators (22.3 +/- 10.6/10(6)) and laboratory controls (14.2 +/- 6.5/10(6), P = 0.039). HPRT MF in the laminators significantly correlated with styrene concentration in air, MA and haemoglobin adducts, as well as with years of employment and age of the employees. No significant difference (P = 0.450) in MF between the laminators and the factory controls was observed. Surprisingly, we detected differences in MF between sexes. When data from all measurements were combined, women showed higher MF (geometric mean 15.4 vs. 11.2 in men, P = 0.020). The styrene-exposed group exhibited significantly higher SSB parameters (tail moment (TM), tail length (TL) and the percentage of DNA in the tail (TP)) than the control group (P < 0.001). SSB parameters correlated with indicators of external exposure and with O6-styrene guanine adducts. No significant correlation was found between SSB parameters and haemoglobin adducts or HPRT MF. The data encompassing biomarkers from repeated measurements of the same population over a 3-year period are discussed with respect to the mechanisms of genotoxic effects of styrene and the interrelationship of individual biomarkers.

Biomonitoring of occupational exposure to styrene in a plastics lamination plant.

A comprehensive approach to biological monitoring of 44 workers occupationally exposed to styrene in a hand lamination plant was performed by using several end-points: styrene in workplace air, styrene in exhaled air, styrene in blood, DNA strand breaks (SBs) and oxidised bases in mononuclear leukocytes, chromosomal aberrations in lymphocytes, immune parameters and genotyping of polymorphic genes of some xenobiotic-metabolizing enzymes (CYP 1A1, EPHX, GSTM1 and GSTP1). We found a significantly higher number of DNA SBs, measured by a modified comet assay, in mononuclear leukocytes of the styrene-exposed workers compared with results from 19 unexposed controls (P<0.001). A fairly strong correlation was observed between SBs and years of exposure (P<0.001, r=0.545). The styrene-exposed workers also showed a significantly increased frequency of chromosomal aberrations (P<0.0001 for highly exposed group, P<0.004 for medium-exposed group, and P=0.0001 for low-exposed group). The proliferative response of T-lymphocytes stimulated with concanavalin A was significantly suppressed in people exposed to styrene (P<0.05). We recorded a significant increase of the percentage of monocytes in differential white blood cell counts in the exposed group (P<0.05). Using flow cytometry, we found an increased expression of adhesion molecules CD62L, CD18, CD11a, CD11b, CD49d and CD54 in the exposed workers as compared with the control group (P<0.05).

Toxicity of rubber chemicals in the chicken embryo. How to interpret results from animal tests.

Results from 80 rubber chemicals in the chicken embryo test were reviewed and compared, when data were found, to results on teratogenicity in mammalian test systems. In addition other sources of literature were used to compare the chicken embryo test to the mammalian tests. Furthermore the results from animal models were analyzed in terms of their ability to predict teratogenicity in humans.

Toxicity of rubber chemicals towards three-day chicken embryos.

Three-day chicken embryos were exposed to 80 different rubber chemicals dissolved in either acetone or water. The following classes of chemicals were studied: thiurams, dithiocarbamates, thioureas, benzothiazoles, benzenesulfohydrazide, dithiodimorpholine, amines, acrylates, guanidines, resorcinol, phthalates, adipates, phosphates, oils, peroxides, heavy metal salts, and sodium nitrite. Dose-response curves and median lethal doses (LD50) or median effective doses (ED50) were calculated for mortality in 2 d after the treatment, for total mortality in 11 d after the treatment, and for the total effect, including deaths and malformations 11 d after the treatment, when the test was finished. Sixteen of the chemicals had no effect on the embryos when injected into the air chamber. Incomplete and irregular dose-response curves for the total effect were obtained with 13 of the chemicals. For them, the ED50 could be calculated. Among the remaining 51 chemicals, the most potent were the dithiocarbamates and cadmium and copper acetates, with the total effect ED50 from 2.4 to 160 nmol/egg. Other chemicals that had an ED50 smaller than 100 nmol/egg were thiurams, cyclohexylthiophthalimide, acrolein, and dithiodimorpholine. The majority of the chemicals had an ED50 between 100 nmol/egg and 10 mumol/egg. The least potent were sodium nitrite and methylmethacrylate with an ED50 of 22 mumol/egg. All the 64 embryotoxic chemicals caused malformations with only one exception (dibutylthiourea). The maximum observed frequencies of malformed embryos varied from 3 to 100% of the treated embryos.

Spontaneous abortions among rubber workers and congenital malformations in their offspring.

Spontaneous abortions of hospitalized women and congenital malformations were analyzed among rubber workers to investigate the possibility of an association between reproductive problems and chemical exposures in the rubber industry. Information on workers was obtained from the membership register of the Union of Rubber and Leather Workers and from the personnel register of a rubber factory. The frequencies of spontaneous abortions did not appreciably differ when the pregnancies occurred during Union membership or during employment in the factory as compared with the pregnancies occurring before or after that time. A case-referent study concerning the association between different exposures and spontaneous abortions showed that the odds ratio for factory workers exposed to rubber chemicals was increased in the footwear department. A corresponding risk was not observed in the tire department. The contradictory observations may be explained by concomitant exposure to solvents in the footwear department or by other nonoccupational factors. The possible association between congenital malformations and exposures in the rubber and leather industries was studied by the case-referent technique. No significant increase in the risk of malformations was observed in any branch of employment. However, the numbers of malformations were rather small.

Occupational chemicals tested for teratogenicity.

Literature was surveyed concerning the teratological testing of chemicals, to which large numbers of workers are occupationally exposed. They include metals, plastics monomers and additives, solvents, and other organic chemicals. The effective doses used in the studies were compared to the potential exposures in the occupational environment as regulated by hygienic standards. In light of the animal experiments, the TLVs for some organic chemicals, particularly for acrylonitrile, methacrylate esters, styrene, carbon disulfide, chloroform, methylene chloride, toluene and xylene, appeared too high to provide absolute safety for pregnant workers. The mechanisms of teratogenesis and the validity of the animal experiments were also considered.

32P-postlabeling of DNA adducts of styrene-exposed lamination workers.

Lamination workers are exposed to high concentrations of styrene. A postlabeling method was developed for the detection of styrene-specific DNA adducts of the workers. To synthesize a standard, styrene oxide was reacted with 2'-deoxyguanosine 3'-monophosphate (dGMP) and the O6-dGMP-adduct was isolated and characterized. The human samples were assayed by the nuclease P1 version of the 32P-postlabeling technique, using magnet transfer of the adducts in chromatography. The human samples were spiked with the standards to ensure identification and quantitation. In lamination workers the O6-adducts, adjusted for adduct recovery, were detected at a level of 5 adducts/10(8) nucleotides, over five times the level in the controls.

Embryotoxic effects of phtalic acid derivatives, phosphates and aromatic oils used in the manufacturing of rubber on three day chicken embryos.

Several chemicals that are used for manufacturing of rubber were tested for embryotoxicity on three day chicken embryos. Cyclohexylthiophtalimide was the most potent of the chemicals, with an ED50 value for the total embryotoxic effect 0.04 mumol (10 micrograms) per egg. Phtalic anhydride was about ten times less potent, having the total ED50 for total embryotoxicity 0.38 mumol (56 micrograms) per egg. Two esters of phtalic acid, dibutylphtalate and butylbenzylphtalate, instead, were relatively impotent, with ED50 values of about 33 mumoles and 27 mumoles per egg, respectively. Two phosphates, tricresylphosphate and synthetic arylphosphate, were not potent embryotoxic agents in the chick embryos. They had ED50 values of 7.0 mumoles (2.6 mg) per egg and 9.5 mg per egg, respectively. Sodium phosphate (NaH2PO4) had the ED50 11 mumoles per egg. Three types of oils were tested, too. A mixture known as "highly aromatic oils" was the most potent, with the ED50 31 micrograms per egg. "Low aromatic, paraffin base oils" was the next potent, with the ED50 87 micrograms per egg, while "naphtenic oils" had the ED50 480 micrograms per egg. Cyclohexylthiophtalimide and phtalic anhydride caused malformations at high frequency. The oils and tricresylphosphate appeared to be efficient teratogens under the experimental conditions used.

Assessment of methods and results of reproductive occupational epidemiology: spontaneous abortions and malformations in the offspring of working women.

Epidemiological studies relating occupational exposures of working women to spontaneous abortions and malformation are reviewed and some methodological considerations are presented. The reproductive epidemiology is less developed than epidemiology in general and seems to involve some specific problems. The ascertainment of exposure and of outcome may be problematic. The exposures may be reported differently by the women depending on the outcome of the pregnancy; thus confirmation of exposure from an independent data source would be an asset. The recognition of spontaneous abortions by women is variable and this should be considered in the study design. An access to medical records could provide objective data on the outcome, but it may introduce other types of asymmetries. The types of occupational exposures of the women, suggested to carry a risk of spontaneous abortions, include anesthetic agents, laboratory work, copper smelting, soldering, and chemical sterilization using ethylene oxide and glutaraldehyde. Maternal employment in laboratories and exposure to solvents has been linked to a risk of congenital malformations in the offspring in five studies. Data on the teratogenic effects of anesthetic gases has been conflicting. In one study, employment in copper smelting was associated with malformations in the offspring.

Spontaneous abortions among women employed in the plastics industry.

A matched case-control study was done to analyze whether certain occupational exposures in the plastics industry were related to the risk of spontaneous abortions. Information on spontaneous abortions (cases) and births (controls) was obtained from the hospital discharge register; data on occupational exposures were obtained from the occupational health services of the workplaces. No increased risk of spontaneous abortions was observed among workers processing polymerized plastics or heated plastics made of vinyl chloride or of styrene. Owing to the low statistical power of the study, only strong effects can be ruled out. The odds ratio for workers actually processing polyurethane was increased (1.9, not statistically significant), and that for all workers in polyurethane-processing factories was significantly increased (3.0, p = 0.02). The finding needs to be investigated further in future studies.

Serum oncogene proteins in foundry workers.

A new technique for detecting oncogene activation based on immunoblotting for oncogene proteins in serum has been applied to screen a cohort of foundry workers with well-defined workplace exposures to polycyclic aromatic hydrocarbon carcinogens. Three of the 18 individuals screened were found to have abnormal expression of the proteins of the ras and fes oncogenes. These three individuals were known to have had medium to high workplace exposures to benzo(a)pyrene and to have correspondingly high levels of benzo(a)pyrene-DNA adducts in their peripheral leukocytes. No individuals among the unexposed controls were found to have abnormal serum oncogene protein expression. These results suggest the feasibility of using serum oncogene proteins along with DNA-carcinogen adducts as potential molecular epidemiological markers in exposed worker populations; further, larger scale studies will be necessary to demonstrate the utility of these markers for identifying individuals at risk for the development of malignant disease due to their occupational exposures.