Toxicology and Industrial Health

The electronics industry is becoming an important mainstream in the workforce in some developed countries and in Taiwan. Among patients with occupational hand dermatitis in northern Taiwan, workers from electronics industries were one of the most important groups. We conducted a field investigation to determine the prevalence, patterns and risk factors of occupational hand dermatoses among electronics workers. The survey was conducted in five electronics plants using a self-administered questionnaire on skin symptoms and risk factors. Skin examination and patch testing were followed for those with symptoms compatible with hand dermatitis. A total of 3070 workers completed the questionnaire. Among them, 302 (9.8%) reported to have symptoms (itching and with either redness/scaling) compatible with contact dermatitis on hands. Hand dermatitis was associated with working in the fabrication unit and personal history of atopy and metal allergy, as well as the following job titles: wafer bonding, cutting, printing/photomasking, softening/degluing, impregnation and tin plating. Among those with reported hand dermatitis, 183 completed skin examination and patch testing, 65/183 (35.5%) were diagnosed as having irritant contact dermatitis (ICD) and 7/183 (3.8%) allergic contact dermatitis. The most important allergens were nickel, cobalt and phenylenediamine. In conclusion, Taiwanese electronics workers have a high risk of having hand dermatitis, especially ICD. Preventive efforts should be focused on the workers with risk factors or at certain worksites.

Previous studies from this and other laboratories have indicated the role of species difference in acrylonitrile (VCN) toxicity and its metabolism to cyanide. Our recent studies also indicated a more pronounced elimination of VCN following oral as compared to i.v. administration. To further characterize the mechanism of these differences on the distribution of VCN, quantitative whole-body autoradiographic distribution and elimination studies were conducted at various time points (0.08, 8, 24, 48 h) following the administration of an equivalent i.v. dose of 2-[¹⁴C]-VCN to male Fischer rats and male CD-1 mice. Whole-body autoradiographs obtained from freeze-dried and acid-extracted sections of rats and mice demonstrated a rapid uptake of ¹⁴C in liver, lungs, spleen and bone marrow at early time intervals. Quantitatively, the uptake, retention and covalent interaction of ¹⁴C were higher in organs of rats as compared to mice, over 48 h. Mice eliminated 74% of the total administered dose of 2-[¹⁴C]-VCN (expired air 4%, urine 16% and feces 54%), while rats eliminated only 26% of the dose (expired air 2%, urine 4% and feces 20%). Species differences in VCN toxicity seem to be correlated with its rate of elimination. The distribution and elimination data demonstrated that mice divest VCN more rapidly than rats. The study also demonstrated that administration of VCN in rats resulted in covalent interactions and retention of 2-[¹⁴C]-VCN/metabolites in the tissues thus exerting more chronic toxicity to rats than to mice.

This study compares the effect of nanosized silicon dioxide (nanosized SiO₂) and microsized silicon dioxide (microsized SiO₂) particles on fibrogenesis in rats. Wistar rats were instilled intratracheally with saline, 20 mg of nanosized SiO₂ or 20 mg of microsized SiO₂, and were sacrificed at 1 and 2 months after instillation. The lungs of rats were analysed for the changes of lung/body coefficient and hydroxyproline content. Changes in pathology and fibrotic grade were observed by use of hematoxylin and eosin and Van Gieson dyeing. The expression of interleukin-4 (IL-4) and transforming growth factor-b1 (TGF-b1) was observed by use of immunohistochemical technique, and protein expression quantitatively analysed by image analysis. The lung/body coefficient and hydroxyproline content of nanosized SiO₂ groups were significantly lower than those of microsized SiO₂ groups at both 1 and 2 months after instillation (PB ^/ 0.05 or PB ^/ 0.01), but without significant differences from those of saline control groups. At 1 month after instillation, there were mainly cellular nodules (Stage I) in nanosized SiO₂ group, while in microsized SiO₂ group Stage II, II of silicotic nodules were observed. At 2 months after instillation, there were still Stage I of silicotic nodules in nanosized SiO₂ group. In microsized SiO₂ group mainly Stage II, III of silicotic nodules were found. Quantity image analysis showed that the expressions of IL-4 and TGF-b1 in nanosized SiO₂ groups were significantly lower than those in microsized SiO₂ groups (PB ^/ 0.01), but without significant difference from those of saline control groups. Our experiment revealed that the effect of fibrogenesis of nanosized SiO₂ might be milder than that of microsized SiO₂ in rats, potentially resulting from nanoparticals tending to be diffused and easily translocated due to their ultrafine particle size compared to microsized particles.

Bisphenol A (BPA) is a known xenoestrogen with similar properties to 17b-estradiol. BPA and estrogen are hydrophobic compounds, and this affects the pharmacokinetics of both compounds in mammals. In a previous study we measured the distribution of BPA in female F344 rats exposed to oral doses of 0.1, 10 and 100 mg/kg. The results showed distribution to target neuroendocrine organs at all doses tested. Using these results, we developed a pharmacokinetic model to predict the dynamic uptake and excretion of BPA by various routes of exposure (po, iv, sc, ip). The model was able to simulate the entire time course (48 h) following various routes of exposure in rats over the dose ranges tested. The model indicated that the ultimate tissue uptake of BPA was established by the rapid initial transfer of free BPA into tissues. After free BPA enters the systemic circulation, metabolism and excretion reactions cause a relatively short duration and rapid decline. This period is followed by a slower long-term decline characteristic of BPA’s biphasic pharmacokinetics. Plasma protein and tissue binding reactions established the long-term half-life of BPA in the body. Route differences in tissue uptake were directly related to the competition between transfer and binding reactions during the absorption phase.

The distribution of ¹⁴C-bisphenol A (BPA) in plasma and neuroendocrine organs was determined in Fischer 344 female rats following three oral doses (0.1, 10 or 100 mg/kg). Plasma and tissue maximum concentrations (C_max) were reached within 15-30 min of dosing. Plasma areas-under-the-curve (AUC) ranged from 0.06 to 53.9 mg-h/mL. The AUCs of the pituitary gland and uterus/gonads were 16-21% higher than that of plasma. The AUCs of hypothalamus and the rest of the brain were 43.7% and 77% of the plasma AUCs, respectively. In the brain tissue, the exposure increased linearly with the oral dose, as the dose was increased from 0.1 to 10 and 100 mg/kg; the exposure in the brain relative to the plasma increased by factors of 1, 1.19 and 1.24. This indicates that the brain barrier systems do not limit the access of the lipophilic BPA to the brain. The increases of the uterus/gonads relative to the plasma were 1, 1.07 and 1.04. Tissue partitioning was also examined in vitro by the uptake of ¹⁴C-BPA. The BPA tissue/blood partition coefficients were as follows: heart, 7.5; liver, 6.1; kidney, 6.4; fat, 3.6; muscle, 2.6; breast, 3.6; ovaries, 9.1; uterus, 5.9; stomach, 5.1; and small intestine, 6.7. The tissue/cerebrospinal fluid partition coefficients were as follows: pituitary gland, 12.8; brain stem, 6.1; cerebellum, 6.4; hippocampus, 7.1; hypothalamus, 6.1; frontal cortex, 4.9; and caudate nucleus, 6.8.

The objective of this study was to assess changes in concentrations of cadmium in the blood (Cd-B), cadmium in the urine (Cd-U), b₂-microglobulin in the serum (b₂-mG-S) and b₂-microglobulin in the urine (b₂-mG-U) of workers at a cadmium (Cd) pigment factory in Japan in which exposure conditions improved. We evaluated reversibility of these markers in continuously employed workers in relation to changes in exposure levels resulting from improvements in the workplace and the reduced production of Cd. Our study involved both environmental and biological monitoring. Data were collected for four years. We measured the Cd concentration in the air of each work area, using the time-weighted average (TWA). Cd-B and Cd-U were measured in workers as direct indices of Cd exposure. b₂-mG-S and b₂-mG-U were measured as markers of renal tubular function. Exposure levels were high in all work areas, according to the criteria set by the American Conference of Governmental Industrial Hygienists (ACGIH). Workers’ Cd-B and Cd-U concentrations reflected high levels of exposure. Correlation was found between these direct indices and b₂-mG-S concentrations. Since the second year, ambient Cd concentrations decreased and reacted markers have been improved. Our results suggest that Cd-B, Cd-U, b₂-mG-S and b₂-mG-U are appropriate markers for monitoring both the level of Cd exposure and the tubular function of workers. Reversibility of urinary low molecular weight protein was observed in the workers over the four years.

An in vitro study was conducted to determine the effects of variable concentrations of trace metals on human cultured mammary cells. Monolayers of human mortal (MCF-12A) and immortal (MDAMB231) mammary epithelial cells were incubated in the absence or presence of increasing concentrations of arsenic (As), mercury (Hg) and copper (Cu) for 24-h, 72-h, 4-d, and 7-d. The MTT assay was used to assess viability for all time periods and cell proliferation was monitored for 4-d and 7-d studies. Monolayers were also labeled with rhodamine-110 (R-6501), Sytox green®, and Celltiter blue^TM fluorescent dyes as indicators for intracellular esterase activity, nucleic acid staining, and cell reduction/viability, respectively. Total incubation time with chemical plus dyes was 24 h. For 24-h and 72-h studies, cells were seeded in 96-well plates, after which confluent monolayers were exposed to increasing concentrations of chemicals. For 4-d and 7-d studies, cells were seeded in 12-well plates at 1/3 confluent density (day 0) and exposed to increasing concentrations of metals on day 1. All cells were counted on days 4 and 7. In addition, test medium was removed from select groups of cultures on day 4, replaced with fresh medium in the absence of chemical (recovery studies), and assays were performed on day 7 as above. The data suggest that there is a consistent protective and/or stimulating effect of metals at the lowest concentrations in MCF-12A cells that is not observed in immortal MDA-MB231 cells. In fact, cell viability of MCF-12A cells is stimulated by otherwise equivalent inhibitory concentrations of As, Cu, and Hg on MDA-MB231 cells at 24-h. Whereas As and Hg suppress proliferation and viability in both cell lines after 4-d and 7-d of exposure, Cu enhances cell proliferation and viability of MCF-12A cells. MDA-MB231, however, recover better after 4-days of toxic insult. In addition, nutritional manipulation of media between the cell lines, or pretreatment with penicillamine, did not alter the hormesis effect displayed by MCF- 12A. Growth of these cells however was not maintained in the alternative medium. The study demonstrates that a hormesis effect from trace metals is detectable in cultured mammary cells; fluorescent indicators, however, are not as sensitive as cell proliferation or MTT in recognizing the subtle responses. Also, sensitivity of mammary cells to lower concentrations of Cu, a biologically important trace metal, may play an important role in controlling cellular processes and proliferation. The ability to detect this in vitro phenomenon implies that similar processes, occurring in vivo, may be responsible for the development, induction, or enhancement of human cancers.

The current study explores the effects of the inhalation of lead (Pb), Cd and its mixture (Pb-Cd) in a mice model, analysing metal concentrations in the lung, and the morphological modifications in the bronchiolar epithelium identified by scanning electron microscopy after eight weeks of inhalation. Our results indicate that metal concentrations in lung were higher compared to controls; however, Pb concentrations drastically decrease in the mixture. This reduction was also observed in the inhalation chamber. The main changes observed in the bronchiole were mostly in the mixture. The modifications were mainly given by Cd alone and in the mixture, with a decreased number of nonciliated bronchiolar cells and an increased number of bundles of dividing cells. The additive effect of Pb-Cd is suggested, as the extensive damage observed was more evident when mice were exposed to the mixture, and the results endured more research in the area of inhaled mixtures.

Welders with radiographic pneumoconiosis abnormalities have shown a gradual clearing of the X-ray identified effects following removal from exposure. In some cases, the pulmonary fibrosis associated with welding fumes appears in a more severe form in welders. Accordingly, for the early detection of welding-fume-exposure-induced pulmonary fibrosis, the gene expression profiles of peripheral mononuclear cells from rats exposed to welding fumes were studied using suppression-subtractive hybridization (SSH) and a cDNA microarray. As such, Sprague-Dawley rats were exposed to a stainless steel arc welding fume for 2 h/day in an inhalation chamber with a 107.59 ^/ 2.6 mg/m³ concentration of total suspended particulate (TSP) for 30 days. Thereafter, the total RNA was extracted from the peripheral blood mononuclear cells, the cDNA synthesized from the total RNA using the SMART^TM PCR cDNA method, and SSH performed to select the welding-fume-exposure-regulated genes. The cDNAs identified by the SSH were then cloned into a plasmid miniprep, sequenced and the sequences analysed using the NCBI BLAST programme. In the SSH cloned cDNA microarray analysis, five genes were found to increase their expression by 1.9-fold or more, including Rgs 14, which plays an important function in cellular signal transduction pathways; meanwhile 36 genes remained the same and 30 genes decreased their expression by more than 59%, including genes associated with the immune response, transcription factors and tyrosine kinases. Among the 5200 genes analysed, 256 genes (5.1%) were found to increase their gene expression, while 742 genes (15%) decreased their gene expression in response to the welding-fume exposure when tested using a commercial 5.0k DNA microarray. Therefore, unlike exposure to other toxic substances, prolonged welding-fume exposure was found to substantially downregulate many genes.