The guinea pig model of diisocyanate sensitization. I. Immunologic studies

Two strains of guinea pigs were parenterally immunized with well-characterized diisocyanate-protein conjugates. Hapten-specific IgE antibodies were detected in the sera of English short-hair strain guinea pigs immunized with either toluene diisocyanate-human serum albumin (TDI-HSA) or hexamethylene diisocyanate-HSA (HDI-HSA) when these sera were analyzed by the 168 hr passive cutaneous anaphylaxis (PCA) technique followed by intravenous challenges with conjugates of respective ligands coupled to an unrelated carrier protein, transferrin. IgG1 antibodies and precipitating antibodies were demonstrated in Hartley strain guinea pigs immunized with TDI/HDI-HSA conjugates. The hapten specificity of these antibodies was proved by PCA inhibition experiments and antibody absorption experiments. In the precipitating antibody system, this was further confirmed by immunoelectrophoretic analysis. Cross-reactivity between HDI and TDI was not observed in the PCA experiments. However, apparent cross-reactivity in the double gel diffusion experiments was due to new antigenic determinants formed by isocyanates after conjugation with proteins. It was therefore apparent that immune responses of guinea pigs immunized with protein conjugates of bifunctional isocyanates were heterogeneous and involved multiple specificities for hapten, carrier protein, and new antigenic determinants. It was postulated that the complex nature of the immune response generated by diisocyanate compounds in the guinea pig may also serve as a more appropriate model of isocyanate-induced human sensitivity reactions, which are known to involve diverse immunologic and nonimmunologic mechanisms.     

The effect of prenatal exposure to a repeat high dose of toluene in the fetal rat

Solvent abuse during pregnancy results in a clinical pattern of adverse outcomes including deafness. The aim of this project was to determine whether high doses of toluene for a short duration during pregnancy produced adverse outcomes in the fetal rat. Pregnant rats were given either 1250 mg/kg of toluene or peanut oil by gavage from gestation day 16-19. The study demonstrated that administration of toluene at the dose used did not result in significant maternal toxicity. However, some maternal renal pathology was noted. There was no significant difference in placental or fetal weights nor was there a significant difference in the number of external or skeletal malformations of fetuses between treatment and control groups. Treated fetuses had an increased frequency and severity of enlarged renal pelveses. A pattern of accelerated development in the upper mid-turn and sometimes apical turns in the treated fetal cochleas was observed. This accelerated development suggests that toluene may induce excessive cell death resulting in premature maturation of the cochlea.     

Toluene impairs learning and memory, has antinociceptive effects, and modifies histone acetylation in the dentate gyrus of adolescent and adult rats

Toluene misuse usually initiates at an early age when the central nervous system is still immature, causing deleterious effects such as cognitive impairment. Epigenetic regulatory mechanisms have been proposed to explain long-term changes involved not only in memory, but also in toluene's actions. The aim of this study was to evaluate the effects of acute and chronic toluene exposure on learning, memory and histone acetylation in the rat hippocampus during two stages of life: adolescence and young adulthood. Because the memory tests used in this work involved object exploration and the perception of a noxious stimulus, general activity and nociception tests were also conducted. Acute and chronic toluene inhalation impaired learning, short-term and long-term memory in an object-recognition test and in an inhibitory avoidance task in both groups of age. This effect was concentration-dependent and occurred even at low toluene concentrations (1000, 2000 ppm) that were otherwise non-effective. Acute toluene inhalation produced antinociception, and tolerance to this effect developed after chronic exposure. Histone acetylation in the dentate gyrus showed differences depending on the histone, treatment and age: a single toluene exposure increased H4 acetylation in adolescents and young adult rats, whereas chronic exposure decreased H3 acetylation, but only in adults. In conclusion, this work provides evidence of toluene-induced impairment on learning, short- and long-term memory in adolescent and young adult rats, and shows that even a single toluene exposure can induce epigenetic modifications in the rat hippocampus.     

长期低浓度苯系物接触的早期职业健康损害

目的研究长期低浓度苯系物接触对作业工人的早期职业健康损害。方法①工作场所空气中苯系物浓度检测与评价;②对接触组106人和对照组110人进行职业健康检查,测定血清中氧化—抗氧化指标和遗传损伤指标。结果①工作场所空气中苯系物浓度低于国家卫生标准;②接触组神经衰弱、牙龈出血、女工月经异常的检出率均高于对照组(P0.05);WBC和PLT均数低于对照组(P0.01),氧化指标SOD活力、MDA含量以及遗传损伤指标(微核,姐妹染色单体互换和染色体畸变)发生率均明显高于对照组(P0.05或P0.01)。结论长期低浓度苯系物接触可造成神经、血液、氧化—抗氧化以及细胞遗传学损害作用。     

工作场所空气中甲苯溶剂解吸气相色谱法测定的不确定度评定

目的建立工作场所空气中甲苯的溶剂解吸气相色谱法测定的不确定度评定方法,通过控制这些因素提高检测结果的置信度和准确性。方法依据中华人民共和国国家计量技术规范JJF1059-1999《测量不确定度评定与表示》和中国金属学会推荐的技术和方法CCM010100-2006《化学仪器分析测量结果不确定度评定导则》。结果甲苯不确定度主要来源:①测量重复性的不确定度;②标准溶液配制过程的不确定度;③标准曲线的变动性的不确定度;④采样过程的不确定度;⑤解吸效率的不确定度;⑥样品解吸的不确定度。取包含因子k=2,扩展不确定度为U=1.7540×2≈3.51mg/m3。结论该不确定度评定方法对甲苯的溶剂解吸气相色谱法检测过程的质量控制意义十分重大,是提高检测结果的置信度和准确性的保证。     

Identification of methylene diphenyl diisocyanate thermal degradation products in a generation chamber by liquid chromatography coupled with tandem mass spectrometry

Isocyanate thermal degradation characterization by liquid chromatography coupled with electrospray tandem mass spectrometry has been performed to elucidate the methylene diphenyl diisocyanate (MDI) thermal degradation structure emitted in a generation chamber using a temperature between 50°C and 180°C to produce MDI vapors. [M+H]⁺ ions containing an isocyanate functional group were studied by tandem mass spectrometry. The [M+H]⁺ ion analyses based on the combination of full scans and precursor ion scans were useful for identifying all structures. The compounds emitted were identified and validated as a mixture of compounds containing amine and isocyanate functions. Residual MDI, methylene diphenyl amino-isocyanate, and methylene diphenyl diamine were identified. Polymerized forms of these structures were also observed because amine and isocyanate chemical functions react rapidly to polymerize. These results must be used with special care by scientists establishing sensitization diagnostics and developing sampling devices using generation chambers as they must be related to MDI behavior in workplaces. Even if pure MDI is introduced in the generation chamber, several different compounds are generated when the MDI is heated at a high temperature. This can result in some misleading interpretations for non-specific isocyanate sampling device development and sensitization diagnostics as MDI is present in the chamber with other compounds with known adverse effects.     

Diazepam influences urinary bioindicator of occupational toluene exposure

In the present study, we investigated the influence of diazepam (DZP) on the excretion of TOL by examining their urinary metabolites, hippuric acid (HA) and ortho-cresol (o-C). Male Wistar rats were exposed to TOL (20 ppm) in a nose-only exposure chamber (6 h/day, 5 days/week for 6 weeks) with simultaneous administration of DZP (10 mg/kg/day). Urinary o-C levels were determined by GC–MS, while HA, creatinine (CR), DZP and its metabolite, nordiazepam, were analysed by HPLC-DAD. The results of a Mann-Whitney U test showed that DZP influenced the urinary excretion of o-C (p < 0.05). This pioneering study revealed that there was an interaction between DZP and TOL, probably by the inhibition of the CYP isoforms (CYP2B6, CYP2C8, CYP2E1, and CYP1A2) involved in the oxidative metabolism of the solvent. This is relevant information to be considered in the biomonitoring of occupational toluene exposure.     

Occupational contact allergy to monomeric isocyanates

Background. The monomeric isocyanates diphenylmethane diisocyanate (MDI), 2,4‐toluene diisocyanate (TDI), isophorone diisocyanate (IPDI) and 1,6‐hexamethylene diisocyanate (HDI) are used in polyurethane products and sometimes cause contact allergy. Objectives. To describe patients with isocyanate contact allergy in an occupational dermatology clinic. Methods. Test files were screened for allergic reactions to isocyanates and 4,4′‐diaminodiphenylmethane (MDA). Patients with allergic reactions to some of the allergens were analysed for occupation, exposure, concomitant reactions to other allergens, and diagnosis. Results. Over a period of almost 13 years, 54 patients reacted to isocyanates (9 to IPDI, 12 to MDI, 6 to TDI, and 1 to HDI) or MDA (44 patients). The motor vehicle, electronics and paint industries, and painting and construction work, were among the most significant occupational fields. An in‐house polymeric MDI (PMDI) test substance was superior to commercial MDI preparations. About half of the occupational cases related to MDI products were diagnosed by testing MDA. The most prominent cause of IPDI allergy comprised polyurethane paint hardeners. Some of the IPDI reactions could be explained by cross‐allergy to isophoronediamine in epoxy products. Specific exposure to MDA was difficult to trace. Conclusions. MDA and PMDI test substances were significant in the diagnosis of MDI contact allergy.