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A further potential breakdown product of MDI in water is an oligourea. An oligourea was synthesized from 4,4’-MDI and 4,4’-MDA and shown to be mainly diurea. It was insoluble in water and found to be not inherently biodegradable (Yakabe et al., 1994).
Exposure of gravid Wistar rats to monomeric MDI resulted in an increased incidence of asymmetric sternebrae in fetuses at 9 mg/m3; however, as the increase was within the limits of biological variability, the NOAEL for developmental toxicity in this study was estimated to be 9 mg/m3. In another study in which rats were exposed to PMDI, the NOAEL for maternal and fetal toxicity was estimated to be 4 mg/m3, based on the finding of premature deaths of pregnant females and statistically significant decreases in placental and fetal weights at 12 mg/m3. There have been no studies that have examined the effect of polymeric or monomeric MDI on reproductive parameters.
Sepai et al. (1995b) examined biological samples (urine and blood) from 20 workers (as well as 2 unexposed reference workers) exposed to MDI vapour during the manufacture of polyurethane products, together with the levels of MDI in the air of the working environment. In most cases (17 out of 20), the air levels were below detection limits. The blood and urine samples were analysed for the presence of adducts and metabolites using gas chromatography–mass spectrometry methods. The amount of MDA released after acid hydrolysis (in hydrochloric acid at 3 mol/litre, at 100 °C, for 60 min) was on average 6.5 times higher than the amount of free MDA and acetylated MDA present in urine.
In humans, MDA levels in urine and (after strong acid hydrolysis) in blood were reported to be correlated with exposure to PMDI/MDI (Schuetze et al., 1995; Sepai et al., 1995b; Skarping & Dalene, 1995). The half-life of MDA in the urine of a worker exposed to PMDI was 70–80 h, and in serum, 21 days (Skarping et al., 1995). Other reports also suggest that plasma acid-hydrolysable MDA may be a useful biomarker of long-term exposure to MDI (Sepai et al., 1995b; Dalene et al., 1996). In a recent study of workers occupationally exposed to either PMDI/MDI or MDA, free MDA was detected in urine prior to acid hydrolysis (Schuetze et al., 1995).
Haemoglobin adducts were found after repeated exposure of rats to MDI aerosols for 17 h per day, 5 days per week, over 3 or 12 months in an inhalation chamber (Sepai et al., 1995a). In laboratory animals exposed to PMDI/MDI, MDA in urine and blood formed by strong acid hydrolysis was used as a biomarker for exposure (Sepai et al., 1995a).
Animal inhalation studies have shown that PMDI exposure (see section 8.4.2 for details of particle size distribution) results in significant deposition both in the nasal region and in the alveolar region of the lungs (Reuzel et al., 1994a,b). Once absorbed, PMDI appears to be predominantly conjugated to protein, but the role of other biomolecules, such as glutathione, has not been investigated (the role of glutathione has been shown for other isocyanates by Day et al., 1997).
Gravid Wistar rats were exposed by whole-body inhalation to clean air (control) and to monomeric 4,4’-MDI at 1, 3, or 9 mg/m3 for 6 h per day from day 6 to day 15 post-conception (Buschmann et al., 1996). The MMAD of the aerosol was 1.1 µm. Rats were sacrificed on day 20. The absolute and relative lung weights in the high-dose group were significantly increased (23%) compared with the sham-treated control animals; this end-point was not examined in the other exposure groups. Treatment did not influence any other maternal or fetal parameters investigated, although a slight but significant increase in litters with fetuses displaying asymmetric sternebra was observed after treatment with the highest dose. Since the number of the effects observed in the 9 mg/m3 group was within the limits of biological variability, a NOAEL for developmental effects of 9 mg/m3 was determined in this study.
Studies of workers have identified free MDA, acetylated MDA, and adducts of both with haemoglobin or albumin in urine and blood. These studies suggest that plasma acid-hydrolysable MDA may be a useful biomarker of long-term exposure to MDI. The half-life of acid-hydrolysable MDA in the urine of a worker exposed to PMDI was 70–80 h, and in serum, 21 days.
Plasma albumin conjugates of MDI found in workers exposed to MDI can cause the onset of respiratory disorders in humans (Sepai et al., 1995a). Lushniak et al. (1998) evaluated whether MDI-specific IgG or IgE could be sensitive biological markers of disease or of MDI exposure. The study group consisted of nine MDI-exposed workers and nine non-exposed workers. Air sampling for MDI and PMDI, occupational and medical histories, respiratory physical examinations, pre- and post-shift spirometry, and self-administered peak expiratory flow rates were performed. Serum-specific IgE and IgG antibodies to an MDI–HSA conjugate were assayed by the radioallergosorbent test (RAST) and the enzyme-linked immunosorbent assay, respectively, and compared with nine non-exposed laboratory controls. The mean level of MDI-specific IgG was significantly greater among exposed workers compared with non-exposed workers and laboratory controls (= 0.044). This study demonstrates that serum concentrations of MDI-specific IgG appear to be a moderately sensitive biological marker of MDI exposure, but not an indicator of occupational asthma. Workers with IgG antibodies specific for one diisocyanate–HSA conjugate exhibit cross-reactivity to antigens prepared with other diisocyanates.
Water molecules result as biomolecules are synthesized.
Hydrolysis reaction: break down molecules into adding water to them.
Enzymes: speeds reaction of dehydration and hydrolysis.
Polymers: the largest of the biomolecules.