The adduct data suggest that, among current workers, o-toluidine exposure substantially exceeds aniline exposure and that 4-ABP exposure, if it occurs at all, is not widespread. These data support the conclusion that occupational exposure to o-toluidine is the most likely causal agent of the bladder cancer excess observed among workers in the rubber chemicals department of the plant under study, although exposures to aniline and 4-ABP cannot be ruled out.
Epidemiological evidence that occupational exposure to o-toluidine and aniline is associated with an increased risk of bladder cancer led to efforts to identify biomarkers of workplace exposures to these aromatic amines. For the determination of o-toluidine and aniline in worker urine specimens, a method using high performance liquid chromatography (HPLC) followed by electrochemical detection was developed. The limits of detection were 0.6 microgram/l and 1.4 micrograms/l for o-toluidine and aniline, respectively. Recovery of o-toluidine and aniline from spiked urine averaged 86% and 93%, respectively, over a range of 4-100 micrograms/l. Reproducibility in the range 2-100 micrograms/l for analyses of split field samples was 13% (average RSD) for o-toluidine and 16% (average RSD) for aniline. Application of this method to pre- and post-shift samples collected from potentially exposed and unexposed workers indicated elevated concentrations of o-toluidine and aniline in urine from exposed workers. To develop methods for biomarkers of internal dose, o-toluidine binding to the blood proteins hemoglobin and albumin was investigated utilizing in-vivo (rodent) and in-vitro (hemoglobin and albumin) studies. Base-hydrolyzable protein adducts were analyzed by HPLC (fluorescence) and/or GC/electron capture (EC). The methods were compared for sample preparation requirements, selectivity and sensitivity. While the GC/EC method was more sensitive than HPLC, the presence of interfering peaks limited the utility of this approach. Results from these studies suggested that the HPLC method could be useful for determination of o-toluidine exposures in individuals acutely or chronically exposed to high levels.
There are approximately 1.2 million workers exposed to metalworking fluids (MWF), which are used to reduce the heat and friction associated with industrial machining and grinding operations. Irritancy and sensitization potential of 9 National Toxicology Program (NTP) nominated MWFs (TRIM 229, TRIM VX, TRIM SC210, CIMTECH 310, CIMPERIAL 1070, CIMSTAR 3800, SYNTILO 1023, SUPEREDGE 6768, and CLEAREDGE 6584) were examined in a combined local lymph node assay (LLNA). BALB/c mice were dermally exposed to each MWF at concentrations up to 50%. Significant irritation was observed after dermal exposure to all MWFs except CIMTECH 310 and SYNTILO 1023. Of the 9 MWFs, 6 induced greater than a 3-fold increase in lymphocyte proliferation and 7 tested positive in the irritancy assay. TRIM VX yielded the lowest EC3 value (6.9%) with respect to lymphocyte proliferation. Chemical components of TRIM VX identified using HPLC were screened for sensitization potential using structural activity relationship (SAR) modeling and the LLNA. TOPKAT predicted triethanolamine (TEA) as a sensitizer while Derek for Windows predicted only 4-chloro-3-methylphenol (CMP) to be positive for sensitization. When tested in the LLNA only CMP (EC3 = 11.6%) and oleic acid (OA) (EC3 = 29.7%) were identified as sensitizers. Exposure to all tested TRIM VX components resulted in statistically significant irritation. An additive proliferative response was observed when mixtures of the two identified sensitizing TRIM VX components, OA and CMP, were tested in the LLNA. This is one explanation of why the EC3 value of TRIM VX, with respect to lymphocyte proliferation, is lower than those assigned to its sensitizing components.
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