Exploring structure/property relationships to health and environmental hazards of polymeric polyisocyanate prepolymer substances-2. Dermal sensitization potential in the mouse local lymph node assay.

The sensitization potencies of twenty custom-designed monomer-depleted polymeric polyisocyanate prepolymer substances and their associated toluene diisocyanate (TDI), methylene diphenyl diisocyanate (MDI), hexamethylene diisocyanate (HDI), and isophorone diisocyanate (IPDI) monomer precursors were investigated by means of the mouse Local Lymph Node Assay (LLNA). These polymeric prepolymers were designed to represent the structural features and physical-chemical properties exhibited by a broad range of commercial polymeric polyisocyanate prepolymers that are produced from the reaction of aromatic and aliphatic diisocyanate monomers with aliphatic polyether and polyester polyols. The normalization of LLNA responses to the applied (15-45-135 mM) concentrations showed that the skin sensitization potency of polymeric polyisocyanate prepolymers is at least 300 times less than that of the diisocyanate monomers from which they are derived. The sensitization potency of the prepolymers was shown to be mainly governed by their hydrophobicity (as expressed by the calculated octanol-water partition coefficient, log Kow) and surfactant properties. Neither hydrophilic (log Kow <0) nor very hydrophobic (log Kow >25) prepolymers stimulated lymphocyte proliferation beyond that of the dosing vehicle control. The findings of this investigation challenge the generally held assumption that all isocyanate (-N=C=O) bearing substances are potential skin (and respiratory) sensitizers. Further, these findings can guide the future development of isocyanate chemistries and associated polyurethane applications toward reduced exposure and health hazard potentials.

Practical learnings from an epidemiology study on TDI-related occupational asthma: Part I-Cumulative exposure is not a good indicator of risk.

The anonymized data of an epidemiology study on incidence of toluene diisocyanate (TDI)-related occupational asthma in three US-based TDI production facilities have been reanalyzed to identify where to best focus exposure reduction efforts in industrial practice to reduce the risk of sensitization to TDI. Since the induction of sensitization has sometimes been attributed to cumulative exposure, this relationship was examined first. Gross cumulative exposure values (i.e. not taking into account whether respiratory protection was used or not) and net cumulative exposure values (i.e. accounting for the use of respiratory protection) per participant were calculated based on the duration of their study participation and the average time-weighted average value of the exposure group to which they belonged. These two sets of cumulative exposure data were compared with asthma incidence using logistic regression. Incidence was zero among workers who rarely come into contact with open plant systems (e.g. during maintenance or spills). Notwithstanding, no statistically significant relationship between asthma incidence and either gross or net cumulative exposure could be determined. This is shown to be consistent with the results of several other epidemiology studies on TDI-related occupational asthma. In conclusion, cumulative exposure values are not a good indicator of the risk of developing TDI-related occupational asthma.

Practical learnings from an epidemiology study on TDI-related occupational asthma: Part II-Exposure without respiratory protection to TWA-8 values indicative of peak events is a good indicator of risk.

The anonymized data of an epidemiology study on the incidence of toluene diisocyanate (TDI)-related occupational asthma in three US-based TDI production facilities have been reanalyzed to identify where to best focus exposure reduction efforts in industrial practice in order to reduce the risk of sensitization to TDI. In Part I, it was demonstrated that cumulative exposure is not a good indicator of the risk of developing TDI-related occupational asthma. In this Part II, an alternative model was developed based on net exposure parameters (i.e. samples taken when no respiratory protection was used). A statistically significant relationship was determined between asthma incidence and the frequency of exposure to TDI levels indicative of peak events that are expressed as time-weighted average-8 (TWA-8) values greater than 3 ppb during which no respiratory protection was used. This relationship suggests a threshold to induction of TDI-related asthma. The findings also highlight the importance of a comprehensive program for controlling workplace atmosphere in the plant by technical measures (e.g. selection of equipment, cleaning procedures) and controlling exposure by organizational measures and situational awareness (e.g. training, use of in-the-field direct reading indicators) during high potential exposure scenarios (e.g. line breaking, spills) to encourage or enforce the appropriate use of respiratory protection.

Development of a method for the determination of bisphenol A at trace concentrations in human blood and urine and elucidation of factors influencing method accuracy and sensitivity.

Bisphenol A (BPA) is an industrial chemical used to make polymers including some used in food contact applications. Virtually complete presystemic clearance of orally administered BPA occurs in humans by metabolism to BPA-glucuronide (BPA-G), but some biomonitoring studies report low concentrations of free (parent) BPA in human blood and urine. Trace contamination of BPA from exogenous sources or hydrolysis of BPA-G to free BPA, either during or after biomonitoring specimen collection, may have contributed to the reported concentrations of free BPA. An analytical method for the determination of free BPA in human blood and urine was developed and validated in two independent laboratories, using the latest generation of high-performance liquid chromatography-tandem mass spectrometry instrumentation to ensure the desired high sensitivity and selectivity. The method was designed to account for and/or eliminate background contamination from all sources and demonstrated that contamination could occur from devices used for specimen collection or storage, as well as other sources. The method employed an internal standard (BPA-d(8)) and demonstrated accuracy and reproducibility in both matrices fortified with BPA or a surrogate analyte ((13)C-BPA) at a low quantitation limit (0.1-0.2 ng/mL). For validation, five replicate samples were analyzed to evaluate reproducibility. Importantly, it was demonstrated that the conditions of the method did not result in the hydrolysis of BPA-G to free BPA, another possible source of error in BPA analysis. Application of the principles defined by this method will be critical to assure valid analytical results in any future biomonitoring studies.

Developmental neurotoxicity study of dietary bisphenol A in Sprague-Dawley rats.

This study was conducted to determine the potential of bisphenol A (BPA) to induce functional and/or morphological effects to the nervous system of F(1) offspring from dietary exposure during gestation and lactation according to the Organization for Economic Cooperation and Development and U.S. Environmental Protection Agency guidelines for the study of developmental neurotoxicity. BPA was offered to female Sprague-Dawley Crl:CD (SD) rats (24 per dose group) and their litters at dietary concentrations of 0 (control), 0.15, 1.5, 75, 750, and 2250 ppm daily from gestation day 0 through lactation day 21. F(1) offspring were evaluated using the following tests: detailed clinical observations (postnatal days [PNDs] 4, 11, 21, 35, 45, and 60), auditory startle (PNDs 20 and 60), motor activity (PNDs 13, 17, 21, and 61), learning and memory using the Biel water maze (PNDs 22 and 62), and brain and nervous system neuropathology and brain morphometry (PNDs 21 and 72). For F(1) offspring, there were no treatment-related neurobehavioral effects, nor was there evidence of neuropathology or effects on brain morphometry. Based on maternal and offspring body weight reductions, the no-observed-adverse-effect level (NOAEL) for systemic toxicity was 75 ppm (5.85 and 13.1 mg/kg/day during gestation and lactation, respectively), with no treatment-related effects at lower doses or nonmonotonic dose responses observed for any parameter. There was no evidence that BPA is a developmental neurotoxicant in rats, and the NOAEL for developmental neurotoxicity was 2250 ppm, the highest dose tested (164 and 410 mg/kg/day during gestation and lactation, respectively).