Update on a Pharmacokinetic-Centric Alternative Tier II Program for MMT—Part I: Program Implementation and Lessons Learned

Concerns have been raised regarding environmental manganese exposure since high exposures have been associated with neurological disorders. The USA Environmental Protection Agency most recent human health risk assessment of inhaled manganese conducted in 1993 identified specific areas of uncertainty regarding manganese pharmacokinetics. This led to the development of a test rule under the USA Clean Air Act that required the generation of pharmacokinetic information on the inorganic manganese combustion products of the organometallic fuel additive methylcyclopentadienyl manganese tricarbonyl (MMT). The Alternative Tier 2 testing program for MMT, described in this paper, has yielded substantial pharmacokinetic data and has enabled the generation of physiologically based pharmacokinetic (PBPK) models for manganese. These models are capable of predicting tissue manganese concentrations across a variety of dose routes, levels, and durations while accounting for factors such as age, gender, and reproductive status, enabling the consideration of tissue dosimetry in future risk assessments

Severity scoring of manganese health effects for categorical regression

Characterizing the U-shaped exposure response relationship for manganese (Mn) is necessary for estimating the risk of adverse health from Mn toxicity due to excess or deficiency. Categorical regression has emerged as a powerful tool for exposure-response analysis because of its ability to synthesize relevant information across multiple studies and species into a single integrated analysis of all relevant data. This paper documents the development of a database on Mn toxicity designed to support the application of categorical regression techniques. Specifically, we describe (i) the conduct of a systematic search of the literature on Mn toxicity to gather data appropriate for dose-response assessment; (ii) the establishment of inclusion/exclusion criteria for data to be included in the categorical regression modeling database; (iii) the development of a categorical severity scoring matrix for Mn health effects to permit the inclusion of diverse health outcomes in a single categorical regression analysis using the severity score as the outcome variable; and (iv) the convening of an international expert panel to both review the severity scoring matrix and assign severity scores to health outcomes observed in studies (including case reports, epidemiological investigations, and in vivo experimental studies) selected for inclusion in the categorical regression database. Exposure information including route, concentration, duration, health endpoint(s), and characteristics of the exposed population was abstracted from included studies and stored in a computerized manganese database (MnDB), providing a comprehensive repository of exposure-response information with the ability to support categorical regression modeling of oral exposure data

Update on a Pharmacokinetic-Centric Alternative Tier II Program for MMT—Part II: Physiologically Based Pharmacokinetic Modeling and Manganese Risk Assessment

Recently, a variety of physiologically based pharmacokinetic (PBPK) models have been developed for the essential element manganese. This paper reviews the development of PBPK models (e.g., adult, pregnant, lactating, and neonatal rats, nonhuman primates, and adult, pregnant, lactating, and neonatal humans) and relevant risk assessment applications. Each PBPK model incorporates critical features including dose-dependent saturable tissue capacities and asymmetrical diffusional flux of manganese into brain and other tissues. Varied influx and efflux diffusion rate and binding constants for different brain regions account for the differential increases in regional brain manganese concentrations observed experimentally. We also present novel PBPK simulations to predict manganese tissue concentrations in fetal, neonatal, pregnant, or aged individuals, as well as individuals with liver disease or chronic manganese inhalation. The results of these simulations could help guide risk assessors in the application of uncertainty factors as they establish exposure guidelines for the general public or workers

Surface Grafting of Poly(L-glutamates). 2. Helix Orientation

In this paper the average helix orientation of surface-grafted poly(γ-benzyl L-glutamate) (PBLG), poly(γ-methyl L-glutamate) (PMLG), and poly(γ-methyl L-glutamate)-co-(γ-n-stearyl L-glutamate) (PMLGSLG 70/30) was investigated by means of FT-IR transmission spectroscopy. The theoretical relation between the average tilt angle (θ) and the absorption peak areas of three different backbone amide bands could be calculated because their transition dipole moment directions with respect to the helix axis were known. From the normalized absorptions, the average tilt angles of grafted helices of PBLG, PMLG, and PMLGSLG 70/30 were determined. The somewhat larger average angle of PMLG helices of 35 ± 5° with respect to the substrate compared to the value of 32 ± 5° of PBLG was due to the higher grafting density of PMLG. Because of the smaller helix diameter as a result of the smaller size of the methyl side group, more PMLG helices grew on the same surface area. Sterical hindrance and unfavorable polar interactions between unidirectional aligned helices forced the PMLG helices in a more upright arrangement. The even more perpendicular orientation of PMLGSLG 70/30 (48 ± 6°) could be the result of incorporation of mainly γ-methyl L-glutamate N-carboxyanhydride (MLG-NCA) monomers during the initiation step. Incorporation of the much larger γ-n-stearyl L-glutamate N-carboxyanhydride (SLG-NCA) monomers afterward lead to enlarged angles with respect to the substrate. Due to swelling, a pronounced change in helix orientation of grafted PMLGSLG 70/30 in n-hexadecane was observed, resulting in an almost perpendicular helix orientation.