Assessment of perfluorocarboxylic acids in fluorinated high-density polyethylene containers and estimation of potential non-cancer risks associated with anticipated use scenarios.

High density polyethylene (HDPE) containers are fluorinated to impart barrier properties that prevent permeation of liquid products filled in the container. The process of fluorination may result in the unintentional formation of certain per- and polyfluoroalkyl substances (PFAS), specifically perfluoroalkyl carboxylic acids (PFCAs), as impurities. This study measured the amounts of PFCAs that may be present in the fluorinated HDPE containers, which could migrate into products stored in these containers. Migration studies were also conducted using water and mineral spirits to estimate the amount of PFCAs that might be found in the products stored in these containers. The migration results were used to conservatively model potential PFCA exposures from use of six product types: indoor-sprayed products, floor products, hand-applied products, manually-sprayed pesticides, hose-end sprayed products, and agricultural (industrial) pesticides. The potential that such uses could result in a non-cancer hazard was assessed by comparing the modeled exposures to both applicable human non-cancer toxicity values and environmental screening levels. Environmental releases were also compared to aquatic and terrestrial predicted no-effect concentrations (PNECs). The results of these analyses indicated no unreasonable non-cancer risk to humans, aquatic species, and terrestrial species from PFCAs in products stored in fluorinated HDPE containers.

Historical evolution of regulatory standards for occupational and consumer exposures to industrial talc.

Talc has been used historically in a wide range of industrial applications and consumer products. The composition and purity of talc used for industrial purposes can vary greatly depending on the source and may contain asbestos minerals. The developing science associated with the health risks of asbestos had an effect on the talc industry throughout the 20th century. This review presents a detailed analysis of the evolution of regulatory standards impacting the use of industrial talc in the U.S. from the early 20th century through the 1990s. While it was recognized by the 1930s that airborne exposures to talc dust at high concentrations could cause lung disease, it was not until later that concerns were raised about the health risks associated with potential occupational exposures to asbestos from industrial talc. Regulatory agencies adopted occupational standards for industrial talc in the early 1970s, but the terminology used to define and characterize talc and other associated minerals varied between agencies. In addition, the complex and varying mineralogy of industrial talc led to inconsistent and imprecise interpretation of studies concerning health risk and occupational health standards among individual agencies.

An assessment of formaldehyde emissions from laminate flooring manufactured in China.

Formaldehyde emissions from two laminate flooring products, labeled as California Air Resources Board (CARB) compliant, were evaluated. Passive 24-hr samples (n = 79) and real-time measurements were collected following installation and removal of the products in two rooms of similar size. Mean formaldehyde concentrations following installation were 0.038 and 0.022 ppm for Products 1 and 2 respectively, and 7 days after flooring removal the concentrations returned to background pre-installation levels. Both products were also evaluated in a small chamber (ASTM D6007) using Deconstructive (de-laminated product) and Non-Deconstructive (intact product) methods. Deconstructive testing showed that Product 1 exceeded the applicable CARB emission standard by 4-fold, while Product 2 was equivalent to the standard. Non-Deconstructive measurements were far below the Deconstructive results and were used to predict 24-hr steady-state room air concentrations. Based on the products that we tested (one of which was found to not be compliant with the CARB standard), the airborne formaldehyde concentrations measured following installation in a real-world setting would not be expected to elicit adverse acute health effects.

Experimental methodology for assessing the environmental fate of organic chemicals in polymer matrices using column leaching studies and OECD 308 water/sediment systems: Application to tire and road wear particles.

Automobile tires require functional rubber additives including curing agents and antioxidants, which are potentially environmentally available from tire and road wear particles (TRWP) deposited in soil and sediment. A novel methodology was employed to evaluate the environmental fate of three commonly-used tire chemicals (N-cyclohexylbenzothiazole-2-sulfenamide (CBS), N-(1,3-dimethylbutyl)-N'-phenyl-1,4-phenylenediamine (6-PPD) and 1,3-diphenylguanidine (DPG)), using a road simulator, an artificial weathering chamber, column leaching tests, and OECD 308 sediment/water incubator studies. Environmental release factors were quantified for curing (f(C)), tire wear (f(W)), terrestrial weathering (f(S)), leaching from TRWP (f(L)), and environmental availability from TRWP (f(A)) by liquid chromatography-tandem mass spectroscopy (LC/MS/MS) analyses. Cumulative fractions representing total environmental availability (F(T)) and release to water (FR) were calculated for the tire chemicals and 13 transformation products. F(T) for CBS, DPG and 6-PPD inclusive of transformation products for an accelerated terrestrial aging time in soil of 0.1 years was 0.08, 0.1, and 0.06, respectively (equivalent to 6 to 10% of formulated mass). In contrast, a wider range of 5.5×10(-4) (6-PPD) to 0.06 (CBS) was observed for F(R) at an accelerated age of 0.1 years, reflecting the importance of hydrophobicity and solubility for determining the release to the water phase. Significant differences (p<0.05) in the weathering factor, f(S), were observed when chemicals were categorized by boiling point or hydrolysis rate constant. A significant difference in the leaching factor, f(L), and environmental availability factor, f(A), was also observed when chemicals were categorized by log K(ow). Our methodology should be useful for lifecycle analysis of other functional polymer chemicals.

Potent activity of the HIV-1 maturation inhibitor bevirimat in SCID-hu Thy/Liv mice.

BACKGROUND: The HIV-1 maturation inhibitor, 3-O-(3',3'-dimethylsuccinyl) betulinic acid (bevirimat, PA-457) is a promising drug candidate with 10 nM in vitro antiviral activity against multiple wild-type (WT) and drug-resistant HIV-1 isolates. Bevirimat has a novel mechanism of action, specifically inhibiting cleavage of spacer peptide 1 (SP1) from the C-terminus of capsid which results in defective core condensation. METHODS AND FINDINGS: Oral administration of bevirimat to HIV-1-infected SCID-hu Thy/Liv mice reduced viral RNA by >2 log(10) and protected immature and mature T cells from virus-mediated depletion. This activity was observed at plasma concentrations that are achievable in humans after oral dosing, and bevirimat was active up to 3 days after inoculation with both WT HIV-1 and an AZT-resistant HIV-1 clinical isolate. Consistent with its mechanism of action, bevirimat caused a dose-dependent inhibition of capsid-SP1 cleavage in HIV-1-infected human thymocytes obtained from these mice. HIV-1 NL4-3 with an alanine-to-valine substitution at the N-terminus of SP1 (SP1/A1V), which is resistant to bevirimat in vitro, was also resistant to bevirimat treatment in the mice, and SP1/AIV had replication and thymocyte kinetics similar to that of WT NL4-3 with no evidence of fitness impairment in in vivo competition assays. Interestingly, protease inhibitor-resistant HIV-1 with impaired capsid-SP1 cleavage was hypersensitive to bevirimat in vitro with a 50% inhibitory concentration 140 times lower than for WT HIV-1. CONCLUSIONS: These results support further clinical development of this first-in-class maturation inhibitor and confirm the usefulness of the SCID-hu Thy/Liv model for evaluation of in vivo antiretroviral efficacy, drug resistance, and viral fitness.

Validation of the SCID-hu Thy/Liv mouse model with four classes of licensed antiretrovirals.

BACKGROUND: The SCID-hu Thy/Liv mouse model of HIV-1 infection is a useful platform for the preclinical evaluation of antiviral efficacy in vivo. We performed this study to validate the model with representatives of all four classes of licensed antiretrovirals. METHODOLOGY/PRINCIPAL FINDINGS: Endpoint analyses for quantification of Thy/Liv implant viral load included ELISA for cell-associated p24, branched DNA assay for HIV-1 RNA, and detection of infected thymocytes by intracellular staining for Gag-p24. Antiviral protection from HIV-1-mediated thymocyte depletion was assessed by multicolor flow cytometric analysis of thymocyte subpopulations based on surface expression of CD3, CD4, and CD8. These mice can be productively infected with molecular clones of HIV-1 (e.g., the X4 clone NL4-3) as well as with primary R5 and R5X4 isolates. To determine whether results in this model are concordant with those found in humans, we performed direct comparisons of two drugs in the same class, each of which has known potency and dosing levels in humans. Here we show that second-generation antiretrovirals were, as expected, more potent than their first-generation predecessors: emtricitabine was more potent than lamivudine, efavirenz was more potent than nevirapine, and atazanavir was more potent than indinavir. After interspecies pharmacodynamic scaling, the dose ranges found to inhibit viral replication in the SCID-hu Thy/Liv mouse were similar to those used in humans. Moreover, HIV-1 replication in these mice was genetically stable; treatment of the mice with lamivudine did not result in the M184V substitution in reverse transcriptase, and the multidrug-resistant NY index case HIV-1 retained its drug-resistance substitutions. CONCLUSION: Given the fidelity of such comparisons, we conclude that this highly reproducible mouse model is likely to predict clinical antiviral efficacy in humans.