Demonstrating the protective effect of a 70-year-old occupational exposure limit against pneumoconiosis caused by mica.

Workers involved in crushing, milling, screening, and bagging of mica scrap are at increased risk to develop pneumoconiosis, a progressive material overloading of the lung that can lead to fibrosis and, in the later stages, to dyspnea. Pneumoconiosis is only seen after 10-20 years of respiratory mica exposure, and it can have a latency period of up to 40 years-today's cases date back to exposures during the second half of the 20th century. An occupational lifetime exposure level of 3 mg/m3 respirable mica dust has been considered to present no risk of pneumoconiosis since 1951 when the American Conference of Governmental Industrial Hygienists (ACGIH) established a 20 million particles per cubic foot (mppcf) (3.5 mg/m3 respirable particles) exposure limit. As a result, numbers of unspecified and other pneumoconioses in the United States have steadily declined since the early 1970s. Data from the National Institute for Occupational Safety and Health documents a 91% decrease between 1972 and 2014 (i.e., the peak of documented cases and the latest reported data) for combined cases of aluminosis, berylliosis, stannosis, siderosis, and fibrosis from production and use of bauxite, graphite fibers, wollastonite, cadmium, Portland cement, emery, kaolin, antimony, and mica. Ample evidence indicates that the 70-year-old occupational lifetime exposure level of 3 mg/m3 respirable mica dust is protective of workers' health.

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) reverses hyperglycemia in a type II diabetes mellitus rat model by a mechanism unrelated to PPAR gamma.

It has been asserted that exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increases the risk for diabetes mellitus in humans, observable as hyperglycemia resulting from insulin resistance. There is no animal model for the induction of diabetes by TCDD. On the contrary, TCDD has been shown to increase insulin sensitivity in rats. Therefore, a diabetic rat model was used to study the effects of TCDD on preexisting diabetes. Type II diabetes was induced in male rats by a high-fat diet and streptozotocin. After manifestation of the disease, these rats received loading dose rates (LDRs) of 3.2, 6.4, and 12.8 microg/kg of TCDD p.o., followed by weekly maintenance dose rates. Rats fed a high-fat diet and not dosed with streptozotocin nor with TCDD served as nondiabetic controls. By day 2, serum-glucose levels in diabetic rats treated with the high LDR of 12.8 microg/kg TCDD were already significantly reduced. By day 8, serum-glucose levels had decreased to control levels and were maintained for the duration of the study (32 days). Thus, TCDD effectively counteracted hyperglycemia in this diabetic rat model. In healthy animals, TCDD induced PPAR gamma transcription and activity in a different dose range than that observed for the hypoglycemic effect.

Relationship between aryl hydrocarbon receptor-affinity and the induction of EROD activity by 2,3,7,8-tetrachlorinated phenothiazine and derivatives.

Reported herein are semi-empirical calculations of the molecular geometry of TCDD, TCPT, TCPT-sulfoxide (TCPT-O), TCPT-sulfone (TCPT-O(2)), N-methyl-TCPT (Me-TCPT), N-methyl-TCPT-sulfoxide (Me-TCPT-O), and N-methyl-TCPT-sulfone (Me-TCPT-O(2)), the characterization of their AhR binding affinity in rat hepatic cytosol, and their ability to induce EROD activity in a rat hepatoma cell line in vitro. Semi-empirical calculations yielded detailed information about the stereochemistry and the preferred conformation of each of these compounds. These results in combination with observations reported in this paper were used to determine structure-activity relationships. In vitro displacement of (3)H-TCDD was measured by increasing concentrations of the respective ligands. This assay revealed a strong binding affinity of TCPT to the AhR with a K(i) value of 1.08 nM. TCDD had a K(i) value of 0.54 nM. The affinity of TCPT derivatives for the AhR decreased with increasing degree of oxidation. Moreover, N-methylation further lowered the affinity, so that the N-methyl sulfone derivative of TCPT displayed the highest K(i) at approximately 1200 nM (=460.4 ng/ml). A corresponding trend was observed regarding the potency of TCPT and derivatives to induce EROD activity in vitro. However, the potencies were considerably lower than that of TCDD. Enzyme induction was measured in a rat hepatoma cell line H4IIEC/T3 by quantification of ethoxyresorufin-O-deethylase (EROD) activity. Induction was measured at 12, 24, 48 and 72 h to determine time dependence. Sulfoxidated and N-methylated phenothiazines displayed a lower potency than their respective parent compounds. TCPT and all derivatives induced enzyme activity at an efficacy similar to TCDD at all time points measured. The reported findings clearly separate the induction of EROD activity by TCPT and derivatives from their binding affinities to the AhR. In contrast, a direct correlation between the two is generally assumed in drug development, leading to - in our view - unwarranted termination of drug candidates. Therefore, a lack of such a correlation for TCPT and derivatives in fact supports their further development as possible drug leads.

From dioxin to drug lead--the development of 2,3,7,8-tetrachlorophenothiazine.

Polychlorinated dibenzo-p-dioxins are persistent environmental pollutants. The most potent congener, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), causes a wasting syndrome and is a potent carcinogen and immunosuppressant in the rat at high doses. However, low doses cause opposite effects to some of those observed at higher doses, resulting in chemoprevention, stimulation of the immune system, and longevity in experimental animals. The new TCDD analogue, 2,3,7,8-tetrachlorophenothiazine (TCPT), was developed to take advantage of the low-dose effects of dioxins that have potential application as therapeutics. Its development marked a deviation from the traditional scope of phenothiazine drug design by deriving biological effects from aryl substituents. TCPT was synthesized in three steps. The key ring-closing step was performed utilizing a Buchwald-Hartwig amination to provide TCPT in 37% yield. Its potency to induce CYP1A1 activity over 24 h was 370 times lower than that of TCDD in vitro. The elimination half-life of the parent compound in serum was 5.4 h in the rat and 2.7 h in the guinea pig, compared to 11 and 30 days, respectively, for TCDD. These initial findings clearly differentiate TCPT from TCDD and provide the basis for further studies of its potential as a drug lead.