Biomedical subjects
Publications and source records attributed to S H Safe.
Large quantities of presumably nontoxic petroleum oil by-products are introduced into the environment as pesticide dispersal agents and emulsifiers. An increase in viral lethality with a concomitant influence on the liver and central nervous system occurs in young mice previously primed with such chemicals.
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3,3',4,4',5-Pentachlorobiphenyl (pentaCB) caused a dose-dependent induction of fetal cleft palate in offspring from pregnant C57BL/6 mice exposed to a single dose (783 or 1044 micrograms/kg) of this compound on gestation day 10. In contrast, 2,2',4,4',5,5'-hexaCB did not cause cleft palate at a dose of 271 mg/kg and, in pregnant mice cotreated with 2,2',4,4',5,5'-hexaCB (271 mg/kg) plus 783 or 1044 micrograms/kg 3,3',4,4',5-pentaCB, fetal cleft palate formation was significantly inhibited. 3,3',4,4',5-PentaCB (6 micrograms/kg) also inhibited the splenic plaque-forming cell (PFC) response and serum IgM levels in C57BL/6 mice treated with the T cell-independent antigen trinitrophenyl-lipopolysaccharide. At doses as high as 72 mg/kg, 2,2',4,4'-5,5'-hexaCB was not immunotoxic; however, in mice cotreated with a immunotoxic dose of 3,3',4,4',5-pentaCB plus different doses of 2,2',4,4',5,5'-hexaCB (18, 36 and 72 mg/kg), there was a dose-dependent inhibition of 3,3',4,4',5-pentaCB-induced immunotoxicity. These non-additive (antagonistic) interactions of prototypical polychlorinated biphenyl (PCB) congeners may be an important consideration in development of a toxic equivalency factor approach for hazard and risk assessment of PCB mixtures.
The results of diverse in vitro neurotoxicity studies demonstrate that there are variations in cellular responsiveness between different types of neural cells. In contrast to experimental systems that have reported cellular responses to relatively high concentrations of various PCB congeners, our studies with rat hippocampal neural cells indicate that neurons and astroglia are responsive to relatively low levels of TCDD. However, these responses are probably not mediated through the classical Ah receptor pathway, which involves nuclear Ah receptor-mediated modulation of gene expression. It has recently been reported that TCDD-induced phosphorylation and other responses can be observed in some cell lines within minutes after treatment (20), and that cell membrane or cytosolic receptors may also play a role in mediating these effects. Future studies are required to determine both Ah receptor-dependent and -independent pathways associated with the neurotoxicity of PCBs, TCDD, and related compounds. The report that low-level dietary or background exposure to HAHs (32) results in neurobehavioral deficits is still a perplexing problem also requiring additional research and consideration of other dietary factors that may contribute to these effects. For example, we have recently been comparing the toxic effects and relative potencies of TCDD (exodioxins) and other "natural occurring" compounds (endodioxins) such as indole-3-carbinol (vegetables) and polynuclear aromatic hydrocarbons (PAHs, cooked foods), which also bind to the Ah receptor. Dr. Clynn Wilker has shown that in utero exposure of rats to indole-3-carbinol and chrysene (a PAH) cause demasculinization of the adult offspring as previously reported for TCDD (19). Thus, the neurotoxicity of low-level dietary exposure to HAHs should at least consider other possible confounding factors, including dietary endodioxins.