摘要:

There has been relatively little attention given to incorporating knowledge of mode of action or of dosimetry of active toxic chemical to target tissue sites in the calculation of noncancer exposure guidelines. One exception is the focus in the revised reference con centration (RfC) process on delivered dose adjustments for inhaled materials. The studies reported here attempt to continue in the spirit of the new RfC guidelines by incorporating both mechanistic and delivered dose information using a physiologically based pharmaco kinetic (PBPK) model, along with quantitative dose-response information using the bench mark dose (BMD) method, into the noncancer risk assessment paradigm. Two examples of the use of PBPK and BMD techniques in noncancer risk assessment are described: methylene chloride, and trichloroethylene. Minimal risk levels (MRLs) based on PBPK analysis of these chemicals were generally similar to those based on the traditional process, but individual MRLs ranged from roughly 10-fold higher to more than 10-fold lower than existing MRLs that were not based on PBPK modeling. Only two MRLs were based on critical studies that presented adequate data for BMD modeling, and in these two cases the BMD models were unable to provide an acceptable fit to the overall dose-response of the data, even using pharmacokinetic dose metrics. A review of 10 additional chemicals indicated that data reporting in the toxicological literature is often inadequate to support BMD modeling. Three general observations regarding the use of PBPK and BMD modeling in noncancer risk assessment were noted. First, a full PBPK model may not be necessary to support a more accurate risk assessment; often only a simple pharmacokinetic description, or an understanding of basic pharmacokinetic principles, is needed. Second, pharmacokinetic and mode of action considerations are a crucial factor in conducting non cancer risk assessments that involve animal-to-human extrapolation. Third, to support the application of BMD modeling in noncancer risk assessment, reporting of toxicity results in the toxicological literature should include both means and standard deviations for each dose group in the case of quantitative endpoints, such as relative organ weights or testing scores, and should report the number of animals affected in the case of qualitative endpoints.

ISSN:0098-4108    

DOI:10.1080/00984109708984077

出版商:Taylor & Francis Group    

年代:1997

数据来源: Taylor

摘要:

Inhalation of diisocyanate vapors is associated with immediate-type hypersensitivity reac tions and direct toxic responses. The genotoxic effects of diisocyanates have not been clarified. The aim of this study was to examine the changes in DNA following in vitro exposure to three most commonly used diisocyanates (toluene diisocyanate, TDI; methyl-enediphenyl-4,4′-diisocyanate, MDI; and hexamethylene diisocyanate, HDI) and to com pare their binding potential using melting behavior of DNA and electrophoresis studies in DNA. Following incubation of DNA with MDI (pure and mix) and HDI we found no dif ferences in the melting behavior compared to the control calf thymus DNA. However, DNA treated with TDI showed differences in the shape of the native DNA curves due to changes in hyperchromicity and exhibited 14% more DNA reconstitution after renaturation. The small changes in the melting behavior of native DNA do not suggest the formation of DNA intrastrand cross-links but rather conformational changes of single- and double-stranded DNA. These conformational changes were further explored by agarose elec trophoresis of native and denatured calf thymus DNA. Control and all diisocyanate-exposed DNA showed no differences in the size of native DNA fragments. Conversely, electrophore sis of TDI mix-incubated DNA, following denaturation, showed a distinct reduction in the double-stranded DNA fragment size compared to the control, MDI-denatured (pure and mix), and HDI-denatured DNA. These findings may help to better understand the mecha nisms of the genotoxic effect of TDI.

ISSN:0098-4108    

DOI:10.1080/00984109708984078

出版商:Taylor & Francis Group    

年代:1997

数据来源: Taylor

摘要:

To date, numerous correlative studies have implicated metallothionein in the detoxification of heavy metals and in the regulation of metal distribution within an organism. In the pre sent study cadmium-binding proteins (metallothionein equivalents), cadmium acute toxicity, and cadmium distribution in tissues and subcellular fractions were compared in metalloth-ionein-l and -II deficient (MT−/−) mice and the parental strain carrying intact metalloth ionein genes (MT+/+) to determine if the absence of metallothionein altered any of these parameters. In an uninduced state, MT−/−mice expressed lower levels of cadmium-binding proteins relative to MT+/+mice in several tissues. Administration of zinc enhanced the levels of cadmium-binding proteins in liver, small intestine, kidney, pancreas, and male sex organs, but not in cecum or brain of MT+/+mice compared to zinc pretreated MT−/−mice. The cadmium LD50 was similar for MT−/−, MT+/+, and zinc-pretreated MT−/−mice (15-17To date, numerous correlative studies have implicated metallothionein in the detoxification of heavy metals and in the regulation of metal distribution within an organism. In the pre sent study cadmium-binding proteins (metallothionein equivalents), cadmium acute toxicity, and cadmium distribution in tissues and subcellular fractions were compared in metalloth-ionein-l and -II deficient (MT−/−) mice and the parental strain carrying intact metalloth ionein genes (MT+/+) to determine if the absence of metallothionein altered any of these parameters. In an uninduced state, MT−/−mice expressed lower levels of cadmium-binding proteins relative to MT+/+mice in several tissues. Administration of zinc enhanced the levels of cadmium-binding proteins in liver, small intestine, kidney, pancreas, and male sex organs, but not in cecum or brain of MT+/+mice compared to zinc pretreated MT−/−mice. The cadmium LD50 was similar for MT−/−, MT+/+, and zinc-pretreated MT−/−mice (15-17 μmol CdCl2/kg body weight delivered ip). However, zinc-pretreated MT+/+mice had a cadmium LD50 of 58-63 μmol CdCIJkg body weight. Over two-thirds of cadmium was found in liver, cecum, small intestine, and kidney in both MT+/+and MT−/−mice; therefore, metallothionein levels do not appear to play a major role in the tissue distribution of cad mium. However, after zinc pretreatment, MT+/+mice accumulated more cadmium in the liver and less in other tissues, whereas the amount of cadmium in the liver was not altered by zinc pretreatment in MT−/−mice. In general, the cytosolic/particulate ratio of cadmium was significantly higher in tissues of noninduced MT+/+mice relative to MT−/−mice. This difference was accentuated after zinc pretreatment. Together these results indi cate that basal levels of metallothionein do not protect from the acute toxicity of a single ip cadmium challenge. Furthermore, it does not appear that the cytosolic compartmental-ization of cadmium is correlated with reduced toxicity.

ISSN:0098-4108    

DOI:10.1080/00984109708984079

出版商:Taylor & Francis Group    

年代:1997

数据来源: Taylor

摘要:

The effect of Dodine on the intestine was studied after a single administration of 1000 mg/kg, which corresponds to the LD50 in male Wistar rats. At this dose, a significant decrease in body weight was observed, accompanied by diarrhea, which may be associated with intestinal alterations. The chemical induced a significant reduction of the protein con tent and in sucrase activity in the jejunum. Morphological alterations included a significant decrease in crypt height and in villus length and depth. The intestinal modifications observed in animals after Dodine administration may explain the observed loss in body weight and diarrhea.

ISSN:0098-4108    

DOI:10.1080/00984109708984080

出版商:Taylor & Francis Group    

年代:1997

数据来源: Taylor

ISSN:0098-4108    

DOI:10.1080/00984109708984081

出版商:Taylor & Francis Group    

年代:1997

数据来源: Taylor