Journal of toxicology and environmental health最新文献

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 concentration (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 pharmacokinetic (PBPK) model, along with quantitative dose-response information using the benchmark 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 noncancer 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.

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 present study cadmium-binding proteins (metallothionein equivalents), cadmium acute toxicity, and cadmium distribution in tissues and subcellular fractions were compared in metallothionein-I and -II deficient (MT-/-) mice and the parental strain carrying intact metallothionein 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 mumol CdCl2/kg body weight delivered i.p.). However, zinc-pretreated MT+/+ mice had a cadmium LD50 of 58-63 mumol CdCl2/kg 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 cadmium. 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 indicate that basal levels of metallothionein do not protect from the acute toxicity of a single i.p. cadmium challenge. Furthermore, it does not appear that the cytosolic compartmentalization of cadmium is correlated with reduced toxicity.

Inhalation of diisocyanate vapors is associated with immediate-type hypersensitivity reactions 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; methylenediphenyl-4,4'-diisocyanate, MDI; and hexamethylene diisocyanate, HDI) and to compare 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 differences 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 electrophoresis of native and denatured calf thymus DNA. Control and all diisocyanate-exposed DNA showed no differences in the size of native DNA fragments. Conversely, electrophoresis 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 mechanisms of the genotoxic effect of TDI.

Physiologically based pharmacokinetic (PBPK) models for pregnancy are inherently more complex than conventional PBPK models due to the growth of the maternal and embryo/fetal tissues. Physiological parameters such as compartmental volumes or flow rates are relatively constant at any particular time during gestation when an acute experiment might be conducted, but vary greatly throughout the course of gestation (e.g., contrast relative fetal weight during the first month of gestation with the ninth month). Maternal physiological parameters change during gestation, depending upon the particular system; for example, cardiac output increases by approximately 50% during human gestation; plasma protein concentration decreases during pregnancy; overall metabolism remains fairly constant. Maternal compartmental volumes may change by 10-30%; embryo/fetal volume increases over a billionfold from conception to birth. Data describing these physiological changes in the human are available from the literature. Human embryo/fetal growth can be well described using the Gompertz equation. By contrast, very little of these same types of data is available for the laboratory animal. In the rodent there is a dearth of information during organogenesis as to embryo weights, and even less organ or tissue weight or volume data during embryonic or fetal periods. Allometric modeling offers a reasonable choice to extrapolate (approximately) from humans to animals; validation, however, is confined to comparisons with limited data during the late embryonic and fetal periods of development (after gestation d 11 in the rat and mouse). Embryonic weight measurements are limited by the small size of the embryo and the current state of technology. However, the application of the laser scanning confocal microscope (LSCM) to optically section intact embryos offers the capability of precise structural measurements and computer-generated three-dimensional reconstruction of early embryos. Application of these PBPK models of pregnancy in laboratory animal models at teratogenically sensitive periods of development provides exposure values at specific target tissues. These exposures provide fundamentally important data to help design and interpret molecular probe investigations into mechanisms of teratogenesis.

Compressed breathing air, used in self-contained breathing apparatus (SCBA) by firefighters and other categories of workers as well as by recreational and commercial divers, is prepared with the aid of high-pressure compressors operating in the range of 5000 psig. There have been reports of unexplained deaths of SCUBA divers and anecdotal accounts of decreased time to exhaustion in firefighters using SCBAs. Compressed breathing air has been found to contain elevated levels of carbon monoxide (CO) and water vapor that are consistent with carboxyhemoglobin (COHb) poisoning and freezing of the user's regulator on the breathing apparatus. The Coburn-Forster-Kane equation (CFK equation) was used to estimate COHb levels at rest and at maximum exercise when exposed to different levels of CO in contaminated breathing air. The results demonstrated that, at maximum exercise, the COHb ranged from 6.0 to 17% with the use of 1 to 4 SCBA cylinders contaminated by 250 ppm CO. Standard operating procedures have been developed at the Montreal Fire Department to minimize the risk of compressed breathing air contamination. Results of the quality analysis/quality control program indicate that implementation of these procedures has improved the quality of the compressed breathing air. Recommendations are made for improvement of the air testing procedures mandated by the Canadian CAN3 180.1-M85 Standard on Compressed Breathing Air and Systems.

The chlorinated acetic acids monochloroacetic acid (MCA) and trichloroacetic acid (TCA) are found as chlorine disinfection by-products in finished drinking-water supplies. TCA has been demonstrated to be a mouse liver carcinogen. A chronic study in which male Fischer 344/N rats were exposed for 104 wk to TCA and MCA in the drinking water is described. Animals, 28 d old, were exposed to 0.05, 0.5, or 2 g/L MCA, or 0.05, 0.5, or 5 g/L TCA. The 2.0 g/L MCA was lowered in stages to 1 g/L when the animals began to exhibit signs of toxicity. A time-weighted mean daily MCA concentration (MDC) of 1.1 g/L was calculated over the 104-wk exposure period. Time-weighted mean daily doses (MDD) based upon measured water consumption were 3.5, 26.1, and 59.9 mg/kg/d for 0.05, 0.5, and 1.1 g/L MCA, respectively; TCA MDD were 3.6, 32.5, and 363.8 mg/kg/d. Nonneoplastic hepatic changes were for the most part spontaneous and age related. No evidence of hepatic neoplasia was found at any of the MCA or TCA doses. The incidence of neoplastic lesions at other sites was not enhanced over that in the control group. Drinking water concentrations of > or = 0.5 g/L MCA produced a moderate to severe toxicity as reflected by a depressed water consumption and growth rate. A no-observed-effects level (NOEL) for carcinogenicity of 0.5 g/L (26.1 mg/kg/d) MCA was calculated. TCA at drinking water levels as high as 5 g/L produced only minimal toxicity and growth inhibition and provided a NOEL of 364 mg/kg/d. Our results demonstrate that under the conditions of this bioassay, MCA and TCA were not tumorigenic in the male F344/N rat.

The remedial investigation/feasibility studies conducted at certain Army installations showed a need to clean up contaminated sites, where high levels of ammunition chemicals such as 2,4,6-trinitrotoluene (TNT), 1,3,5-trinitrobenzene (TNB), 1,3-dinitrobenzene (DNB), and their degradation products/metabolites were detected in surface soil and groundwater. TNB is a photodegradation product of TNT; it is not easily degraded, and persists in the environment. The toxicity data on TNB are scanty. Hence the U.S. Environmental Protection Agency in 1988 (U.S. EPA, 1997) developed a reference dose (RfD) for TNB (0.00005 mg/kg/d for chronic toxicity) based on the toxicity of DNB, which is structurally similar to TNB. Since then we have completed acute, subacute, subchronic, chronic, reproductive, and developmental toxicity studies and toxicokinetics studies. We have reviewed the mammalian toxicity data for TNB and have determined the no observed adverse effect levels (NOAEL) and low observed adverse effect levels (LOAEL) for subchronic, chronic, reproductive, and developmental toxicity. Based on the newly determined NOAEL and LOAEL values, we have now developed a new RfD for TNB (0.03 mg/kg/d), based on the chronic toxic effects on hematology and histopathological changes in testes and kidney.

Cypermethrin is a synthetic pyrethroid that belongs to a group of insecticides with low mammalian toxicity but high insecticidal activity. The present study was designed to investigate the toxicity of cypermethrin on freshly isolated hepatocytes from male and female rats. Hepatocytes were harvested by a collagenase perfusion technique and were exposed to different concentrations of cypermethrin (100, 200, 400, or 800 ng/2 x 10(6) cells) for up to 2 h. Cell viability and the leakage of aspartate transaminase (AST) and alanine transaminase (ALT) were determined throughout the incubation period. The cell viability of the hepatocytes from male and female rats exposed to 400 ng and 800 ng was significantly reduced after 60 and 30 min of incubation, respectively. With cells from female rats, viability was also reduced upon exposure to 200 ng cypermethrin for 2 h. The decrease in cell viability was dose and time dependent. The leakage of ALT and AST was significantly increased with 400 and 800 ng concentrations at 60 and 30 min, respectively. ALT leakage from female hepatocytes was significantly increased at 60 min of incubation with the 200-ng dose, whereas 2 h of incubation was required for the leakage of ALT from the cells of male rats. The present data indicate that cypermethrin has toxic effects on male and female rat hepatocytes in a dose- and time-dependent manner. The data suggest that female rat hepatocytes may be more sensitive to the toxic effects of cypermethrin than male cells.