摘要:

Recently, a major topic of discussion has been the impact of synthetic chemicals that possess the capacity to alter hormonal activity, the so-called “endocrine modulators,” with potentially the capacity to alter the reproductive capability of humans. Particularly, various synthetic pesticides and industrial chemicals that persist in the environment and/or bioac-cumulate have been implicated. Further, it has been alleged that the standard tests for pesticide registration as required by the U.S. Environmental Protection Agency (EPA) and other regulatory agencies may be inadequate to detect endocrine modulating effects. To address these shortcomings, it has been proposed that very specific tests for estrogen receptor binding, or in vitro cell response to chemicals, be used to identify potential endocrine modulators. However, such approaches have certain flaws that limit their application as screens. First, very specific tests, like receptor binding, evaluate only a single chemical event per test. Such tests do not measure toxicity or biological response. Isolated systems are very important for studying mechanisms of action or structure activity relationships, but can only provide a preliminary screen for a single mechanism of toxicity. Isolated systems can not be used to regulate a chemical without additional information. Second, they fail to test many other parts of the neuroendocrine control of the reproduc-tive system. Testing for adverse effects in highly specific in vitro systems failed to replace whole-animal models in carcinogenesis and will also fail in reproductive toxicology because this system is too complicated for such as in vitro approach to be accurately predictive. Advanced tests, such as the EPA multigeneration study, are more effective and reliable means for evaluation than any specific and narrowly focused screening tests. Experience has shown that a better approach to testing chemicals is to evaluate their effects on the whole animal. When one part of the system is adversely affected, various processes may be indirectly affected and can be detected in the animal model. For example, a modulation of testosterone synthesis could lead to (1) altered accessory sex organ morphology, size, and function; (2) decreased sperm counts; and (3) even decreased fertility. These and many other effects would be noted in toxicity studies that are already required for the registration of crop protection chemicals. The developmental and reproductive toxicity guidelines were recently reviewed in a hearing that included the representatives from the EPA, the public, and the Scientific Advisory Panel. The EPA kept the basic study design the same, but added a few new endpoints to further assess chemical-induced effects on reproductive development and function. The review presented herein concentrates on the required Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) testing for pesticides, and demonstrates how the massive arrays of sensitive endocrine endpoints that are delineated in FIFRA Subdivision F have been successfully used to detect both weak and potent hormonally modulating chemicals. For example, (1) diethyl-stilbestrol (DES), which is a potent synthetic therapeutic estrogen, (2) DDT, which is weakly estrogenic but persistent and bioaccumulating, and (3) dioxins, which have anti-estrogenic properties, were all found as being hormonally active in tests similar or identical to FIFRA tests. All food-use pesticides have been evaluated using a comprehensive multi-generation reproduction test. Hence, the FIFRA testing procedures have been demonstrated to identify endocrine modulators of sufficient potency to represent a concern to human health.

ISSN:0098-4108    

DOI:10.1080/00984109708983999

出版商:Taylor & Francis Group    

年代:1997

数据来源: Taylor

摘要:

Chemicals such as ds-platinum, formaldehyde, chromate, copper, and certain arsenic compounds have been shown to produce DNA-protein cross-links in human in vitro cell systems at high doses, such as those in the cytotoxic range. Thus far there have only been a limited number of other chemicals evaluated for their ability to produce cross-links. The purpose of the work described here was to evaluate whether select industrial chemicals can form DNA-protein cross-links in human cells in vitro. We evaluated acetaldehyde, acrolein, diepoxybutane, paraformaldehyde, 2-furaldehyde, prop't onaldehyde, chloroacetaldehyde, sodium arsenite, and a deodorant tablet [Mega Blue; hazardous component listed as tris(hydroxymethyl)nitromethane]. Short- and long-term cytotoxicity was evaluated and used to select appropriate doses for in vitro testing. DNA-protein cross-linking was evaluated at no fewer than three doses and two cell lysate washing temperatures (45 and 65°CJ in Epstein-Barr virus (EBV) human Burkitt's lymphoma cells. The two washing temperatures were used to assess the heat stability of the DNA-protein cross-link. 2-Furaldehyde, acetaldehyde, and propionaldehyde produced statistically significant increases in DNA-protein cross-links at washing temperatures of 45°C, but not 65°C, and at or above concentrations of 5, 77.5, and 75 mM, respectively. Acrolein, diepoxybutane, paraformaldehyde, and Mega Blue produced statistically significant increases in DNA-protein cross-links washed at 45 and 65°C at or above concentrations of 0.15. mM, 12.5 mM, 0.003%, and 0.1%, respectively. Sodium arsenite and chloroacetaldehyde did not produce significantly increased DNA-protein cross-links at either temperature nor at any dose tested. Excluding paraformaldehyde and 2-furaldehyde treatments, significant increases in DNA-protein cross-links were observed only at doses that resulted in complete cell death within 4 d following dosing. This work demonstrates that DNA-protein cross-links can be formed in vitro following exposure to a variety of industrial compounds and that most cross-links are formed at cytotoxic concentrations.

ISSN:0098-4108    

DOI:10.1080/00984109708984000

出版商:Taylor & Francis Group    

年代:1997

数据来源: Taylor

摘要:

3-Chloro-p-toluidine hydrochloride (CPT-HCI) is an aniline derivative used in the manufacture of the dye palatine fast yellow; it is also registered as a selective, low-volume-use (<45 kg/yr) avicide. Three in vitro mutagenicity tests of CPT-HCI were performed according to methods recommended by the U.S. Environmental Protection Agency (EPA): the Ames/Salmonella assay, the Chinese hamster ovary/hypoxanthine-guanine phosphoribosyl-transferase (CHO/HPRT) mammalian cell forward gene mutation assay, and the CHO chromosome aberration assay. CPT-HCI did not display mutagenic activity using the /4mesAalmonella or CHO/HPRT assays. However, CPT-HCI induced statistically significant, concentration-dependent, metabolically activated increases in the proportion of aberrant cells and aberrations/cell in cultured CHO cells. Results are suggestive of minimal mutagenicity effects associated with exposure to anilines and their derivatives.

ISSN:0098-4108    

DOI:10.1080/00984109708984001

出版商:Taylor & Francis Group    

年代:1997

数据来源: Taylor

摘要:

Previous work suggested that arsine- (AsH3-) induced hemoglobin (Hb02) damage may lead to hemolysis (Hatlelid et al., 1996). The purpose of the work presented here was to determine whether reactive oxygen species are formed by AsH3in solution, in hemoglobin solutions, or in intact red blood cells, and, if so, to determine whether these species are responsible for the observed hemoglobin damage. Hydrogen peroxide (H202) was detected in aqueous solutions containing AsH3and Hb02or AsH3alone but not in intact red blood cells or lysates. Additionally, high-activity catalase (19,200 U/ml) or glutathione peroxidase (68 U/ml) added to solutions of Hb02and AsH3had only a minor protective effect against AsHyinduced damage. Further, the differences between the visible spectra of AsH3-treated Hb02and H202-treated HbO2indicate that two different degradative processes occur. The presence of superoxide anion (Of) was measured by O2-dependent reduction of nitro blue tetrazolium (NBT). The results were negative for Of. Exogenous superoxide dismutase (100 ug/ml) did not affect AsH3-induced Hb02spectral changes, nor did the hydroxyl radical scavengers, mannitol, and DMSO (20 mM each). The general antioxidants ascorbate (<10 mM) and glutathione (<1 mM) also had no effect. These results indicate that the superoxide anion and the hydroxyl radical COH) are not involved in the mechanism of AsH3-induced Hb02damage. The results also indicate that although AsH3contributes to H202production in vitro, cellular defenses are adequate to detoxify the amount formed. An alternative mechanism by which an arsenic species is the hemolytic agent is proposed.

ISSN:0098-4108    

DOI:10.1080/00984109708984002

出版商:Taylor & Francis Group    

年代:1997

数据来源: Taylor

摘要:

To facilitate the development of regional respiratory tract dosimetry comparisons between laboratory animal species and humans, published surface area (SA) and volume (VOL) data for the upper respiratory tract (URT) were reviewed. The review of the literature revealed that (1) different studies used different techniques to prepare specimens and make measurements, (2) different areas of the URT were measured, and (3) URT surface

ISSN:0098-4108    

DOI:10.1080/00984109708984003

出版商:Taylor & Francis Group    

年代:1997

数据来源: Taylor

摘要:

The effect of beryllium (Be) compounds on porphyrins was investigated in pregnant mice. The blood protoporphyrin (Proto) and zinc protoporphyrin (Zn Proto) concentrations were increased in pregnancy. Regardless of pregnancy or nonpregnancy, the Proto concentration was decreased after Be injection. Delta-aminolevulinic acid dehydratase (ALA-D) and porphobilinogen deaminase (PBC-D) activities in blood were significantly elevated in the pregnant untreated (Con-pregnant) group, compared to the nonpregnant mice untreated (Con-nonpregnant) and nonpregnant mice treated with Be (Be-nonpregnant) groups. The blood ALA-D activity of the pregnant mice treated with Be (Be-pregnant group) tended to decrease, compared to Con-pregnant group. The blood PBG-D activity in the Be-pregnant group was significantly lower compared with that of the Con-pregnant group. The ALA-D and PBC-D activities in the spleen were also significantly elevated in the Con-pregnant group, compared to nonpregnant groups. However, it was noted that these values in the Be-pregnant group were almost the same as that of the Con-nonpregnant group and were significantly lower than that in the Con-pregnant group. The elevation of ALA-D and PBC-D activities in the blood and spleen, which play a role in the hematopoietic function of mice, was observed in the Con-pregnant mice compared to the nonpregnant mice. However, the phenomenon was not observed in the Be-pregnant mice, it suggesting that Be suppressed the pregnancy-induced increase in hematopoietic function.

ISSN:0098-4108    

DOI:10.1080/00984109708984004

出版商:Taylor & Francis Group    

年代:1997

数据来源: Taylor

摘要:

The carcinogenic potential of phenobarbital (PB) and 3-methylcholanthrene (3-MC) was assayed in a new medium-term carcinogenicity bioassay using D-galactosamine (DCA) as a nonsurgical method to induce liver cell regeneration in place of partial hepatectomy (PH). Rats were initially given a single ip injection (200 mg/kg) of diethylnitrosamine (DEN) and after 2 wk on basal diet received 2 ip injections of DCA (300 mg/kg) at the end of wk 2 and 5. They were treated with one of the test compounds PB or 3-MC in the diet or fed basal diet for wk 3-8. Carcinogenic potential was assessed by comparing the numbers and areas per square centimeter of glutathione S-transferase placental form-positive (CST-P*) foci in the livers of test chemical-treated animals with those of the control animals given DEN/DCA alone. Positive estimations of carcinogenicity were obtained for PB, which is a nongenotoxic liver tumor promoter, and for 3-MC, which is a genotoxic nonliver carcinogen. Increases of liver/body weight ratios and serum total cholesterol were observed in rats treated with PB or 3-MC. Interestingly, interlobe differences were found on the development of CST-P* liver cell foci. Our results thus confirm that the present bioassay protocol with repeated administration of DCA instead of PH may offer a new and sensitive method to screen large numbers of environmental liver and nonliver carcinogens.

ISSN:0098-4108    

DOI:10.1080/00984109708984005

出版商:Taylor & Francis Group    

年代:1997

数据来源: Taylor