H. Tryphonas, G. Bondy, J. Miller, F. Lacroix, M. Hodgen, P. Mcguire, S. Fernie, D. Miller, S. Hayward
The effects of fumonisin B1 (FB1) on the immune system of Sprague-Dawley rats were investigated. Groups of male and female rats (10 rats/group) were gavaged daily for 14 days with doses of 0, 5, 15, and 25 mg/kg body wt/day and the primary (IgM) response to sheep red blood cells expressed as plaque-forming cell numbers/10(6) spleen mononuclear leukocytes (PFC/10(6) splenocytes) and PFC/spleen was determined. There was a significant dose-related linear trend toward decreased PFC/10(6) splenocytes (p = 0.003) and PFC/spleen cells (p = 0.001) in the male rats. Body weights, expressed as a percentage of the control, were significantly reduced (p = 0.002) in the male rats administered 15 and 25 mg/kg doses. The PFC numbers in female rats were not affected significantly by treatment (p > 0.05). For the remaining immunotoxicity studies, groups of male rats (10 rats/group) were gavaged with FB1 doses of 0, 1, 5, and 15 mg/kg body wt/day for 14 days. There was a weakly significant dose-related trend toward increased numbers of serum immunoglobulin class G (p = 0.04). Also a significant dose-related increase (p = 0.013) in Listeria monocytogenes numbers was observed in the spleen at 24 hr postinfection. Treatment did not have a significant effect on organ weights, hematology, mitogen-induced lymphocyte transformation, calcium mobilization, the numbers of leukocytes and T-lymphocyte subsets, the natural killer cell activity, and phagocytosis (p >/= 0. 05). These observations suggested that FB1 may have indirect consequences for human health and warrant further investigations.
{"title":"Effects of fumonisin B1 on the immune system of sprague-dawley rats following a 14-day oral (gavage) exposure.","authors":"H. Tryphonas, G. Bondy, J. Miller, F. Lacroix, M. Hodgen, P. Mcguire, S. Fernie, D. Miller, S. Hayward","doi":"10.1093/TOXSCI/39.1.53","DOIUrl":"https://doi.org/10.1093/TOXSCI/39.1.53","url":null,"abstract":"The effects of fumonisin B1 (FB1) on the immune system of Sprague-Dawley rats were investigated. Groups of male and female rats (10 rats/group) were gavaged daily for 14 days with doses of 0, 5, 15, and 25 mg/kg body wt/day and the primary (IgM) response to sheep red blood cells expressed as plaque-forming cell numbers/10(6) spleen mononuclear leukocytes (PFC/10(6) splenocytes) and PFC/spleen was determined. There was a significant dose-related linear trend toward decreased PFC/10(6) splenocytes (p = 0.003) and PFC/spleen cells (p = 0.001) in the male rats. Body weights, expressed as a percentage of the control, were significantly reduced (p = 0.002) in the male rats administered 15 and 25 mg/kg doses. The PFC numbers in female rats were not affected significantly by treatment (p > 0.05). For the remaining immunotoxicity studies, groups of male rats (10 rats/group) were gavaged with FB1 doses of 0, 1, 5, and 15 mg/kg body wt/day for 14 days. There was a weakly significant dose-related trend toward increased numbers of serum immunoglobulin class G (p = 0.04). Also a significant dose-related increase (p = 0.013) in Listeria monocytogenes numbers was observed in the spleen at 24 hr postinfection. Treatment did not have a significant effect on organ weights, hematology, mitogen-induced lymphocyte transformation, calcium mobilization, the numbers of leukocytes and T-lymphocyte subsets, the natural killer cell activity, and phagocytosis (p >/= 0. 05). These observations suggested that FB1 may have indirect consequences for human health and warrant further investigations.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"21 1","pages":"53-9"},"PeriodicalIF":0.0,"publicationDate":"1997-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77487697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A guinea pig intratracheal test was used to set occupational operating guidelines for new enzyme proteins used in the detergent industry. In these studies, animals were intratracheally dosed with different levels of enzyme protein and sera from the animals were titered for allergic antibody to the enzyme. The amount of antibody produced to an enzyme was compared to the amount of antibody produced to the same protein doses of Alcalase, for which effective operating guidelines exist. These comparisons were used to determine if a new enzyme was more potent, less potent, or equivalent to Alcalase; operating guidelines were then established for the new enzyme. Termamyl was about 10-fold more potent than Alcalase and the protease subtilisin B was shown to be less potent. Another protease, Savinase, was shown to be equivalent in potency to Alcalase. The operating guidelines for Termamyl were adjusted lower, whereas the operating guidelines for the proteases were set the same as that of Alcalase. Under these conditions, we would predict that sensitizations to new enzymes would be comparable to or lower than the sensitizations to Alcalase. Prospective evaluation of skin prick test data of factory workers showed that sensitizations to Termamyl and Savinase were similar to sensitizations to Alcalase. The sensitizations to subtilisin B were lower than those to Alcalase. During this time period (7 years), only three respiratory incidents (rhinitis) were reported, demonstrating that employees with positive skin prick tests can continue to work. These comparisons indicate that the guinea pig intratracheal test is a good animal model for evaluating enzymes as respiratory allergens and that the data generated can be used to set operating guidelines for occupational allergens.
{"title":"Respiratory allergenicity of detergent enzymes in the guinea pig intratracheal test: association with sensitization of occupationally exposed individuals.","authors":"K. Sarlo, E. R. Fletcher, W. Gaines, H. Ritz","doi":"10.1093/TOXSCI/39.1.44","DOIUrl":"https://doi.org/10.1093/TOXSCI/39.1.44","url":null,"abstract":"A guinea pig intratracheal test was used to set occupational operating guidelines for new enzyme proteins used in the detergent industry. In these studies, animals were intratracheally dosed with different levels of enzyme protein and sera from the animals were titered for allergic antibody to the enzyme. The amount of antibody produced to an enzyme was compared to the amount of antibody produced to the same protein doses of Alcalase, for which effective operating guidelines exist. These comparisons were used to determine if a new enzyme was more potent, less potent, or equivalent to Alcalase; operating guidelines were then established for the new enzyme. Termamyl was about 10-fold more potent than Alcalase and the protease subtilisin B was shown to be less potent. Another protease, Savinase, was shown to be equivalent in potency to Alcalase. The operating guidelines for Termamyl were adjusted lower, whereas the operating guidelines for the proteases were set the same as that of Alcalase. Under these conditions, we would predict that sensitizations to new enzymes would be comparable to or lower than the sensitizations to Alcalase. Prospective evaluation of skin prick test data of factory workers showed that sensitizations to Termamyl and Savinase were similar to sensitizations to Alcalase. The sensitizations to subtilisin B were lower than those to Alcalase. During this time period (7 years), only three respiratory incidents (rhinitis) were reported, demonstrating that employees with positive skin prick tests can continue to work. These comparisons indicate that the guinea pig intratracheal test is a good animal model for evaluating enzymes as respiratory allergens and that the data generated can be used to set operating guidelines for occupational allergens.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"25 1","pages":"44-52"},"PeriodicalIF":0.0,"publicationDate":"1997-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90059484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
B. Bolon, T. Bucci, A. Warbritton, James J. Chen, D. Mattison, J. Heindel
Ovaries from National Toxicology Program Reproductive Assessment by Continuous Breeding (RACB) bioassays were used to directly compare differential ovarian follicle counts and reproductive performance for 15 chemicals. Ovaries of 10 animals per group from 16 studies in CD-1 mice and 1 study each in C3H and C57BL/6 mice were sectioned serially at 6 microm. Counts of small, growing, and antral follicles were obtained in every 10th section. For all follicle types, younger mice had more follicles than older mice, and CD-1 mice had more follicles than age-matched animals from either inbred strain. The in-life portion of the RACB protocols demonstrated that 9 of 15 chemicals altered reproductive outcome in one or both sexes of mice, with six agents affecting females (R. E. Morrissey et al., 1989, Fundam. Appl. Toxicol. 13, 747-777). Three of six female toxicants [2,2-bis(bromoethyl)-1,3-propanediol, BPD; ethylene glycol monomethyl ether, EGME; methoxyacetic acid, MAA] significantly decreased counts of small and/or growing follicles by 33 to 92% in CD-1 mice; EGME also reduced follicle counts in the other strains. Follicle counts were decreased in progeny of animals treated with EGME or its active metabolite, MAA. For BPD, reductions in follicle numbers were proportional to dose. In CD-1 mice, female toxicants di-N-hexyl phthalate, propantheline bromide, and tricresyl phosphate reduced reproductive performance but not follicle numbers. Counts were not affected by toxicants for which the susceptible sex could not be determined (bisphenol A, ethylene glycol, oxalic acid). Altered follicle counts without apparent reproductive impairment occurred in CD-1 mice at lower doses of BPD but were not observed for nontoxic chemicals. These data suggest that differential follicle counts (1) are a quantifiable endpoint of ovarian injury in conventional bioassays, and (2) in some instances, may provide a more sensitive indicator of female reproductive toxicity than fertility.
采用国家毒理学计划连续育种生殖评估(RACB)生物测定法直接比较了15种化学物质的卵巢差异卵泡计数和生殖性能。CD-1小鼠16个实验，C3H和C57BL/6小鼠各1个实验，每组10只动物的卵巢按6微米连续切片。每10个切片取小卵泡、生长卵泡和窦卵泡计数。对于所有的卵泡类型，年轻的小鼠比年长的小鼠有更多的卵泡，CD-1小鼠比来自近亲繁殖的年龄匹配的动物有更多的卵泡。RACB方案的生活部分表明，15种化学物质中有9种改变了一种或两性小鼠的生殖结果，其中6种影响雌性小鼠(R. E. Morrissey et al.， 1989, Fundam)。达成。毒物，13,747-777)。六种女性毒物中的三种[2,2-双(溴乙基)-1,3-丙二醇，BPD;乙二醇单甲醚;甲氧基乙酸(MAA)显著降低CD-1小鼠小卵泡和/或生长卵泡计数33%至92%;EGME也降低了其他菌株的卵泡计数。用EGME或其活性代谢物MAA治疗的动物后代卵泡计数减少。对于BPD，卵泡数量的减少与剂量成正比。在CD-1小鼠中，雌性毒物邻苯二甲酸二n -己基酯、溴化丙烯和磷酸三甲酰基降低了生殖性能，但没有降低卵泡数量。计数不受无法确定易感性别的毒物(双酚A、乙二醇、草酸)的影响。在低剂量BPD的CD-1小鼠中，卵泡计数发生改变，但没有明显的生殖损伤，但在无毒化学物质中没有观察到。这些数据表明，差异卵泡计数(1)是传统生物检测中卵巢损伤的可量化终点，(2)在某些情况下，可能提供比生育能力更敏感的女性生殖毒性指标。
{"title":"Differential follicle counts as a screen for chemically induced ovarian toxicity in mice: results from continuous breeding bioassays.","authors":"B. Bolon, T. Bucci, A. Warbritton, James J. Chen, D. Mattison, J. Heindel","doi":"10.1093/TOXSCI/39.1.1","DOIUrl":"https://doi.org/10.1093/TOXSCI/39.1.1","url":null,"abstract":"Ovaries from National Toxicology Program Reproductive Assessment by Continuous Breeding (RACB) bioassays were used to directly compare differential ovarian follicle counts and reproductive performance for 15 chemicals. Ovaries of 10 animals per group from 16 studies in CD-1 mice and 1 study each in C3H and C57BL/6 mice were sectioned serially at 6 microm. Counts of small, growing, and antral follicles were obtained in every 10th section. For all follicle types, younger mice had more follicles than older mice, and CD-1 mice had more follicles than age-matched animals from either inbred strain. The in-life portion of the RACB protocols demonstrated that 9 of 15 chemicals altered reproductive outcome in one or both sexes of mice, with six agents affecting females (R. E. Morrissey et al., 1989, Fundam. Appl. Toxicol. 13, 747-777). Three of six female toxicants [2,2-bis(bromoethyl)-1,3-propanediol, BPD; ethylene glycol monomethyl ether, EGME; methoxyacetic acid, MAA] significantly decreased counts of small and/or growing follicles by 33 to 92% in CD-1 mice; EGME also reduced follicle counts in the other strains. Follicle counts were decreased in progeny of animals treated with EGME or its active metabolite, MAA. For BPD, reductions in follicle numbers were proportional to dose. In CD-1 mice, female toxicants di-N-hexyl phthalate, propantheline bromide, and tricresyl phosphate reduced reproductive performance but not follicle numbers. Counts were not affected by toxicants for which the susceptible sex could not be determined (bisphenol A, ethylene glycol, oxalic acid). Altered follicle counts without apparent reproductive impairment occurred in CD-1 mice at lower doses of BPD but were not observed for nontoxic chemicals. These data suggest that differential follicle counts (1) are a quantifiable endpoint of ovarian injury in conventional bioassays, and (2) in some instances, may provide a more sensitive indicator of female reproductive toxicity than fertility.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"78 1","pages":"1-10"},"PeriodicalIF":0.0,"publicationDate":"1997-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80989995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jennifer L. Almekinder, David E. Lennard, David K. Walmer, David K. Walmer, Barbara J. Davis
Ethylene glycol monomethyl ether (EGME) and its proximate metabolite, 2-methoxyacetic acid (MAA), increase ovarian luteal cell progesterone production in the female rat in vivo and in cultured rat luteal cells in vitro, respectively. In order to better assess the potential hazard of EGME and MAA to women, these studies were conducted to determine whether the same concentrations of MAA increase progesterone in human luteinized granulosa cells as in rat luteal cells. Human cells were collected from healthy anonymous oocyte donors, washed, plated 25,000 viable cells per well, and treated with 10 IU hCG and 0-5 mM MAA for 6-48 hr. Progesterone in media was significantly elevated after 24 hr incubation at >/=1 mM MAA. MAA had no effect on ATP levels at 6 or 24 hr. Thus, MAA increased progesterone production in cultured human luteal cells at the same concentration as MAA increased progesterone in rat luteal cells. The implication is that EGME has the potential to alter ovarian luteal function in women. These data should be useful for determining the real health hazards and potential risks of EGME exposure.
乙二醇单甲醚(EGME)及其近似代谢物2-甲氧基乙酸(MAA)分别在体内和体外培养的大鼠黄体细胞中增加卵巢黄体细胞孕酮的产生。为了更好地评估EGME和MAA对女性的潜在危害，进行了这些研究，以确定相同浓度的MAA是否会增加人黄体化颗粒细胞中的黄体酮，就像在大鼠黄体细胞中一样。从健康的匿名卵母细胞供体中收集人类细胞，清洗，每孔镀25,000个活细胞，并用10 IU hCG和0-5 mM MAA处理6-48小时。>/=1 mM MAA孵育24小时后，培养液中黄体酮水平显著升高。MAA对6小时或24小时的ATP水平没有影响。因此，MAA增加培养的人黄体细胞中黄体酮的产生，其浓度与MAA增加大鼠黄体细胞中黄体酮的浓度相同。这意味着EGME有可能改变女性卵巢黄体功能。这些数据应有助于确定暴露于EGME的实际健康危害和潜在风险。
{"title":"Toxicity of methoxyacetic acid in cultured human luteal cells.","authors":"Jennifer L. Almekinder, David E. Lennard, David K. Walmer, David K. Walmer, Barbara J. Davis","doi":"10.1093/TOXSCI/38.2.191","DOIUrl":"https://doi.org/10.1093/TOXSCI/38.2.191","url":null,"abstract":"Ethylene glycol monomethyl ether (EGME) and its proximate metabolite, 2-methoxyacetic acid (MAA), increase ovarian luteal cell progesterone production in the female rat in vivo and in cultured rat luteal cells in vitro, respectively. In order to better assess the potential hazard of EGME and MAA to women, these studies were conducted to determine whether the same concentrations of MAA increase progesterone in human luteinized granulosa cells as in rat luteal cells. Human cells were collected from healthy anonymous oocyte donors, washed, plated 25,000 viable cells per well, and treated with 10 IU hCG and 0-5 mM MAA for 6-48 hr. Progesterone in media was significantly elevated after 24 hr incubation at >/=1 mM MAA. MAA had no effect on ATP levels at 6 or 24 hr. Thus, MAA increased progesterone production in cultured human luteal cells at the same concentration as MAA increased progesterone in rat luteal cells. The implication is that EGME has the potential to alter ovarian luteal function in women. These data should be useful for determining the real health hazards and potential risks of EGME exposure.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"21 4","pages":"191-4"},"PeriodicalIF":0.0,"publicationDate":"1997-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91434637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Organophosphate (OP) pesticides can bind to carboxylesterase (CaE), which may lower the concentration of OPs at the target site enzyme, acetylcholinesterase (ChE). It is unclear from the literature whether it is the CaE's affinity for the OP and/or the number of CaE molecules which is the dominant factor in determining the protective potential of CaE. We undertook a detailed, in vitro and in vivo survey of both CaE and ChE to ascertain if in vitro sensitivity of CaE and ChE predicted the pattern of inhibition seen after in vivo dosing with chlorpyrifos (CPF; 80 mg/kg, p.o.) in male or female adult Long-Evans rats. For the brain, the in vitro sensitivity to CPF-oxon did predict the in vivo patterns of inhibition: In vitro, brain ChE was approximately 25 times more sensitive to the active metabolite, CPF-oxon, than brain CaE, and in vivo brain ChE was more inhibited than brain CaE. In contrast, the in vitro sensitivity of plasma ChE and CaE did not correlate well with the in vivo pattern of inhibition: In vitro, plasma ChE was approximately 6.5 times less sensitive to CPF-oxon than plasma CaE, but in vivo, plasma ChE was more inhibited than CaE. In order to understand the role of CaE in protecting the brain ChE from inhibition by CPF-oxon in vitro, adult rat striatal tissue was incubated in the presence and absence of adult rat liver tissue and IC50s of CPF-oxon were determined. The increase in the striatal CPF-oxon IC50 value noted for ChE in the presence of liver suggested that CaE was binding the CPF-oxon and limiting its access to ChE. Male liver CaE, which has the same affinity for binding CPF-oxon as female liver CaE but has twice as many binding sites, caused a greater increase in the striatal CPF-oxon IC50 than female liver, suggesting that the number of binding sites does play a role in the detoxification potential of a tissue. In summary, we found that (1) there are tissue and gender-related differences for basal ChE and CaE activity; (2) the in vitro sensitivity of CaE or ChE to CPF-oxon is highly tissue-specific; (3) the pattern of ChE and CaE inhibition after in vivo dosing with CPF is not necessarily predictable from the in vitro IC50 for these same enzymes, and (4) the number of CaE molecules may play a role in modifying the toxicity of CPF.
{"title":"Tissue-specific effects of chlorpyrifos on carboxylesterase and cholinesterase activity in adult rats: an in vitro and in vivo comparison.","authors":"S. Chanda, S. Mortensen, V. Moser, S. Padilla","doi":"10.1093/TOXSCI/38.2.148","DOIUrl":"https://doi.org/10.1093/TOXSCI/38.2.148","url":null,"abstract":"Organophosphate (OP) pesticides can bind to carboxylesterase (CaE), which may lower the concentration of OPs at the target site enzyme, acetylcholinesterase (ChE). It is unclear from the literature whether it is the CaE's affinity for the OP and/or the number of CaE molecules which is the dominant factor in determining the protective potential of CaE. We undertook a detailed, in vitro and in vivo survey of both CaE and ChE to ascertain if in vitro sensitivity of CaE and ChE predicted the pattern of inhibition seen after in vivo dosing with chlorpyrifos (CPF; 80 mg/kg, p.o.) in male or female adult Long-Evans rats. For the brain, the in vitro sensitivity to CPF-oxon did predict the in vivo patterns of inhibition: In vitro, brain ChE was approximately 25 times more sensitive to the active metabolite, CPF-oxon, than brain CaE, and in vivo brain ChE was more inhibited than brain CaE. In contrast, the in vitro sensitivity of plasma ChE and CaE did not correlate well with the in vivo pattern of inhibition: In vitro, plasma ChE was approximately 6.5 times less sensitive to CPF-oxon than plasma CaE, but in vivo, plasma ChE was more inhibited than CaE. In order to understand the role of CaE in protecting the brain ChE from inhibition by CPF-oxon in vitro, adult rat striatal tissue was incubated in the presence and absence of adult rat liver tissue and IC50s of CPF-oxon were determined. The increase in the striatal CPF-oxon IC50 value noted for ChE in the presence of liver suggested that CaE was binding the CPF-oxon and limiting its access to ChE. Male liver CaE, which has the same affinity for binding CPF-oxon as female liver CaE but has twice as many binding sites, caused a greater increase in the striatal CPF-oxon IC50 than female liver, suggesting that the number of binding sites does play a role in the detoxification potential of a tissue. In summary, we found that (1) there are tissue and gender-related differences for basal ChE and CaE activity; (2) the in vitro sensitivity of CaE or ChE to CPF-oxon is highly tissue-specific; (3) the pattern of ChE and CaE inhibition after in vivo dosing with CPF is not necessarily predictable from the in vitro IC50 for these same enzymes, and (4) the number of CaE molecules may play a role in modifying the toxicity of CPF.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"18 1","pages":"148-57"},"PeriodicalIF":0.0,"publicationDate":"1997-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82871101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The database of Continuous Breeding mouse studies was evaluated to determine the relationships between the functional indicators of reproduction (pup measures) and the various necropsy endpoints collected for males and females. Of 72 chemicals studied, both males and females were affected in 33 studies, while females and/or conceptuses were affected in 7. Two compounds affected only males, 17 studies were negative, and in 13 studies with effects it was not possible to clearly determine the affected gender(s). Greater F0 dam weight was correlated with increased pup mass per litter; this relationship was strongest for the first litter, and weakest for the fifth litter. For both generations of treated females (F0 and F1), longer estrous cycles correlated with reduced numbers of pups; the relationship was stronger in F0 than in F1 females and was not seen in controls. Sperm parameters had different distributions in treated mice than in control mice. Fertility (total live pups/number of pairs cohabited) was reduced if there were > approximately 15% sperm abnormalities or if sperm motility (moving/not moving) was < approximately 37%. Both of these relationships appeared to have thresholds. Epididymal sperm count in treated animals, however, was linearly related to fertility, even within the control range, suggesting strongly that other factors are important. Using both treated and control data together, combining sperm count with motility could explain much (r = 0.77) of the variation in fertility; adding morphology did not significantly improve the correlation. The model was almost as strong using count and morphology, in which case adding motility did not strengthen the model. This analysis of these studies shows that while some endpoints (e.g., random-estrous-cycle-point ovary weight) correlate poorly with fertility, other necropsy endpoints (epididymal sperm count and motility, estrous cycle length, and testis and epididymal weights) can be useful (though not complete) surrogates of overall reproductive function. Indeed, over many studies, epididymal sperm count in treated animals correlates with fertility so well that even small reductions (approximately 20%) in count result in reduced fertility, suggesting that mice may be better models of human fertility than was previously believed.
{"title":"The relationships among reproductive endpoints in Swiss mice, using the reproductive assessment by Continuous Breeding database.","authors":"R. Chapin, R. Sloane, J. Haseman","doi":"10.1093/TOXSCI/38.2.129","DOIUrl":"https://doi.org/10.1093/TOXSCI/38.2.129","url":null,"abstract":"The database of Continuous Breeding mouse studies was evaluated to determine the relationships between the functional indicators of reproduction (pup measures) and the various necropsy endpoints collected for males and females. Of 72 chemicals studied, both males and females were affected in 33 studies, while females and/or conceptuses were affected in 7. Two compounds affected only males, 17 studies were negative, and in 13 studies with effects it was not possible to clearly determine the affected gender(s). Greater F0 dam weight was correlated with increased pup mass per litter; this relationship was strongest for the first litter, and weakest for the fifth litter. For both generations of treated females (F0 and F1), longer estrous cycles correlated with reduced numbers of pups; the relationship was stronger in F0 than in F1 females and was not seen in controls. Sperm parameters had different distributions in treated mice than in control mice. Fertility (total live pups/number of pairs cohabited) was reduced if there were > approximately 15% sperm abnormalities or if sperm motility (moving/not moving) was < approximately 37%. Both of these relationships appeared to have thresholds. Epididymal sperm count in treated animals, however, was linearly related to fertility, even within the control range, suggesting strongly that other factors are important. Using both treated and control data together, combining sperm count with motility could explain much (r = 0.77) of the variation in fertility; adding morphology did not significantly improve the correlation. The model was almost as strong using count and morphology, in which case adding motility did not strengthen the model. This analysis of these studies shows that while some endpoints (e.g., random-estrous-cycle-point ovary weight) correlate poorly with fertility, other necropsy endpoints (epididymal sperm count and motility, estrous cycle length, and testis and epididymal weights) can be useful (though not complete) surrogates of overall reproductive function. Indeed, over many studies, epididymal sperm count in treated animals correlates with fertility so well that even small reductions (approximately 20%) in count result in reduced fertility, suggesting that mice may be better models of human fertility than was previously believed.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"292 1","pages":"129-42"},"PeriodicalIF":0.0,"publicationDate":"1997-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91545767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This study was carried out to provide information on the effects of inhalation of diethylene glycol monoethyl ether, a substance used in industry which may be accidentally inhaled by man. Sprague-Dawley CD rats were exposed by inhalation to a test atmosphere containing diethylene glycol monoethyl ether in a nose-only exposure system for 6 hr a day, 5 days a week for 28 days. Mean exposure levels were 0. 09, 0.27, and 1.1 mg/liter. At the two lowest exposure levels the test substance was present entirely as vapor, but at the highest exposure level the test atmosphere was approximately equally divided by mass into respirable droplets (aerosol) and vapor. A comprehensive battery of toxicological evaluations including food consumption, body weight, clinical signs, hematology, and biochemistry revealed no evidence of a systemic effect of exposure. Histopathological examination showed changes indicative of mild nonspecific irritation in the upper respiratory tract of rats exposed at the two highest exposure levels. These changes consisted of foci of necrosis in the ventral cartilage of the larynx of rats exposed at 0.27 or 1.1 mg/liter and an increase in eosinophilic inclusions in the olfactory epithelium of the nasal mucosa of rats exposed at 1.1 mg/liter. The no observed adverse effect level for systemic effects was 1.1 mg/liter and the no observed adverse effect level for signs indicative of mild nonspecific irritation of the upper respiratory tract was 0.09 mg/liter.
{"title":"Twenty-eight-day repeated-dose inhalation exposure of rats to diethylene glycol monoethyl ether.","authors":"C. Hardy, D. W. Coombs, D. J. Lewis, H. Klimisch","doi":"10.1093/TOXSCI/38.2.143","DOIUrl":"https://doi.org/10.1093/TOXSCI/38.2.143","url":null,"abstract":"This study was carried out to provide information on the effects of inhalation of diethylene glycol monoethyl ether, a substance used in industry which may be accidentally inhaled by man. Sprague-Dawley CD rats were exposed by inhalation to a test atmosphere containing diethylene glycol monoethyl ether in a nose-only exposure system for 6 hr a day, 5 days a week for 28 days. Mean exposure levels were 0. 09, 0.27, and 1.1 mg/liter. At the two lowest exposure levels the test substance was present entirely as vapor, but at the highest exposure level the test atmosphere was approximately equally divided by mass into respirable droplets (aerosol) and vapor. A comprehensive battery of toxicological evaluations including food consumption, body weight, clinical signs, hematology, and biochemistry revealed no evidence of a systemic effect of exposure. Histopathological examination showed changes indicative of mild nonspecific irritation in the upper respiratory tract of rats exposed at the two highest exposure levels. These changes consisted of foci of necrosis in the ventral cartilage of the larynx of rats exposed at 0.27 or 1.1 mg/liter and an increase in eosinophilic inclusions in the olfactory epithelium of the nasal mucosa of rats exposed at 1.1 mg/liter. The no observed adverse effect level for systemic effects was 1.1 mg/liter and the no observed adverse effect level for signs indicative of mild nonspecific irritation of the upper respiratory tract was 0.09 mg/liter.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"46 1","pages":"143-7"},"PeriodicalIF":0.0,"publicationDate":"1997-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83284910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
In oral carcinogenicity bioassays, zidovudine (ZDV) induced vaginal epithelial cell tumors in mice given 30 or 40 mg/kg/day and rats given 300 mg/kg/day. To determine if lifetime exposure to ZDV, beginning perinatally, would alter this pattern of carcinogenicity, two groups of 60 pregnant CD-1 mice were given 20 or 40 mg/kg/day of ZDV in 0.5% methyl cellulose from Gestation Day 10 through Lactation Day 21. At weaning, 2 pups per sex from each of 35 litters in each group were assigned to the study and given 20 or 40 mg/kg/day of ZDV in the drinking water until 17-35 days of age, followed by daily gavage for 24 months. Two additional groups of 60 pregnant CD-1 mice each were given 40 mg/kg/day of ZDV daily from Gestation Day 10 through Lactation Day 21; in one, ZDV treatment was halted at weaning and in the other, treatment was stopped 90 days after weaning. Two other groups of 60 pregnant CD-1 mice were left untreated (environmental control) or were given 0.5% methyl cellulose beginning on Gestation Day 10 (vehicle control). Vehicle control progeny received plain drinking water for 17-35 days postweaning and then 0.5% methyl cellulose daily by gavage for 24 months. ZDV treatment did not affect survival or body weight in either sex. In females given 20 or 40 mg/kg/day of ZDV for 24 months there was mild macrocytic anemia. Similar, non-dose-related changes were seen in males in these groups. ZDV-related tumor findings were limited to the vagina, where there were 2 and 11 vaginal squamous cell carcinomas in mice given 20 or 40 mg/kg/day of ZDV daily, respectively. This incidence was not remarkably different from that seen in previously reported bioassays. It was concluded that lifetime oral treatment of mice with ZDV, beginning perinatally, did not alter the previously reported pattern of carcinogenicity and that under the conditions tested ZDV was not a transplacental carcinogen.
{"title":"A transplacental carcinogenicity bioassay in CD-1 mice with zidovudine.","authors":"K. M. Ayers, Carla E. Torrey, David J. Reynolds","doi":"10.1093/TOXSCI/38.2.195","DOIUrl":"https://doi.org/10.1093/TOXSCI/38.2.195","url":null,"abstract":"In oral carcinogenicity bioassays, zidovudine (ZDV) induced vaginal epithelial cell tumors in mice given 30 or 40 mg/kg/day and rats given 300 mg/kg/day. To determine if lifetime exposure to ZDV, beginning perinatally, would alter this pattern of carcinogenicity, two groups of 60 pregnant CD-1 mice were given 20 or 40 mg/kg/day of ZDV in 0.5% methyl cellulose from Gestation Day 10 through Lactation Day 21. At weaning, 2 pups per sex from each of 35 litters in each group were assigned to the study and given 20 or 40 mg/kg/day of ZDV in the drinking water until 17-35 days of age, followed by daily gavage for 24 months. Two additional groups of 60 pregnant CD-1 mice each were given 40 mg/kg/day of ZDV daily from Gestation Day 10 through Lactation Day 21; in one, ZDV treatment was halted at weaning and in the other, treatment was stopped 90 days after weaning. Two other groups of 60 pregnant CD-1 mice were left untreated (environmental control) or were given 0.5% methyl cellulose beginning on Gestation Day 10 (vehicle control). Vehicle control progeny received plain drinking water for 17-35 days postweaning and then 0.5% methyl cellulose daily by gavage for 24 months. ZDV treatment did not affect survival or body weight in either sex. In females given 20 or 40 mg/kg/day of ZDV for 24 months there was mild macrocytic anemia. Similar, non-dose-related changes were seen in males in these groups. ZDV-related tumor findings were limited to the vagina, where there were 2 and 11 vaginal squamous cell carcinomas in mice given 20 or 40 mg/kg/day of ZDV daily, respectively. This incidence was not remarkably different from that seen in previously reported bioassays. It was concluded that lifetime oral treatment of mice with ZDV, beginning perinatally, did not alter the previously reported pattern of carcinogenicity and that under the conditions tested ZDV was not a transplacental carcinogen.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"8 1","pages":"195-8"},"PeriodicalIF":0.0,"publicationDate":"1997-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87882682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Organophosphate (OP) pesticides can bind to carboxylesterase (CaE), which may lower the concentration of OPs at the target site enzyme, acetylcholinesterase (ChE). It is unclear from the literature whether it is the CaE's affinity for the OP and/or the number of CaE molecules which is the dominant factor in determining the protective potential of CaE. We undertook a detailed, in vitro and in vivo survey of both CaE and ChE to ascertain if in vitro sensitivity of CaE and ChE predicted the pattern of inhibition seen after in vivo dosing with chlorpyrifos (CPF; 80 mg/kg, p.o.) in male or female adult Long-Evans rats. For the brain, the in vitro sensitivity to CPF-oxon did predict the in vivo patterns of inhibition: In vitro, brain ChE was approximately 25 times more sensitive to the active metabolite, CPF-oxon, than brain CaE, and in vivo brain ChE was more inhibited than brain CaE. In contrast, the in vitro sensitivity of plasma ChE and CaE did not correlate well with the in vivo pattern of inhibition: In vitro, plasma ChE was approximately 6.5 times less sensitive to CPF-oxon than plasma CaE, but in vivo, plasma ChE was more inhibited than CaE. In order to understand the role of CaE in protecting the brain ChE from inhibition by CPF-oxon in vitro, adult rat striatal tissue was incubated in the presence and absence of adult rat liver tissue and IC50s of CPF-oxon were determined. The increase in the striatal CPF-oxon IC50 value noted for ChE in the presence of liver suggested that CaE was binding the CPF-oxon and limiting its access to ChE. Male liver CaE, which has the same affinity for binding CPF-oxon as female liver CaE but has twice as many binding sites, caused a greater increase in the striatal CPF-oxon IC50 than female liver, suggesting that the number of binding sites does play a role in the detoxification potential of a tissue. In summary, we found that (1) there are tissue and gender-related differences for basal ChE and CaE activity; (2) the in vitro sensitivity of CaE or ChE to CPF-oxon is highly tissue-specific; (3) the pattern of ChE and CaE inhibition after in vivo dosing with CPF is not necessarily predictable from the in vitro IC50 for these same enzymes, and (4) the number of CaE molecules may play a role in modifying the toxicity of CPF.
{"title":"Tissue-specific effects of chlorpyrifos on carboxylesterase and cholinesterase activity in adult rats: an in vitro and in vivo comparison.","authors":"S M Chanda, S R Mortensen, V C Moser, S Padilla","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Organophosphate (OP) pesticides can bind to carboxylesterase (CaE), which may lower the concentration of OPs at the target site enzyme, acetylcholinesterase (ChE). It is unclear from the literature whether it is the CaE's affinity for the OP and/or the number of CaE molecules which is the dominant factor in determining the protective potential of CaE. We undertook a detailed, in vitro and in vivo survey of both CaE and ChE to ascertain if in vitro sensitivity of CaE and ChE predicted the pattern of inhibition seen after in vivo dosing with chlorpyrifos (CPF; 80 mg/kg, p.o.) in male or female adult Long-Evans rats. For the brain, the in vitro sensitivity to CPF-oxon did predict the in vivo patterns of inhibition: In vitro, brain ChE was approximately 25 times more sensitive to the active metabolite, CPF-oxon, than brain CaE, and in vivo brain ChE was more inhibited than brain CaE. In contrast, the in vitro sensitivity of plasma ChE and CaE did not correlate well with the in vivo pattern of inhibition: In vitro, plasma ChE was approximately 6.5 times less sensitive to CPF-oxon than plasma CaE, but in vivo, plasma ChE was more inhibited than CaE. In order to understand the role of CaE in protecting the brain ChE from inhibition by CPF-oxon in vitro, adult rat striatal tissue was incubated in the presence and absence of adult rat liver tissue and IC50s of CPF-oxon were determined. The increase in the striatal CPF-oxon IC50 value noted for ChE in the presence of liver suggested that CaE was binding the CPF-oxon and limiting its access to ChE. Male liver CaE, which has the same affinity for binding CPF-oxon as female liver CaE but has twice as many binding sites, caused a greater increase in the striatal CPF-oxon IC50 than female liver, suggesting that the number of binding sites does play a role in the detoxification potential of a tissue. In summary, we found that (1) there are tissue and gender-related differences for basal ChE and CaE activity; (2) the in vitro sensitivity of CaE or ChE to CPF-oxon is highly tissue-specific; (3) the pattern of ChE and CaE inhibition after in vivo dosing with CPF is not necessarily predictable from the in vitro IC50 for these same enzymes, and (4) the number of CaE molecules may play a role in modifying the toxicity of CPF.</p>","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"38 2","pages":"148-57"},"PeriodicalIF":0.0,"publicationDate":"1997-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20239799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Valentovic, J. Ball, B. A. Rogers, M. K. Meadows, R. Harmon, J. Moles
Previous work has shown a reduction in cephaloridine nephrotoxicity in a diabetic rat model. The following studies examined in vitro cephaloridine toxicity in renal slices from normoglycemic and diabetic Fischer 344 rats. Diabetes was induced by acute intraperitoneal injection of 35 mg/kg streptozotocin. Renal cortical slices were isolated from normoglycemic and diabetic animals. Tissues were exposed to 0-5 mM cephaloridine for 15-120 min. Pyruvate-directed gluconeogenesis was diminished in all groups exposed to 2-5 mM cephaloridine for 60-120 min. Leakage of lactate dehydrogenase (LDH) was apparent only in the normoglycemic group in the presence of 4-5 mM cephaloridine for 120 min. LDH leakage was not increased at any cephaloridine concentration in the diabetic tissue. Total glutathione levels were compared in renal cortical slices exposed to cephaloridine for 30-120 min. Baseline values for glutathione were comparable between normoglycemic and diabetic tissue suggesting that the mechanism for reduced toxicity was not due to higher glutathione levels in diabetic tissue. Total glutathione levels were diminished more rapidly in normoglycemic than diabetic tissue by incubation with 5 mM cephaloridine. Comparison of cephaloridine accumulation indicated that diabetic tissue accumulated less cephaloridine than the normoglycemic group when tissues were incubated with 0-2 mM cephaloridine. However, renal slice accumulation was similar between normoglycemic and diabetic groups following in vitro incubation with 4-5 mM cephaloridine. These results suggest that the mechanism for reduced in vitro cephaloridine toxicity in diabetic tissue cannot be limited to differences in accumulation and must include an unidentified cellular component.
{"title":"Cephaloridine in vitro toxicity and accumulation in renal slices from normoglycemic and diabetic rats.","authors":"M. Valentovic, J. Ball, B. A. Rogers, M. K. Meadows, R. Harmon, J. Moles","doi":"10.1093/TOXSCI/38.2.184","DOIUrl":"https://doi.org/10.1093/TOXSCI/38.2.184","url":null,"abstract":"Previous work has shown a reduction in cephaloridine nephrotoxicity in a diabetic rat model. The following studies examined in vitro cephaloridine toxicity in renal slices from normoglycemic and diabetic Fischer 344 rats. Diabetes was induced by acute intraperitoneal injection of 35 mg/kg streptozotocin. Renal cortical slices were isolated from normoglycemic and diabetic animals. Tissues were exposed to 0-5 mM cephaloridine for 15-120 min. Pyruvate-directed gluconeogenesis was diminished in all groups exposed to 2-5 mM cephaloridine for 60-120 min. Leakage of lactate dehydrogenase (LDH) was apparent only in the normoglycemic group in the presence of 4-5 mM cephaloridine for 120 min. LDH leakage was not increased at any cephaloridine concentration in the diabetic tissue. Total glutathione levels were compared in renal cortical slices exposed to cephaloridine for 30-120 min. Baseline values for glutathione were comparable between normoglycemic and diabetic tissue suggesting that the mechanism for reduced toxicity was not due to higher glutathione levels in diabetic tissue. Total glutathione levels were diminished more rapidly in normoglycemic than diabetic tissue by incubation with 5 mM cephaloridine. Comparison of cephaloridine accumulation indicated that diabetic tissue accumulated less cephaloridine than the normoglycemic group when tissues were incubated with 0-2 mM cephaloridine. However, renal slice accumulation was similar between normoglycemic and diabetic groups following in vitro incubation with 4-5 mM cephaloridine. These results suggest that the mechanism for reduced in vitro cephaloridine toxicity in diabetic tissue cannot be limited to differences in accumulation and must include an unidentified cellular component.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"4 1","pages":"184-90"},"PeriodicalIF":0.0,"publicationDate":"1997-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79236938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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