S. Casteel, R. P. Cowart, C. Weis, G. Henningsen, E. Hoffman, W. Brattin, R. E. Guzman, M. Starost, J. T. Payne, S. Stockham, Stephen Becker, J. Drexler, J. Turk
Bioavailability of lead (Pb) has become an issue in quantifying exposure of sensitive populations and, where necessary, establishing cleanup levels for contaminated soil. Immature swine were used as a model for young children to estimate the degree to which Pb from two fully characterized composite samples from the Smuggler Mountain Superfund Site in Aspen, Colorado may be bioavailable to resident children. The composite soils contained 14,200 and 3870 micrograms Pb/g of soil. Relative and absolute enteric bioavailabilities of Pb in soil (oral dose groups of 75,225, and 675 micrograms Pb/kg body wt/day) were estimated by comparison with an orally administered soluble Pb salt (lead acetate = PbAc2.3H2O) (dose groups of 0, 75, and 225 micrograms Pb/kg body wt/day) and an intravenously administered aqueous solution of Pb (100 micrograms Pb/kg/ day) from the same trihydrate salt administered daily for 15 days to 50 juvenile swine. The biological responses (area under the blood Pb concentration-time curve, and the terminal liver-, kidney-, and bone-lead concentrations) produced by Pb from PbAc2.3H2O and lead-contaminated soils were determined. This study revealed Pb from soil containing 14,200 micrograms Pb/g of soil had a bioavailability relative to Pb from PbAc (RBA), ranging from 56% based on the area under the blood lead concentration-time curve (AUC) versus dose, to 86% based on calculations from liver-Pb loading versus dose. Similarly, Pb from soil containing 3870 micrograms Pb/g of soil had an RBA ranging from 58% based on the AUC versus dose, to 74% based on calculations from liver- and kidney-Pb loading versus dose. Bioavailability of Pb in soils may be more or less than EPA's default RBA of 60%, therefore, measuring site-specific RBAs provides a basis for improved exposure and risk assessment.
{"title":"Bioavailability of lead to juvenile swine dosed with soil from the Smuggler Mountain NPL Site of Aspen, Colorado.","authors":"S. Casteel, R. P. Cowart, C. Weis, G. Henningsen, E. Hoffman, W. Brattin, R. E. Guzman, M. Starost, J. T. Payne, S. Stockham, Stephen Becker, J. Drexler, J. Turk","doi":"10.1093/TOXSCI/36.2.177","DOIUrl":"https://doi.org/10.1093/TOXSCI/36.2.177","url":null,"abstract":"Bioavailability of lead (Pb) has become an issue in quantifying exposure of sensitive populations and, where necessary, establishing cleanup levels for contaminated soil. Immature swine were used as a model for young children to estimate the degree to which Pb from two fully characterized composite samples from the Smuggler Mountain Superfund Site in Aspen, Colorado may be bioavailable to resident children. The composite soils contained 14,200 and 3870 micrograms Pb/g of soil. Relative and absolute enteric bioavailabilities of Pb in soil (oral dose groups of 75,225, and 675 micrograms Pb/kg body wt/day) were estimated by comparison with an orally administered soluble Pb salt (lead acetate = PbAc2.3H2O) (dose groups of 0, 75, and 225 micrograms Pb/kg body wt/day) and an intravenously administered aqueous solution of Pb (100 micrograms Pb/kg/ day) from the same trihydrate salt administered daily for 15 days to 50 juvenile swine. The biological responses (area under the blood Pb concentration-time curve, and the terminal liver-, kidney-, and bone-lead concentrations) produced by Pb from PbAc2.3H2O and lead-contaminated soils were determined. This study revealed Pb from soil containing 14,200 micrograms Pb/g of soil had a bioavailability relative to Pb from PbAc (RBA), ranging from 56% based on the area under the blood lead concentration-time curve (AUC) versus dose, to 86% based on calculations from liver-Pb loading versus dose. Similarly, Pb from soil containing 3870 micrograms Pb/g of soil had an RBA ranging from 58% based on the AUC versus dose, to 74% based on calculations from liver- and kidney-Pb loading versus dose. Bioavailability of Pb in soils may be more or less than EPA's default RBA of 60%, therefore, measuring site-specific RBAs provides a basis for improved exposure and risk assessment.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"15 1","pages":"177-87"},"PeriodicalIF":0.0,"publicationDate":"1997-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89994452","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}
Increased detection thresholds for pure tones were observed in a large cohort of children exposed to lead environmentally while smaller studies in lead-exposed workers have reported conflicting results on assessments of auditory function. Pure tone detection thresholds were determined in a group of monkeys (Macaca fascicularis) dosed with 2 mg/kg/day of lead from birth through testing at 13 years of age. Blood lead concentrations were stable at about 30 micrograms/dl until monkeys were 10-11 years of age at which time they increased to between 50 and 70 micrograms/dl. Five age- and rearing-matched monkeys served as controls. Detection thresholds were determined at six frequencies between 0.125 and 31.5 kHz. Ear phones were fit over both ears, and thresholds were determined for each ear separately. The monkey signaled detection of the tone by breaking contact with a stainless steel bar. Three lead-exposed monkeys exhibited normal pure tone detection functions. Three monkeys had thresholds outside of the control range at some frequencies; there was a tendency for higher frequencies to be differentially more affected. These findings are consistent with reports of elevated pure tone thresholds in humans exposed to lead developmentally, although the effect is smaller than might have been predicted given the concurrent blood lead concentrations of these monkeys.
{"title":"Effects of lifetime lead exposure in monkeys on detection of pure tones.","authors":"D. Rice","doi":"10.1093/TOXSCI/36.2.112","DOIUrl":"https://doi.org/10.1093/TOXSCI/36.2.112","url":null,"abstract":"Increased detection thresholds for pure tones were observed in a large cohort of children exposed to lead environmentally while smaller studies in lead-exposed workers have reported conflicting results on assessments of auditory function. Pure tone detection thresholds were determined in a group of monkeys (Macaca fascicularis) dosed with 2 mg/kg/day of lead from birth through testing at 13 years of age. Blood lead concentrations were stable at about 30 micrograms/dl until monkeys were 10-11 years of age at which time they increased to between 50 and 70 micrograms/dl. Five age- and rearing-matched monkeys served as controls. Detection thresholds were determined at six frequencies between 0.125 and 31.5 kHz. Ear phones were fit over both ears, and thresholds were determined for each ear separately. The monkey signaled detection of the tone by breaking contact with a stainless steel bar. Three lead-exposed monkeys exhibited normal pure tone detection functions. Three monkeys had thresholds outside of the control range at some frequencies; there was a tendency for higher frequencies to be differentially more affected. These findings are consistent with reports of elevated pure tone thresholds in humans exposed to lead developmentally, although the effect is smaller than might have been predicted given the concurrent blood lead concentrations of these monkeys.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"13 1","pages":"112-8"},"PeriodicalIF":0.0,"publicationDate":"1997-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87488371","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}
H. Burleigh-Flayer, R. Garman, D. Neptun, C. Bevan, T. Gardiner, R. Kapp, T. Tyler, Gary A. Wright
The potential oncogenic effects of isopropanol, a widely used solvent, were investigated. Four groups of animals, each consisting of 75 CD-1 mice/sex and 75 Fischer 344 rats/sex, were exposed to isopropanol vapor (CAS No. 67-63-0) at target concentrations of 0 (filtered air control), 500, 2500, or 5000 ppm. Animals assigned to the core group (55 mice/sex/group and 65 rats/sex/group) were exposed for 6 hr/day, 5 consecutive days/week for at least 78 weeks for the mice or 104 weeks for the rats. Ten mice/sex/group and 10 rats/sex/group were assigned to an interim euthanasia group and were terminated during Weeks 54 and 73, respectively. In addition, 10 mice/sex/group were assigned to a recovery group and did not receive any further exposure following Week 53 but were retained until the core group of animals was euthanized. Transient signs of narcosis were observed for both mice and rats during exposure to 2500 and 5000 ppm and following exposure for mice from the 5000-ppm group. Increased mortality (100% versus 82% for controls) and a decreased mean survival time (577 days versus 631 days for controls) were noted for male rats from the 5000-ppm group. Increases in body weight and/or body weight gain were typically observed for both sexes of mice and rats from the 2500- and 5000-ppm groups throughout the study. Urinalysis and urine chemistry changes indicative of impaired kidney function (i.e., decreased osmolality and increased total protein, volume, and glucose) were noted for male rats from the 2500-ppm group as well as for male and female rats from the 5000-ppm group. At the interim euthanasia, a concentration-related increase in testes weight (absolute and relative as a percentage of body and brain weight) was observed for male rats. Concentration-related increases in absolute and relative liver weight (as a percentage of body weight) were observed for male and female mice. In addition, increased absolute and/or relative (as a percentage of body and brain weight) liver and kidney weights were observed for male and/or female rats from the 2500- and 5000-ppm groups. At necropsy, an increased incidence of seminal vesicle enlargement was observed grossly for male mice from the 2500- and 5000-ppm groups. Microscopically, some of the nonneoplastic lesions noted for mice included an increased incidence of ectasia of the seminal vesicles for male mice from the 2500- and 5000-ppm groups, minimal renal tubular proteinosis for male and female mice from all isopropanol groups, and renal tubular dilation for female mice from the 5000-ppm group. A number of nonneoplastic lesions were observed for male and female rats from the 2500- and 5000-ppm groups, with the most significant lesions being observed in the kidney and associated with chronic renal disease. The lesions noted with increased severity and/or frequency included mineralization, tubular dilation, glomerulosclerosis, interstitial nephritis, interstitial fibrosis, hydronephrosis, and transitional cel
{"title":"Isopropanol vapor inhalation oncogenicity study in Fischer 344 rats and CD-1 mice.","authors":"H. Burleigh-Flayer, R. Garman, D. Neptun, C. Bevan, T. Gardiner, R. Kapp, T. Tyler, Gary A. Wright","doi":"10.1093/TOXSCI/36.2.95","DOIUrl":"https://doi.org/10.1093/TOXSCI/36.2.95","url":null,"abstract":"The potential oncogenic effects of isopropanol, a widely used solvent, were investigated. Four groups of animals, each consisting of 75 CD-1 mice/sex and 75 Fischer 344 rats/sex, were exposed to isopropanol vapor (CAS No. 67-63-0) at target concentrations of 0 (filtered air control), 500, 2500, or 5000 ppm. Animals assigned to the core group (55 mice/sex/group and 65 rats/sex/group) were exposed for 6 hr/day, 5 consecutive days/week for at least 78 weeks for the mice or 104 weeks for the rats. Ten mice/sex/group and 10 rats/sex/group were assigned to an interim euthanasia group and were terminated during Weeks 54 and 73, respectively. In addition, 10 mice/sex/group were assigned to a recovery group and did not receive any further exposure following Week 53 but were retained until the core group of animals was euthanized. Transient signs of narcosis were observed for both mice and rats during exposure to 2500 and 5000 ppm and following exposure for mice from the 5000-ppm group. Increased mortality (100% versus 82% for controls) and a decreased mean survival time (577 days versus 631 days for controls) were noted for male rats from the 5000-ppm group. Increases in body weight and/or body weight gain were typically observed for both sexes of mice and rats from the 2500- and 5000-ppm groups throughout the study. Urinalysis and urine chemistry changes indicative of impaired kidney function (i.e., decreased osmolality and increased total protein, volume, and glucose) were noted for male rats from the 2500-ppm group as well as for male and female rats from the 5000-ppm group. At the interim euthanasia, a concentration-related increase in testes weight (absolute and relative as a percentage of body and brain weight) was observed for male rats. Concentration-related increases in absolute and relative liver weight (as a percentage of body weight) were observed for male and female mice. In addition, increased absolute and/or relative (as a percentage of body and brain weight) liver and kidney weights were observed for male and/or female rats from the 2500- and 5000-ppm groups. At necropsy, an increased incidence of seminal vesicle enlargement was observed grossly for male mice from the 2500- and 5000-ppm groups. Microscopically, some of the nonneoplastic lesions noted for mice included an increased incidence of ectasia of the seminal vesicles for male mice from the 2500- and 5000-ppm groups, minimal renal tubular proteinosis for male and female mice from all isopropanol groups, and renal tubular dilation for female mice from the 5000-ppm group. A number of nonneoplastic lesions were observed for male and female rats from the 2500- and 5000-ppm groups, with the most significant lesions being observed in the kidney and associated with chronic renal disease. The lesions noted with increased severity and/or frequency included mineralization, tubular dilation, glomerulosclerosis, interstitial nephritis, interstitial fibrosis, hydronephrosis, and transitional cel","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"88 1","pages":"95-111"},"PeriodicalIF":0.0,"publicationDate":"1997-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75159909","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}
S. Stern, C. Cox, R. Preston, A. Sharma, G. B. Inglis, M. Balys, B. Weiss
The use of methanol as a component of automobile fuel will increase perinatal exposures in the general population. Few studies have addressed questions concerning neurotoxicity stemming from such exposures. In the current study, four cohorts of pregnant Long-Evans rats, each cohort consisting of an exposure and a control group, were exposed to 4500 ppm methanol vapor in Rochester-type inhalation chambers for 6 hr daily beginning on Gestation Day 6. Exposure continued for both dams and pups through Postnatal Day 21 (PND 21) to model gestational and neonatal toxicity in humans. Several behavioral procedures were used to assess exposure effects in the offspring. Male-female littermates were studied whenever possible to examine sex differences, with one pair from a litter for each procedure. Exposure to methanol did not affect suckling latency and nipple attachment on PND 5 or performance on an aversive olfactory conditioning procedure on PND 10. Exposure to methanol did alter performances in a motor activity procedure. Methanol-exposed neonates were less active on PND 18, but more active on PND 25 than the equivalent control group pups. Two operant conditioning procedures, not used previously in this context, assayed other littermates as adults. A fixed ratio schedule required the rat to rotate a running wheel a specified number of revolutions to obtain food-pellet reinforcers. When the fixed ratio requirement changed, number of responses (revolutions) per 1-hr session displayed a complex interaction with treatment. Changes in performance over the course of training differed between males and females depending on exposure to methanol. Compared to initial baseline performances, methanol-exposed males showed decreases, and methanol-exposed females increases, in the rate of running. A stochastic spatial discrimination procedure permitted subjects to respond on any three levers, with the probabilities of food-pellet delivery determined by the location of the preceding response. A reinforcement matrix defined the response sequence required to maximize reinforcements. When the matrix was changed, the methanol-exposed subjects responded less efficiently at asymptotic levels of performance than controls. Across procedures, developmental exposure to 4500 ppm methanol vapor was associated with subtle behavioral changes in both neonates and adults.
{"title":"Perinatal methanol exposure in the rat. II. Behavioral effects in neonates and adults.","authors":"S. Stern, C. Cox, R. Preston, A. Sharma, G. B. Inglis, M. Balys, B. Weiss","doi":"10.1093/TOXSCI/36.2.163","DOIUrl":"https://doi.org/10.1093/TOXSCI/36.2.163","url":null,"abstract":"The use of methanol as a component of automobile fuel will increase perinatal exposures in the general population. Few studies have addressed questions concerning neurotoxicity stemming from such exposures. In the current study, four cohorts of pregnant Long-Evans rats, each cohort consisting of an exposure and a control group, were exposed to 4500 ppm methanol vapor in Rochester-type inhalation chambers for 6 hr daily beginning on Gestation Day 6. Exposure continued for both dams and pups through Postnatal Day 21 (PND 21) to model gestational and neonatal toxicity in humans. Several behavioral procedures were used to assess exposure effects in the offspring. Male-female littermates were studied whenever possible to examine sex differences, with one pair from a litter for each procedure. Exposure to methanol did not affect suckling latency and nipple attachment on PND 5 or performance on an aversive olfactory conditioning procedure on PND 10. Exposure to methanol did alter performances in a motor activity procedure. Methanol-exposed neonates were less active on PND 18, but more active on PND 25 than the equivalent control group pups. Two operant conditioning procedures, not used previously in this context, assayed other littermates as adults. A fixed ratio schedule required the rat to rotate a running wheel a specified number of revolutions to obtain food-pellet reinforcers. When the fixed ratio requirement changed, number of responses (revolutions) per 1-hr session displayed a complex interaction with treatment. Changes in performance over the course of training differed between males and females depending on exposure to methanol. Compared to initial baseline performances, methanol-exposed males showed decreases, and methanol-exposed females increases, in the rate of running. A stochastic spatial discrimination procedure permitted subjects to respond on any three levers, with the probabilities of food-pellet delivery determined by the location of the preceding response. A reinforcement matrix defined the response sequence required to maximize reinforcements. When the matrix was changed, the methanol-exposed subjects responded less efficiently at asymptotic levels of performance than controls. Across procedures, developmental exposure to 4500 ppm methanol vapor was associated with subtle behavioral changes in both neonates and adults.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"330 1","pages":"163-76"},"PeriodicalIF":0.0,"publicationDate":"1997-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77606771","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 human corneal epithelial cell line, 10.014 pRSV-T (HCR-T cells), has been used to develop a three-dimensional in vitro model of the human corneal epithelium (HCE-T model). HCE-T cells form a stratified culture when grown at the air-liquid interface on a collagen membrane in serum-free medium. This model served as the basis for assays which supported the ocular irritancy assessment of water-soluble test substances. Cellular alterations in the HCE-T model were measured following 5-min topical exposures to 20 chemicals [listed in the European Center for Ecotoxicology and Toxicology of Chemicals (ECETOC) Reference Chemicals Data Bank] and 25 surfactant-based product formulations [utilized in the Cosmetic, Toiletry, and Fragrance Association (CTFA) Alternatives Program Phase III]. In vitro assays used were transepithelial permeability to sodium fluorescein (TEP) and transepithelial electrical resistance (TER). These measured alterations in the barrier function of this corneal epithelial equivalent. Barrier function is a well-developed property in the HCE-T model that supports the mechanistic relevance of these assays. In vitro data, averaged from replicate assays, were compared to respective Draize rabbit eye irritation data from the publicly available ECETOC and CTFA databases using linear regression with Pearson's correlation analysis. For chemicals, Pearson's correlation coefficients, r, from comparisons of Draize maximum average scores (MAS) to TEP and TER data were 0.71 and 0.55, respectively. For product formulations, Pearson's correlation coefficients from comparisons of Draize MAS to TEP and TER data were 0.86 and 0.80, respectively. Data indicated that barrier function alterations in the HCE-T model correlated with ocular irritancy and corneal toxicity. While the irritancy of the chemicals tested was effectively assessed only by the TEP assay, that for the surfactant-based product formulations was effectively assessed by both the TEP and TER assays. Results also suggested that the HCE-T TEP and TER assays vary in their effectiveness for evaluating specific classes of test materials.
利用人角膜上皮细胞系10.014 prv - t (HCR-T细胞)建立了人角膜上皮三维体外模型(HCE-T模型)。当HCE-T细胞在无血清培养基中胶原膜的气液界面上生长时，形成分层培养物。该模型可作为支持水溶性试验物质眼刺激性评价的试验基础。在局部暴露于20种化学物质(列在欧洲生态毒理学和化学品毒理学中心(ECETOC)参考化学品数据库中)和25种基于表面活性剂的产品配方(在化妆品、洗浴用品和香水协会(CTFA)替代品计划III期中使用)5分钟后，测量了HCE-T模型中的细胞变化。体外测定经上皮对荧光素钠的通透性(TEP)和经上皮电阻(TER)。这些测量了角膜上皮等效物屏障功能的改变。屏障功能是HCE-T模型中发育良好的特性，支持这些检测的机制相关性。使用线性回归和Pearson相关分析，将重复试验的体外数据与来自公开的ECETOC和CTFA数据库的Draize兔眼刺激数据进行比较。对于化学品，从Draize最大平均分数(MAS)与TEP和TER数据的比较中得出的Pearson相关系数r分别为0.71和0.55。对于产品配方，Draize MAS与TEP和TER数据比较的Pearson相关系数分别为0.86和0.80。数据表明，HCE-T模型中屏障功能的改变与眼部刺激和角膜毒性相关。虽然被测试化学品的刺激性仅通过TEP测定有效评估，但表面活性剂为基础的产品配方的刺激性可通过TEP和TER测定有效评估。结果还表明，HCE-T TEP和TER分析在评估特定类别测试材料的有效性方面存在差异。
{"title":"Evaluation of a human corneal epithelial cell line as an in vitro model for assessing ocular irritation.","authors":"F H Kruszewski, T L Walker, L C DiPasquale","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>A human corneal epithelial cell line, 10.014 pRSV-T (HCR-T cells), has been used to develop a three-dimensional in vitro model of the human corneal epithelium (HCE-T model). HCE-T cells form a stratified culture when grown at the air-liquid interface on a collagen membrane in serum-free medium. This model served as the basis for assays which supported the ocular irritancy assessment of water-soluble test substances. Cellular alterations in the HCE-T model were measured following 5-min topical exposures to 20 chemicals [listed in the European Center for Ecotoxicology and Toxicology of Chemicals (ECETOC) Reference Chemicals Data Bank] and 25 surfactant-based product formulations [utilized in the Cosmetic, Toiletry, and Fragrance Association (CTFA) Alternatives Program Phase III]. In vitro assays used were transepithelial permeability to sodium fluorescein (TEP) and transepithelial electrical resistance (TER). These measured alterations in the barrier function of this corneal epithelial equivalent. Barrier function is a well-developed property in the HCE-T model that supports the mechanistic relevance of these assays. In vitro data, averaged from replicate assays, were compared to respective Draize rabbit eye irritation data from the publicly available ECETOC and CTFA databases using linear regression with Pearson's correlation analysis. For chemicals, Pearson's correlation coefficients, r, from comparisons of Draize maximum average scores (MAS) to TEP and TER data were 0.71 and 0.55, respectively. For product formulations, Pearson's correlation coefficients from comparisons of Draize MAS to TEP and TER data were 0.86 and 0.80, respectively. Data indicated that barrier function alterations in the HCE-T model correlated with ocular irritancy and corneal toxicity. While the irritancy of the chemicals tested was effectively assessed only by the TEP assay, that for the surfactant-based product formulations was effectively assessed by both the TEP and TER assays. Results also suggested that the HCE-T TEP and TER assays vary in their effectiveness for evaluating specific classes of test materials.</p>","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"36 2","pages":"130-40"},"PeriodicalIF":0.0,"publicationDate":"1997-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20091343","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}
Sparfloxacin (SPFX) and levofloxacin (LVFX) with ultraviolet-A (UVA) irradiation have been reported to induce skin inflammation due to phototoxicity in Balb/c mice. We examined the production of arachidonic acid metabolites induced by quinolone phototoxicity in Balb/c 3T3 mouse fibroblast cells in vitro. The cells were simultaneously treated with SPFX or LVFX at 1, 10, or 100 microM and UVA irradiation for 5 min (0.5 J/cm2). They were then cultured in quinolone-free medium for 24 hr, and the concentrations of prostaglandin E2 (PGE2), 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), and leukotriene B4 (LTB4) in the incubation medium were measured. Furthermore, the effect of quinolone photoproducts on the production of the inflammatory mediators and that of indomethacin on PGE2 level were also examined. Treatment with SPFX at 100 microM plus UVA irradiation markedly increased levels of PGE2 and 6-keto-PGF1 alpha, but not that of LTB4. SPFX or LVFX alone at up to 100 microM, 10 microM SPFX, or 100 microM LVFX, or less plus UVA irradiation, or UVA-preirradiated quinolone up to 100 microM had no effect. Indomethacin even at 0.1 microM completely inhibited the PGE2 elevation induced by 100 microM SPFX with UVA. These results suggest that PGs released from dermal fibroblasts in the simultaneous presence of quinolone and UVA could contribute in part to the development of skin inflammation in vivo.
{"title":"Stimulation of prostaglandin production by quinolone phototoxicity in Balb/c 3T3 mouse fibroblast cells in vitro.","authors":"K. Shimoda, N. Wagai, M. Kato","doi":"10.1093/TOXSCI/36.2.157","DOIUrl":"https://doi.org/10.1093/TOXSCI/36.2.157","url":null,"abstract":"Sparfloxacin (SPFX) and levofloxacin (LVFX) with ultraviolet-A (UVA) irradiation have been reported to induce skin inflammation due to phototoxicity in Balb/c mice. We examined the production of arachidonic acid metabolites induced by quinolone phototoxicity in Balb/c 3T3 mouse fibroblast cells in vitro. The cells were simultaneously treated with SPFX or LVFX at 1, 10, or 100 microM and UVA irradiation for 5 min (0.5 J/cm2). They were then cultured in quinolone-free medium for 24 hr, and the concentrations of prostaglandin E2 (PGE2), 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), and leukotriene B4 (LTB4) in the incubation medium were measured. Furthermore, the effect of quinolone photoproducts on the production of the inflammatory mediators and that of indomethacin on PGE2 level were also examined. Treatment with SPFX at 100 microM plus UVA irradiation markedly increased levels of PGE2 and 6-keto-PGF1 alpha, but not that of LTB4. SPFX or LVFX alone at up to 100 microM, 10 microM SPFX, or 100 microM LVFX, or less plus UVA irradiation, or UVA-preirradiated quinolone up to 100 microM had no effect. Indomethacin even at 0.1 microM completely inhibited the PGE2 elevation induced by 100 microM SPFX with UVA. These results suggest that PGs released from dermal fibroblasts in the simultaneous presence of quinolone and UVA could contribute in part to the development of skin inflammation in vivo.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"1 1","pages":"157-62"},"PeriodicalIF":0.0,"publicationDate":"1997-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86838297","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 human corneal epithelial cell line, 10.014 pRSV-T (HCR-T cells), has been used to develop a three-dimensional in vitro model of the human corneal epithelium (HCE-T model). HCE-T cells form a stratified culture when grown at the air-liquid interface on a collagen membrane in serum-free medium. This model served as the basis for assays which supported the ocular irritancy assessment of water-soluble test substances. Cellular alterations in the HCE-T model were measured following 5-min topical exposures to 20 chemicals [listed in the European Center for Ecotoxicology and Toxicology of Chemicals (ECETOC) Reference Chemicals Data Bank] and 25 surfactant-based product formulations [utilized in the Cosmetic, Toiletry, and Fragrance Association (CTFA) Alternatives Program Phase III]. In vitro assays used were transepithelial permeability to sodium fluorescein (TEP) and transepithelial electrical resistance (TER). These measured alterations in the barrier function of this corneal epithelial equivalent. Barrier function is a well-developed property in the HCE-T model that supports the mechanistic relevance of these assays. In vitro data, averaged from replicate assays, were compared to respective Draize rabbit eye irritation data from the publicly available ECETOC and CTFA databases using linear regression with Pearson's correlation analysis. For chemicals, Pearson's correlation coefficients, r, from comparisons of Draize maximum average scores (MAS) to TEP and TER data were 0.71 and 0.55, respectively. For product formulations, Pearson's correlation coefficients from comparisons of Draize MAS to TEP and TER data were 0.86 and 0.80, respectively. Data indicated that barrier function alterations in the HCE-T model correlated with ocular irritancy and corneal toxicity. While the irritancy of the chemicals tested was effectively assessed only by the TEP assay, that for the surfactant-based product formulations was effectively assessed by both the TEP and TER assays. Results also suggested that the HCE-T TEP and TER assays vary in their effectiveness for evaluating specific classes of test materials.
利用人角膜上皮细胞系10.014 prv - t (HCR-T细胞)建立了人角膜上皮三维体外模型(HCE-T模型)。当HCE-T细胞在无血清培养基中胶原膜的气液界面上生长时，形成分层培养物。该模型可作为支持水溶性试验物质眼刺激性评价的试验基础。在局部暴露于20种化学物质(列在欧洲生态毒理学和化学品毒理学中心(ECETOC)参考化学品数据库中)和25种基于表面活性剂的产品配方(在化妆品、洗浴用品和香水协会(CTFA)替代品计划III期中使用)5分钟后，测量了HCE-T模型中的细胞变化。体外测定经上皮对荧光素钠的通透性(TEP)和经上皮电阻(TER)。这些测量了角膜上皮等效物屏障功能的改变。屏障功能是HCE-T模型中发育良好的特性，支持这些检测的机制相关性。使用线性回归和Pearson相关分析，将重复试验的体外数据与来自公开的ECETOC和CTFA数据库的Draize兔眼刺激数据进行比较。对于化学品，从Draize最大平均分数(MAS)与TEP和TER数据的比较中得出的Pearson相关系数r分别为0.71和0.55。对于产品配方，Draize MAS与TEP和TER数据比较的Pearson相关系数分别为0.86和0.80。数据表明，HCE-T模型中屏障功能的改变与眼部刺激和角膜毒性相关。虽然被测试化学品的刺激性仅通过TEP测定有效评估，但表面活性剂为基础的产品配方的刺激性可通过TEP和TER测定有效评估。结果还表明，HCE-T TEP和TER分析在评估特定类别测试材料的有效性方面存在差异。
{"title":"Evaluation of a human corneal epithelial cell line as an in vitro model for assessing ocular irritation.","authors":"F. Kruszewski, T. L. Walker, L. Dipasquale","doi":"10.1093/TOXSCI/36.2.130","DOIUrl":"https://doi.org/10.1093/TOXSCI/36.2.130","url":null,"abstract":"A human corneal epithelial cell line, 10.014 pRSV-T (HCR-T cells), has been used to develop a three-dimensional in vitro model of the human corneal epithelium (HCE-T model). HCE-T cells form a stratified culture when grown at the air-liquid interface on a collagen membrane in serum-free medium. This model served as the basis for assays which supported the ocular irritancy assessment of water-soluble test substances. Cellular alterations in the HCE-T model were measured following 5-min topical exposures to 20 chemicals [listed in the European Center for Ecotoxicology and Toxicology of Chemicals (ECETOC) Reference Chemicals Data Bank] and 25 surfactant-based product formulations [utilized in the Cosmetic, Toiletry, and Fragrance Association (CTFA) Alternatives Program Phase III]. In vitro assays used were transepithelial permeability to sodium fluorescein (TEP) and transepithelial electrical resistance (TER). These measured alterations in the barrier function of this corneal epithelial equivalent. Barrier function is a well-developed property in the HCE-T model that supports the mechanistic relevance of these assays. In vitro data, averaged from replicate assays, were compared to respective Draize rabbit eye irritation data from the publicly available ECETOC and CTFA databases using linear regression with Pearson's correlation analysis. For chemicals, Pearson's correlation coefficients, r, from comparisons of Draize maximum average scores (MAS) to TEP and TER data were 0.71 and 0.55, respectively. For product formulations, Pearson's correlation coefficients from comparisons of Draize MAS to TEP and TER data were 0.86 and 0.80, respectively. Data indicated that barrier function alterations in the HCE-T model correlated with ocular irritancy and corneal toxicity. While the irritancy of the chemicals tested was effectively assessed only by the TEP assay, that for the surfactant-based product formulations was effectively assessed by both the TEP and TER assays. Results also suggested that the HCE-T TEP and TER assays vary in their effectiveness for evaluating specific classes of test materials.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"57 1","pages":"130-40"},"PeriodicalIF":0.0,"publicationDate":"1997-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82137710","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 risk from inhaled volatile organic compounds (VOCs) is presently assessed on the basis of lifetime exposure to average concentrations of the vapor. This strategy yields rational predictions of risk if the product of concentration (C) and the duration of exposure (t) yields constant effects on health (Haber's Rule). The validity of this assumption was evaluated by assessing the acute behavioral effects of inhaled trichloroethylene (TCE) vapor at various values of C and t. Adult male Long-Evans rats (n = 11) were trained to perform a signal detection task in which a press on one lever produced food on trials containing a signal (a brief, unpredictable light flash); a press on a second lever produced food on trials lacking a signal. Response time (RT) and indices of sensitivity (SI) and bias (RI) derived from the theory of signal detection were calculated at three times during repeated daily 60-min tests conducted in air containing 0, 400, 800, 1200, 1600, 2000, or 2400 ppm TCE. Behavior remained stable during tests in air. In TCE, SI declined and RT increased as functions of both C and t. RI was not affected by TCE. Effects on SI and RT were not predictable from the C x t product: both endpoints were more affected by C than by t. To quantify the change in the effect of TCE across exposure times, concentration-effect relationships for inhaled TCE on SI and RT were modeled with cubic polynomial functions at each of the three exposure durations. Concentrations of inhaled TCE associated with preselected changes in SI and RT were then estimated for each animal from these functions. Criterion concentrations, SI0.1 and RT100, were defined as the concentration of TCE associated with a 0.1-unit decrease in SI or a 100-msec increase in RT, respectively. Both SI0. 1 and RT100 increased as exposure duration decreased, but did so more slowly than would be predicted by Haber's Rule. This pattern indicates that application of Haber's Rule overestimates the concentration of inhaled TCE associated with changes in signal detection and thus underestimates the risk of behavior change from short-term exposures to TCE. On the other hand, the fact that SI0.1 and RT100 did increase with shorter exposure times indicates that the converse assumption, that the toxicity of inhaled TCE is independent of the duration of exposure, yields an overly conservative estimate of risk.
吸入挥发性有机化合物(VOCs)的风险目前是根据终生暴露于平均浓度的蒸汽来评估的。如果浓度(C)和暴露时间(t)的乘积对健康产生恒定的影响(哈伯规则)，这种策略就会产生合理的风险预测。通过评估吸入三氯乙烯(TCE)蒸汽在不同C值和t值下的急性行为影响，评估了这一假设的有效性。成年雄性Long-Evans大鼠(n = 11)被训练执行信号检测任务，在包含信号(短暂的、不可预测的闪光)的试验中，按下一个杠杆产生食物;在没有信号的情况下，按下第二个杠杆产生食物。响应时间(RT)、灵敏度指数(SI)和偏置指数(RI)由信号检测理论推导，在含有0、400、800、1200、1600、2000或2400 ppm TCE的空气中进行每日60分钟的重复测试，计算三次。在空气中测试时，性能保持稳定。TCE组SI下降，RT随C和t的作用而升高。RI不受TCE的影响。对SI和RT的影响不能从C x t乘积中预测:两个终点受C的影响比受t的影响更大。为了量化TCE在暴露时间内的影响变化，吸入TCE对SI和RT的浓度-效应关系在三个暴露时间中的每一个都用三次多项式函数建模。吸入的TCE浓度与预先选择的SI和RT变化相关，然后根据这些功能对每只动物进行估计。标准浓度SI0.1和RT100分别被定义为与SI降低0.1个单位或RT增加100毫秒相关的TCE浓度。SI0。1和RT100随着暴露时间的减少而增加，但比哈伯规则预测的要慢。这种模式表明，哈伯规则的应用高估了与信号检测变化相关的吸入TCE的浓度，从而低估了短期接触TCE导致行为改变的风险。另一方面，SI0.1和RT100确实随着暴露时间的缩短而增加，这一事实表明，相反的假设，即吸入TCE的毒性与暴露时间无关，对风险的估计过于保守。
{"title":"Concentration-time relationships for the effects of inhaled trichloroethylene on signal detection behavior in rats.","authors":"P. Bushnell","doi":"10.1093/TOXSCI/36.1.30","DOIUrl":"https://doi.org/10.1093/TOXSCI/36.1.30","url":null,"abstract":"The risk from inhaled volatile organic compounds (VOCs) is presently assessed on the basis of lifetime exposure to average concentrations of the vapor. This strategy yields rational predictions of risk if the product of concentration (C) and the duration of exposure (t) yields constant effects on health (Haber's Rule). The validity of this assumption was evaluated by assessing the acute behavioral effects of inhaled trichloroethylene (TCE) vapor at various values of C and t. Adult male Long-Evans rats (n = 11) were trained to perform a signal detection task in which a press on one lever produced food on trials containing a signal (a brief, unpredictable light flash); a press on a second lever produced food on trials lacking a signal. Response time (RT) and indices of sensitivity (SI) and bias (RI) derived from the theory of signal detection were calculated at three times during repeated daily 60-min tests conducted in air containing 0, 400, 800, 1200, 1600, 2000, or 2400 ppm TCE. Behavior remained stable during tests in air. In TCE, SI declined and RT increased as functions of both C and t. RI was not affected by TCE. Effects on SI and RT were not predictable from the C x t product: both endpoints were more affected by C than by t. To quantify the change in the effect of TCE across exposure times, concentration-effect relationships for inhaled TCE on SI and RT were modeled with cubic polynomial functions at each of the three exposure durations. Concentrations of inhaled TCE associated with preselected changes in SI and RT were then estimated for each animal from these functions. Criterion concentrations, SI0.1 and RT100, were defined as the concentration of TCE associated with a 0.1-unit decrease in SI or a 100-msec increase in RT, respectively. Both SI0. 1 and RT100 increased as exposure duration decreased, but did so more slowly than would be predicted by Haber's Rule. This pattern indicates that application of Haber's Rule overestimates the concentration of inhaled TCE associated with changes in signal detection and thus underestimates the risk of behavior change from short-term exposures to TCE. On the other hand, the fact that SI0.1 and RT100 did increase with shorter exposure times indicates that the converse assumption, that the toxicity of inhaled TCE is independent of the duration of exposure, yields an overly conservative estimate of risk.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"331 1","pages":"30-8"},"PeriodicalIF":0.0,"publicationDate":"1997-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76578368","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. Lington, M. Bird, R. T. Plutnick, W. Stubblefield, R. Scala
Groups of 110 Fischer 344 rats/sex were fed diisononyl phthalate (DINP) at dietary levels of 0, 0.03, 0.3, and 0.6 wt% for periods up to 2 years. Interim sacrifices of 10 predesignated rats/sex/dose were at 6, 12, and 18 months with surviving animals sacrificed at 24 months. At study termination, survival was in excess of 60% for every group. At the mid or high dose, the following biological effects were noted: slight decreases in food consumption and body weight; slight increase in mortality; a dose-related increase in relative organ weights of liver and kidney; and some slight effects on urinalysis, hematologic, and clinical chemistry parameters. No peroxisome induction was observed in livers of treated rats compared with controls. No clear treatment-related nonneoplastic or neoplastic lesions were found. However, mononuclear cell leukemia (MNCL) and changes known to be associated with an increased incidence of MNCL were seen in the mid-dose and high-dose groups. A literature review suggests that MNCL is a common finding in aging F344 rats and that this increased incidence in rats treated with DINP is not relevant to man. A clear no-observed-effect level was demonstrated for all biological end points at a dietary level of 0. 03 wt% or approximately 17 mg/kg/day of DINP.
{"title":"Chronic toxicity and carcinogenic evaluation of diisononyl phthalate in rats.","authors":"A. Lington, M. Bird, R. T. Plutnick, W. Stubblefield, R. Scala","doi":"10.1093/TOXSCI/36.1.79","DOIUrl":"https://doi.org/10.1093/TOXSCI/36.1.79","url":null,"abstract":"Groups of 110 Fischer 344 rats/sex were fed diisononyl phthalate (DINP) at dietary levels of 0, 0.03, 0.3, and 0.6 wt% for periods up to 2 years. Interim sacrifices of 10 predesignated rats/sex/dose were at 6, 12, and 18 months with surviving animals sacrificed at 24 months. At study termination, survival was in excess of 60% for every group. At the mid or high dose, the following biological effects were noted: slight decreases in food consumption and body weight; slight increase in mortality; a dose-related increase in relative organ weights of liver and kidney; and some slight effects on urinalysis, hematologic, and clinical chemistry parameters. No peroxisome induction was observed in livers of treated rats compared with controls. No clear treatment-related nonneoplastic or neoplastic lesions were found. However, mononuclear cell leukemia (MNCL) and changes known to be associated with an increased incidence of MNCL were seen in the mid-dose and high-dose groups. A literature review suggests that MNCL is a common finding in aging F344 rats and that this increased incidence in rats treated with DINP is not relevant to man. A clear no-observed-effect level was demonstrated for all biological end points at a dietary level of 0. 03 wt% or approximately 17 mg/kg/day of DINP.","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"1 1","pages":"79-89"},"PeriodicalIF":0.0,"publicationDate":"1997-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82978520","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}
K Rodgers, P Klykken, J Jacobs, C Frondoza, V Tomazic, J Zelikoff
Determination of the ability of a medical device to interact with the immune system currently involves assessment of the immunogenic potential and biocompatibility of the device or an extract of the device. However, implants are often in the body for extended periods of time and/or are placed by a surgical procedure that in and of itself will generate an acute inflammatory response. This symposium discussed studies that have been performed to evaluate the immunogenicity of various devices consisting of several different compositions (i.e., silicone, metals, and latex) in contact with different anatomical sites, the ability of a device to modulate an inflammatory response generated by a surgical procedure or trauma, and the response of the body to a material left in place for extended periods of time. This symposium brought together scientists from many different disciplines to begin to identify and fill in the gaps in this area.
{"title":"Immunotoxicity of medical devices. Symposium overview.","authors":"K Rodgers, P Klykken, J Jacobs, C Frondoza, V Tomazic, J Zelikoff","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Determination of the ability of a medical device to interact with the immune system currently involves assessment of the immunogenic potential and biocompatibility of the device or an extract of the device. However, implants are often in the body for extended periods of time and/or are placed by a surgical procedure that in and of itself will generate an acute inflammatory response. This symposium discussed studies that have been performed to evaluate the immunogenicity of various devices consisting of several different compositions (i.e., silicone, metals, and latex) in contact with different anatomical sites, the ability of a device to modulate an inflammatory response generated by a surgical procedure or trauma, and the response of the body to a material left in place for extended periods of time. This symposium brought together scientists from many different disciplines to begin to identify and fill in the gaps in this area.</p>","PeriodicalId":12658,"journal":{"name":"Fundamental and applied toxicology : official journal of the Society of Toxicology","volume":"36 1","pages":"1-14"},"PeriodicalIF":0.0,"publicationDate":"1997-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20028115","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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