D. Basketter, N. Gilmour, Z. Wright, T. Walters, A. Boman, C. Lidén
Biocides used in many every day products often are able to act as haptens and so may cause allergic reactions in the skin. In addition, where exposure of the respiratory tract may occur, they should also be evaluated for their ability to cause respiratory allergy. Here we have used local lymph node assay (LLNA) data to compare the relative potency of four biocides together with cytokine profiling to determine whether these biocides can induce skin and/or respiratory allergy. Formaldehyde, glutaraldehyde, 5‐chloro‐2‐methyl‐4‐isothiazolin‐3‐one and 2‐methyl‐2H‐isothiazol‐3‐one mix (3:1) (CMI/MI), and 2‐methyl‐2H‐isothiazol‐3‐one alone (MI) were tested in the LLNA in two vehicles [acetone:olive oil (AOO) and propylene glycol (PG)]. Their relative allergenic potency was measured by derivation of the EC3 value (the estimated concentration that will induce a stimulation index of 3 following topical application of chemical). In AOO, the EC3 value for the chemicals were ranked as follows: formaldehyde = MI < glutaraldehyde < CMI/MI, CMI/MI thus being the most potent allergen as it has the lowest EC3 figure. In PG, a similar rank order of biocides was achieved but the estimated potency in PG was at least 1 log lower than that in AOO. Data are available indicating that while formaldehyde is a contact allergen, glutaraldehyde is both a contact and respiratory allergen. Cytokine profiling was carried out to determine whether CMI/MI and MI also have the potential to cause sensitization of the respiratory tract. The data obtained for CMI/MI were consistent with behavior as a contact sensitizer. The MI is less strongly sensitizing than CMI/MI, being comparable to formaldehyde, and due to this weaker response it has not been possible to evaluate fully its cytokine profile, an outcome indicating it is unlikely to be a significant chemical respiratory allergen.
许多日常用品中使用的杀菌剂通常可以作为半抗原，因此可能引起皮肤过敏反应。此外，在可能发生呼吸道暴露的地方，也应评估其引起呼吸道过敏的能力。在这里，我们使用局部淋巴结测定(LLNA)数据来比较四种杀菌剂的相对效力以及细胞因子谱，以确定这些杀菌剂是否会引起皮肤和/或呼吸道过敏。甲醛、戊二醛、5‐氯‐2‐甲基‐4‐异噻唑啉‐3‐1和2‐甲基‐2H‐异噻唑‐3‐1混合物(3:1)(CMI/MI)和单独2‐甲基‐2H‐异噻唑‐3‐1 (MI)在两种载体[丙酮:橄榄油(AOO)和丙二醇(PG)]的LLNA中进行了测试。它们的相对致敏效力是通过推导EC3值来测量的(局部应用化学物质后将诱导刺激指数为3的估计浓度)。在AOO中，化学物质的EC3值排名如下:甲醛= MI <戊二醛< CMI/MI, CMI/MI因此是最有效的过敏原，因为它具有最低的EC3值。在PG中，获得了类似的杀菌剂等级顺序，但PG的估计效价至少比AOO低1 log。现有数据表明，虽然甲醛是一种接触性过敏原，但戊二醛既是接触性过敏原，也是呼吸道过敏原。进行细胞因子谱分析以确定CMI/MI和MI是否也有可能引起呼吸道致敏。CMI/MI获得的数据与作为接触敏化剂的行为一致。MI的致敏性不如CMI/MI强，与甲醛相当，由于这种较弱的反应，无法全面评估其细胞因子谱，结果表明它不太可能是一种重要的化学呼吸道过敏原。
{"title":"Biocides: Characterization of the Allergenic Hazard of Methylisothiazolinone","authors":"D. Basketter, N. Gilmour, Z. Wright, T. Walters, A. Boman, C. Lidén","doi":"10.1081/CUS-120026299","DOIUrl":"https://doi.org/10.1081/CUS-120026299","url":null,"abstract":"Biocides used in many every day products often are able to act as haptens and so may cause allergic reactions in the skin. In addition, where exposure of the respiratory tract may occur, they should also be evaluated for their ability to cause respiratory allergy. Here we have used local lymph node assay (LLNA) data to compare the relative potency of four biocides together with cytokine profiling to determine whether these biocides can induce skin and/or respiratory allergy. Formaldehyde, glutaraldehyde, 5‐chloro‐2‐methyl‐4‐isothiazolin‐3‐one and 2‐methyl‐2H‐isothiazol‐3‐one mix (3:1) (CMI/MI), and 2‐methyl‐2H‐isothiazol‐3‐one alone (MI) were tested in the LLNA in two vehicles [acetone:olive oil (AOO) and propylene glycol (PG)]. Their relative allergenic potency was measured by derivation of the EC3 value (the estimated concentration that will induce a stimulation index of 3 following topical application of chemical). In AOO, the EC3 value for the chemicals were ranked as follows: formaldehyde = MI < glutaraldehyde < CMI/MI, CMI/MI thus being the most potent allergen as it has the lowest EC3 figure. In PG, a similar rank order of biocides was achieved but the estimated potency in PG was at least 1 log lower than that in AOO. Data are available indicating that while formaldehyde is a contact allergen, glutaraldehyde is both a contact and respiratory allergen. Cytokine profiling was carried out to determine whether CMI/MI and MI also have the potential to cause sensitization of the respiratory tract. The data obtained for CMI/MI were consistent with behavior as a contact sensitizer. The MI is less strongly sensitizing than CMI/MI, being comparable to formaldehyde, and due to this weaker response it has not been possible to evaluate fully its cytokine profile, an outcome indicating it is unlikely to be a significant chemical respiratory allergen.","PeriodicalId":17547,"journal":{"name":"Journal of Toxicology-cutaneous and Ocular Toxicology","volume":"42 1","pages":"187 - 199"},"PeriodicalIF":0.0,"publicationDate":"2003-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73960198","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}
N. Monteiro-Riviere, J. V. Van Miller, G. Simon, R. Joiner, J. Brooks, J. Riviere
Skin contact with nonylphenol ethoxylates (NPE), a group of widely used surfactants, is the primary source of human exposure. Previous studies have shown that the absorption of NPE through human and animal skin in vitro is limited (<1% over 8 hr) [Monteiro-Riviere et al. Toxicol Indust Health 2000; 16:49–57]. The purpose of this study was to examine the percutaneous absorption of NPE and the chemical precursor, nonylphenol (NP), in the isolated perfused porcine skin flap (IPPSF) model for comparison to the in vitro porcine skin flow through (PSFT) diffusion studies. The IPPSF model is considered to accurately predict absorption of chemicals through human skin. The IPPSF was dosed with 100 μl of 1% 14C ring-labeled NP, 14C ring-labeled NPE-4, or 14C ring-labeled NPE-9 in aqueous polyethylene glycol (PEG-400) solution and perfused for 8 hr. All three chemicals were minimally absorbed, with only approximately 0.1% of the applied dose found in the perfusate over the 8-hr collection. This absorbed material represents the systemic exposure expected following skin contact in humans. In addition, less than 1% of the applied dose penetrated into the stratum corneum and underlying dermis, but remained within the skin and did not go through to the perfusate. Thus, the overall potential systemic exposure to these chemicals from skin contact, using a model considered similar to human skin in vivo, is less than 1%. The absorption results of this study were consistent with previous studies in the PSFT model. The penetration of NPEs and NP in the IPPSF was less than the PSFT and is probably more predictive of in vivo human absorption as this model is physiologically closer to human skin. This suggests that the overall potential for skin absorption of these chemicals in humans is even lower than previous estimates.
{"title":"In Vitro Percutaneous Absorption of Nonylphenol (NP) and Nonylphenol Ethoxylates (NPE-4 and NPE-9) in Isolated Perfused Skin","authors":"N. Monteiro-Riviere, J. V. Van Miller, G. Simon, R. Joiner, J. Brooks, J. Riviere","doi":"10.1081/CUS-120019325","DOIUrl":"https://doi.org/10.1081/CUS-120019325","url":null,"abstract":"Skin contact with nonylphenol ethoxylates (NPE), a group of widely used surfactants, is the primary source of human exposure. Previous studies have shown that the absorption of NPE through human and animal skin in vitro is limited (<1% over 8 hr) [Monteiro-Riviere et al. Toxicol Indust Health 2000; 16:49–57]. The purpose of this study was to examine the percutaneous absorption of NPE and the chemical precursor, nonylphenol (NP), in the isolated perfused porcine skin flap (IPPSF) model for comparison to the in vitro porcine skin flow through (PSFT) diffusion studies. The IPPSF model is considered to accurately predict absorption of chemicals through human skin. The IPPSF was dosed with 100 μl of 1% 14C ring-labeled NP, 14C ring-labeled NPE-4, or 14C ring-labeled NPE-9 in aqueous polyethylene glycol (PEG-400) solution and perfused for 8 hr. All three chemicals were minimally absorbed, with only approximately 0.1% of the applied dose found in the perfusate over the 8-hr collection. This absorbed material represents the systemic exposure expected following skin contact in humans. In addition, less than 1% of the applied dose penetrated into the stratum corneum and underlying dermis, but remained within the skin and did not go through to the perfusate. Thus, the overall potential systemic exposure to these chemicals from skin contact, using a model considered similar to human skin in vivo, is less than 1%. The absorption results of this study were consistent with previous studies in the PSFT model. The penetration of NPEs and NP in the IPPSF was less than the PSFT and is probably more predictive of in vivo human absorption as this model is physiologically closer to human skin. This suggests that the overall potential for skin absorption of these chemicals in humans is even lower than previous estimates.","PeriodicalId":17547,"journal":{"name":"Journal of Toxicology-cutaneous and Ocular Toxicology","volume":"9 1","pages":"1 - 11"},"PeriodicalIF":0.0,"publicationDate":"2003-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89854121","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}
Michael C. Babin, K. M. Ricketts, R. C. Kiser, M. Gazaway, Nathaniel Krogel, L. W. Mitcheltree, Danielle M. Moore, K. Skvorak, R. Sweeney, I. Koplovitz, R. Casillas
The mouse ear vesicant model (MEVM) is a screening tool used to identify protective compounds against acute sulfur mustard (SM)‐induced skin injury. It provides endpoints of edema and histopathology 24 h following a topical SM exposure to assess protection against inflammation and tissue damage. To further evaluate successful compounds, the MEVM was modified for use as a 7‐day model. Dose response studies were conducted with SM to select an optimal challenge dose for the new model. Due to severity of SM‐induced tissue damage by Day 7, edema and histopathology were determined unreliable endpoints. Therefore, a modified Draize scoring system (no damage to extensive necrosis) was incorporated as an endpoint to evaluate tissue damage out to Day 7. To aid in optimal SM dose selection, retro synthetic capsaicin (RSCAP), a protective compound in the MEVM, was evaluated as a treatment 15 min before exposure to 0.06, 0.08, and 0.16 mg SM. The RSCAP compound provided similar significant protection at Day 7 against the 0.06‐ (42% reduction) and 0.08‐mg doses (32% reduction), but was not effective against the severely necrotizing 0.16‐mg SM dose. Based on these results, an optimum SM dose of 0.08 mg was selected. Retro synthetic capsaicin and two pharmacologically inactive analogs were tested as topical treatments 15 min prior to SM challenge. The RSCAP compound significantly reduced injury, whereas the inactive analogs had no protective effect. The RSCAP also significantly reduced SM injury when administered topically 10 min after SM challenge. These data support the use of the 7‐day mouse ear vesicant treatment model (MEVTM) in evaluating candidate antivesicant compounds.
{"title":"A 7‐Day Mouse Model to Assess Protection from Sulfur Mustard (SM) Skin Injury","authors":"Michael C. Babin, K. M. Ricketts, R. C. Kiser, M. Gazaway, Nathaniel Krogel, L. W. Mitcheltree, Danielle M. Moore, K. Skvorak, R. Sweeney, I. Koplovitz, R. Casillas","doi":"10.1081/CUS-120026302","DOIUrl":"https://doi.org/10.1081/CUS-120026302","url":null,"abstract":"The mouse ear vesicant model (MEVM) is a screening tool used to identify protective compounds against acute sulfur mustard (SM)‐induced skin injury. It provides endpoints of edema and histopathology 24 h following a topical SM exposure to assess protection against inflammation and tissue damage. To further evaluate successful compounds, the MEVM was modified for use as a 7‐day model. Dose response studies were conducted with SM to select an optimal challenge dose for the new model. Due to severity of SM‐induced tissue damage by Day 7, edema and histopathology were determined unreliable endpoints. Therefore, a modified Draize scoring system (no damage to extensive necrosis) was incorporated as an endpoint to evaluate tissue damage out to Day 7. To aid in optimal SM dose selection, retro synthetic capsaicin (RSCAP), a protective compound in the MEVM, was evaluated as a treatment 15 min before exposure to 0.06, 0.08, and 0.16 mg SM. The RSCAP compound provided similar significant protection at Day 7 against the 0.06‐ (42% reduction) and 0.08‐mg doses (32% reduction), but was not effective against the severely necrotizing 0.16‐mg SM dose. Based on these results, an optimum SM dose of 0.08 mg was selected. Retro synthetic capsaicin and two pharmacologically inactive analogs were tested as topical treatments 15 min prior to SM challenge. The RSCAP compound significantly reduced injury, whereas the inactive analogs had no protective effect. The RSCAP also significantly reduced SM injury when administered topically 10 min after SM challenge. These data support the use of the 7‐day mouse ear vesicant treatment model (MEVTM) in evaluating candidate antivesicant compounds.","PeriodicalId":17547,"journal":{"name":"Journal of Toxicology-cutaneous and Ocular Toxicology","volume":"265 1","pages":"231 - 242"},"PeriodicalIF":0.0,"publicationDate":"2003-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79010250","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}
There is increasing evidence that epidermal cytokines play an essential role during the induction of cutaneous immune responses. In the current investigations, we have compared the pattern of cytokines provoked by exposure to allergen with that stimulated by epidermal cytokines and paracrine regulation of cytokine expression. The kinetics of cytokine-induced changes in cutaneous expression of the cytokines interleukin (IL)-1β, tumor necrosis factor α (TNF-α), and IL-6 have been measured at the protein level. These data confirm that exposure to chemical allergen results in the sequential up-regulation of epidermal cytokines, with a rapid and relatively transient induction of TNF-α protein expression, followed by a more sustained increase in IL-6 production. Intradermal administration of recombinant murine TNF-α and IL-1β each stimulated increases in cutaneous IL-6 protein, although with different tempos. Treatment with TNF-α provoked a rapid (within 2 h) increase in IL-6 expression, whereas IL-1β-induced changes in IL-6 had a more delayed tempo. IL-1β-induced IL-6 production was dependent upon expression of TNF-α such that systemic pretreatment of mice with neutralizing anti-TNF-α antibody markedly inhibited the subsequent induction of cutaneous IL-6 induced by intradermal injection of IL-1β. Thus, intradermal administration of IL-1β apparently induces a similar sequence of events in the skin to that provoked by topical exposure to allergen: up-regulation of IL-6 in a TNF-α-dependent manner. However, treatment with neither allergen nor TNF-α affected the total cumulative levels of cutaneous IL-1β. These data demonstrate that topical exposure to allergen results in the ordered expression of key epidermal cytokines and that the increased bioavailability of each cytokine in turn regulates subsequent cytokine expression. Furthermore, these data suggest that it is the availability of bioactive IL-1β, not changes in total IL-1β expression in the skin, that is the critical factor in IL-1β-dependent events occurring following topical exposure to allergen.
{"title":"Cutaneous Cytokine Expression: Induction by Chemical Allergen and Paracrine Regulation","authors":"R. Dearman, M. Cumberbatch, I. Kimber","doi":"10.1081/CUS-120020313","DOIUrl":"https://doi.org/10.1081/CUS-120020313","url":null,"abstract":"There is increasing evidence that epidermal cytokines play an essential role during the induction of cutaneous immune responses. In the current investigations, we have compared the pattern of cytokines provoked by exposure to allergen with that stimulated by epidermal cytokines and paracrine regulation of cytokine expression. The kinetics of cytokine-induced changes in cutaneous expression of the cytokines interleukin (IL)-1β, tumor necrosis factor α (TNF-α), and IL-6 have been measured at the protein level. These data confirm that exposure to chemical allergen results in the sequential up-regulation of epidermal cytokines, with a rapid and relatively transient induction of TNF-α protein expression, followed by a more sustained increase in IL-6 production. Intradermal administration of recombinant murine TNF-α and IL-1β each stimulated increases in cutaneous IL-6 protein, although with different tempos. Treatment with TNF-α provoked a rapid (within 2 h) increase in IL-6 expression, whereas IL-1β-induced changes in IL-6 had a more delayed tempo. IL-1β-induced IL-6 production was dependent upon expression of TNF-α such that systemic pretreatment of mice with neutralizing anti-TNF-α antibody markedly inhibited the subsequent induction of cutaneous IL-6 induced by intradermal injection of IL-1β. Thus, intradermal administration of IL-1β apparently induces a similar sequence of events in the skin to that provoked by topical exposure to allergen: up-regulation of IL-6 in a TNF-α-dependent manner. However, treatment with neither allergen nor TNF-α affected the total cumulative levels of cutaneous IL-1β. These data demonstrate that topical exposure to allergen results in the ordered expression of key epidermal cytokines and that the increased bioavailability of each cytokine in turn regulates subsequent cytokine expression. Furthermore, these data suggest that it is the availability of bioactive IL-1β, not changes in total IL-1β expression in the skin, that is the critical factor in IL-1β-dependent events occurring following topical exposure to allergen.","PeriodicalId":17547,"journal":{"name":"Journal of Toxicology-cutaneous and Ocular Toxicology","volume":"163 1","pages":"69 - 86"},"PeriodicalIF":0.0,"publicationDate":"2003-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77506240","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}
Christine M. Hutak, Marie E. Kavanagh, V. Agarwal, M. Afouna, M. Khan, I. Reddy
The objective of this study was to assess and compare the morphologic and permeability characteristics of SIRC rabbit corneal cells grown on two filter types, polycarbonate-based Costar Transwell and polyester-based Costar Transwell Clear using pilocarpine in presence and absence of benzalkonium chloride. Technically, the microwell inserts were seeded with SIRC rabbit corneal cells and suspended in growth medium. The inserts were covered and kept in a humidified incubator for 10 days. The inserts were rinsed with Dulbecco's phosphate buffered saline at pH 7.3 and placed into microwell plates containing buffer at the same pH. Formulations containing pilocarpine with and without benzalkonium chloride were inoculated into each insert. The inserts were covered and incubated for the predetermined time period. The cell lines were examined with a light microscope using hematoxylin and eosin-stained cross-sections. The permeabilities of pilocarpine across the SIRC cell layers grown on the two filters were quantitatively determined. The results of these experiments show no significant differences in the morphological characteristics between the two filters exposed to either pilocarpine alone or to pilocarpine with benzalkonium chloride. The apparent permeability coefficient values for pilocarpine from both formulations across Costar Transwell-grown SIRC cell layers were relatively higher than that with Costar Transwell Clear-grown layers, and the flux enhancement ratios in the presence of benzalkonium chloride across the two filter types were comparable. These results revealed that the morphologic and the permeability data of SIRC rabbit corneal cells grown on the two filters are comparable for the compounds tested, suggesting their interchangeable use in assessment of the in vitro corneal drug transport and toxicity screening studies for ophthalmic drugs and additives.
{"title":"Use of SIRC Rabbit Corneal Cell Lines Grown on Polycarbonate- or Polyester-Based Filters to Assess the In Vitro Corneal Transport/Toxicity Screening Using Pilocarpine With or Without Benzalkonium Chloride","authors":"Christine M. Hutak, Marie E. Kavanagh, V. Agarwal, M. Afouna, M. Khan, I. Reddy","doi":"10.1081/CUS-120020383","DOIUrl":"https://doi.org/10.1081/CUS-120020383","url":null,"abstract":"The objective of this study was to assess and compare the morphologic and permeability characteristics of SIRC rabbit corneal cells grown on two filter types, polycarbonate-based Costar Transwell and polyester-based Costar Transwell Clear using pilocarpine in presence and absence of benzalkonium chloride. Technically, the microwell inserts were seeded with SIRC rabbit corneal cells and suspended in growth medium. The inserts were covered and kept in a humidified incubator for 10 days. The inserts were rinsed with Dulbecco's phosphate buffered saline at pH 7.3 and placed into microwell plates containing buffer at the same pH. Formulations containing pilocarpine with and without benzalkonium chloride were inoculated into each insert. The inserts were covered and incubated for the predetermined time period. The cell lines were examined with a light microscope using hematoxylin and eosin-stained cross-sections. The permeabilities of pilocarpine across the SIRC cell layers grown on the two filters were quantitatively determined. The results of these experiments show no significant differences in the morphological characteristics between the two filters exposed to either pilocarpine alone or to pilocarpine with benzalkonium chloride. The apparent permeability coefficient values for pilocarpine from both formulations across Costar Transwell-grown SIRC cell layers were relatively higher than that with Costar Transwell Clear-grown layers, and the flux enhancement ratios in the presence of benzalkonium chloride across the two filter types were comparable. These results revealed that the morphologic and the permeability data of SIRC rabbit corneal cells grown on the two filters are comparable for the compounds tested, suggesting their interchangeable use in assessment of the in vitro corneal drug transport and toxicity screening studies for ophthalmic drugs and additives.","PeriodicalId":17547,"journal":{"name":"Journal of Toxicology-cutaneous and Ocular Toxicology","volume":"16 1","pages":"101 - 114"},"PeriodicalIF":0.0,"publicationDate":"2003-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90834545","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}
R. Pendlington, E. J. Brown, D. Sanders, H. Minter, S. Hyde, M. Snow, C. K. Smith Pease
Diethylenetriaminepenta-acetic acid (DTPA) is a metal ion-chelating agent that has antimicrobial properties and potential therapeutic properties against metal-induced toxicities such as nickel allergy. In this study, the absorption properties of DTPA applied topically to rat skin are investigated in vitro, using a flow-through diffusion skin absorption model. [14C]DTPA was applied in solution in 60% ethanol (pH 6). Overall skin penetration into receptor fluid resulting from a topical dose of 0.13 mg/cm2 DTPA for 24 h was low at 1.27%. The local tissue distribution of DTPA was investigated using microautoradiography, and effects on the tissue were assessed by histology. Diethylenetriaminepenta-acetic acid was primarily associated with the stratum corneum and upper layers of the skin; minimal levels were observed in the dermis.
{"title":"In Vitro Skin Absorption of the Topically Applied Metal Ion-Chelating Agent Diethylenetriaminepenta-acetic Acid","authors":"R. Pendlington, E. J. Brown, D. Sanders, H. Minter, S. Hyde, M. Snow, C. K. Smith Pease","doi":"10.1081/CUS-120022752","DOIUrl":"https://doi.org/10.1081/CUS-120022752","url":null,"abstract":"Diethylenetriaminepenta-acetic acid (DTPA) is a metal ion-chelating agent that has antimicrobial properties and potential therapeutic properties against metal-induced toxicities such as nickel allergy. In this study, the absorption properties of DTPA applied topically to rat skin are investigated in vitro, using a flow-through diffusion skin absorption model. [14C]DTPA was applied in solution in 60% ethanol (pH 6). Overall skin penetration into receptor fluid resulting from a topical dose of 0.13 mg/cm2 DTPA for 24 h was low at 1.27%. The local tissue distribution of DTPA was investigated using microautoradiography, and effects on the tissue were assessed by histology. Diethylenetriaminepenta-acetic acid was primarily associated with the stratum corneum and upper layers of the skin; minimal levels were observed in the dermis.","PeriodicalId":17547,"journal":{"name":"Journal of Toxicology-cutaneous and Ocular Toxicology","volume":"21 1","pages":"117 - 124"},"PeriodicalIF":0.0,"publicationDate":"2003-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86209546","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}
Purpose. To assess the response of human corneas to minor irritancy using cell counts from contact lens cytology. Methods. Three potential irritants were investigated: 0.01% benzalkonium chloride (BAC), surface exposure produced by voluntarily holding the eye open (EXP), and irrigation of the corneal surface (IRR). One of the two eyes was randomly selected to be tested and the other eye served as a control. Following the treatment corneal surface cells were collected from soft contact lenses with four insertions and removals. Cells were counted using fluorescent staining of acridine orange and Hoechst. Ten normal human subjects took part in each experiment. Results. Nucleated cell counts increased significantly (p<0.05) with both BAC and EXP, but not with IRR (p>0.05). Cell structures without nuclei were always present (cell ghosts), and they were counted separately. These structures showed green fluorescent staining from acridine orange, but no nuclear staining with Hoechst. The number of cell ghosts increased with EXP (p<0.05), but not with BAC or IRR (p>0.05). No correlation was found between the number of cell ghosts and nucleated cells in the same eye. Conclusions. Both BAC and exposure increased nucleated cell counts. The finding that BAC affects nucleated cells and cell ghosts differently suggests separate mechanisms for the two pathways of cell shedding. The noninvasive technique of cell collection and cell counting may be useful for assessing minor irritancy to the corneal surface of human eyes.
{"title":"Quantifying Minor Irritancy to the Human Corneal Surface","authors":"Ying Guo, Debra Renner, C. Begley, G. Wilson","doi":"10.1081/CUS-120022755","DOIUrl":"https://doi.org/10.1081/CUS-120022755","url":null,"abstract":"Purpose. To assess the response of human corneas to minor irritancy using cell counts from contact lens cytology. Methods. Three potential irritants were investigated: 0.01% benzalkonium chloride (BAC), surface exposure produced by voluntarily holding the eye open (EXP), and irrigation of the corneal surface (IRR). One of the two eyes was randomly selected to be tested and the other eye served as a control. Following the treatment corneal surface cells were collected from soft contact lenses with four insertions and removals. Cells were counted using fluorescent staining of acridine orange and Hoechst. Ten normal human subjects took part in each experiment. Results. Nucleated cell counts increased significantly (p<0.05) with both BAC and EXP, but not with IRR (p>0.05). Cell structures without nuclei were always present (cell ghosts), and they were counted separately. These structures showed green fluorescent staining from acridine orange, but no nuclear staining with Hoechst. The number of cell ghosts increased with EXP (p<0.05), but not with BAC or IRR (p>0.05). No correlation was found between the number of cell ghosts and nucleated cells in the same eye. Conclusions. Both BAC and exposure increased nucleated cell counts. The finding that BAC affects nucleated cells and cell ghosts differently suggests separate mechanisms for the two pathways of cell shedding. The noninvasive technique of cell collection and cell counting may be useful for assessing minor irritancy to the corneal surface of human eyes.","PeriodicalId":17547,"journal":{"name":"Journal of Toxicology-cutaneous and Ocular Toxicology","volume":"48 1","pages":"147 - 155"},"PeriodicalIF":0.0,"publicationDate":"2002-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82472287","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}
Protein contact with skin is associated with a number of clinical conditions, including protein contact dermatitis and immunologic contact urticaria. This article reviews the clinical, in vivo, and in vitro evidence that proteinaceous materials penetrate skin. It is concluded that while penetration of intact proteins through normal skin is extremely low and normally without consequence, any damage to the skin barrier may allow penetration. As a result, risk assessment for contact of protein with skin must take into account potential barrier impairment and thus the possibility of both the induction and the elicitation of allergic skin reactions.
{"title":"PROTEIN ALLERGENS: THE IMPORTANCE OF SKIN AS A ROUTE OF EXPOSURE","authors":"C. K. Smith Pease, I. White, D. Basketter","doi":"10.1081/CUS-120013038","DOIUrl":"https://doi.org/10.1081/CUS-120013038","url":null,"abstract":"Protein contact with skin is associated with a number of clinical conditions, including protein contact dermatitis and immunologic contact urticaria. This article reviews the clinical, in vivo, and in vitro evidence that proteinaceous materials penetrate skin. It is concluded that while penetration of intact proteins through normal skin is extremely low and normally without consequence, any damage to the skin barrier may allow penetration. As a result, risk assessment for contact of protein with skin must take into account potential barrier impairment and thus the possibility of both the induction and the elicitation of allergic skin reactions.","PeriodicalId":17547,"journal":{"name":"Journal of Toxicology-cutaneous and Ocular Toxicology","volume":"76 1","pages":"175 - 190"},"PeriodicalIF":0.0,"publicationDate":"2002-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75812451","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}
Endemic fluorosis is a chronic crippling skeletal and dental disease caused by ingestion or inhalation of large amounts of fluoride. Although the prevalence of this disease has decreased considerably, it still occurs in some parts of the world. Our province Isparta is a naturally occurring endemic fluorosis area. The aim of this study is to investigate the ocular manifestations of the disorder in a group of patients with fluorosis. Fifty (32 F, 18 M) consecutive patients, ages ranging between 29 and 74 years (54.44±12.28), with endemic fluorosis constituted the study group. Age and sex matched fifty consecutive patients without clinical findings of fluorosis were selected as controls. Patients with and without fluorosis underwent a routine ophthalmologic examination. To assess the levels of hyperpigmentation in anterior chamber angle, we constituted a grading system (from 1 to 4) based on selected brownish colors from Pantone® Color Formula Guide. The differences between two groups with respect to serum, urine, and water fluoride levels are statistically significant (for all p<0.001). With respect to iridocorneal angle hyperpigmentation (ICA HP) grades, the difference between fluorosis and control group was statistically significant (p<0.001). In the fluorosis group, we observed eight cases (16%) of open angle glaucoma (OAG). Remarkably, ICA HP grade was 4+ in six out of eight cases; this finding was statistically significant (p<0.001). The remaining two showed grade 1+ ICA HP. Difference between number of cataracts or previous cataract operations of the two groups [fluorosis group: 15 cases (30%), controls: 12 cases (24%)] was not statistically significant (p>0.05). We suggest that heavy trabecular hyperpigmentation appearance may be a feature of endemic fluorosis. This disorder should be kept in mind in differential diagnosis of pathologic trabecular hyperpigmentation in patients with fluorosis and without the causes and symptoms of iris pigment dispersion. We also propose that endemic fluorosis may lead or augment the severity of glaucoma. Further studies are warranted in order to comprehend the exact mechanism of trabecular changes in patients with endemic fluorosis.
{"title":"HEAVY IRIDOCORNEAL ANGLE HYPERPIGMENTATION AND GLAUCOMA ASSOCIATED WITH FLUOROSIS","authors":"E. Aytuluner, E. Mensiz","doi":"10.1081/CUS-120014093","DOIUrl":"https://doi.org/10.1081/CUS-120014093","url":null,"abstract":"Endemic fluorosis is a chronic crippling skeletal and dental disease caused by ingestion or inhalation of large amounts of fluoride. Although the prevalence of this disease has decreased considerably, it still occurs in some parts of the world. Our province Isparta is a naturally occurring endemic fluorosis area. The aim of this study is to investigate the ocular manifestations of the disorder in a group of patients with fluorosis. Fifty (32 F, 18 M) consecutive patients, ages ranging between 29 and 74 years (54.44±12.28), with endemic fluorosis constituted the study group. Age and sex matched fifty consecutive patients without clinical findings of fluorosis were selected as controls. Patients with and without fluorosis underwent a routine ophthalmologic examination. To assess the levels of hyperpigmentation in anterior chamber angle, we constituted a grading system (from 1 to 4) based on selected brownish colors from Pantone® Color Formula Guide. The differences between two groups with respect to serum, urine, and water fluoride levels are statistically significant (for all p<0.001). With respect to iridocorneal angle hyperpigmentation (ICA HP) grades, the difference between fluorosis and control group was statistically significant (p<0.001). In the fluorosis group, we observed eight cases (16%) of open angle glaucoma (OAG). Remarkably, ICA HP grade was 4+ in six out of eight cases; this finding was statistically significant (p<0.001). The remaining two showed grade 1+ ICA HP. Difference between number of cataracts or previous cataract operations of the two groups [fluorosis group: 15 cases (30%), controls: 12 cases (24%)] was not statistically significant (p>0.05). We suggest that heavy trabecular hyperpigmentation appearance may be a feature of endemic fluorosis. This disorder should be kept in mind in differential diagnosis of pathologic trabecular hyperpigmentation in patients with fluorosis and without the causes and symptoms of iris pigment dispersion. We also propose that endemic fluorosis may lead or augment the severity of glaucoma. Further studies are warranted in order to comprehend the exact mechanism of trabecular changes in patients with endemic fluorosis.","PeriodicalId":17547,"journal":{"name":"Journal of Toxicology-cutaneous and Ocular Toxicology","volume":"72 1","pages":"203 - 212"},"PeriodicalIF":0.0,"publicationDate":"2002-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80435652","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 the past two decades, a number of papers and monographs have dealt with different aspects of inflammation. These include laboratory models for the testing of anti-inflammatory drugs, experimental models of inflammation, etc. Many models of inflammation have been developed, but those that involve the skin offer a particular advantage. In particular for the screening of new drugs for the topical treatment of inflammatory skin diseases, strong emphasis should be placed on mouse ear models. In the following I shall deal with skin irritants, with mouse ear edema, and with the different types of mouse ear inflammation models, including irritation induced with croton oil, 12-O-tetradecanoylphorbol-13-acetate (TPA), cantharidin, mustard oil, arachidonic acid, dithranol (anthralin), capsaicin, ethyl phenylpropiolate (EPP), interleukin-1 (IL-1), zymosan, or carrageenin.
在过去的二十年里，许多论文和专著都涉及了炎症的不同方面。其中包括抗炎药物试验的实验室模型、炎症实验模型等。许多炎症模型已经被开发出来，但那些涉及皮肤的模型提供了一个特别的优势。特别是对于外用治疗炎症性皮肤病的新药的筛选，应重点关注小鼠耳模型。下面我将讨论皮肤刺激物、小鼠耳部水肿以及不同类型的小鼠耳部炎症模型，包括巴豆油、12- o -十四烷醇-13-乙酸酯(TPA)、斑斑素、芥菜油、花生四烯酸、二糖醇(炭疽素)、辣椒素、苯基丙酸乙酯(EPP)、白细胞介素-1 (IL-1)、酶生蛋白或角叉菜素引起的刺激。
{"title":"THE MOUSE EAR AS A MODEL FOR CUTANEOUS IRRITATION","authors":"M. Gábor","doi":"10.1081/CUS-120013039","DOIUrl":"https://doi.org/10.1081/CUS-120013039","url":null,"abstract":"In the past two decades, a number of papers and monographs have dealt with different aspects of inflammation. These include laboratory models for the testing of anti-inflammatory drugs, experimental models of inflammation, etc. Many models of inflammation have been developed, but those that involve the skin offer a particular advantage. In particular for the screening of new drugs for the topical treatment of inflammatory skin diseases, strong emphasis should be placed on mouse ear models. In the following I shall deal with skin irritants, with mouse ear edema, and with the different types of mouse ear inflammation models, including irritation induced with croton oil, 12-O-tetradecanoylphorbol-13-acetate (TPA), cantharidin, mustard oil, arachidonic acid, dithranol (anthralin), capsaicin, ethyl phenylpropiolate (EPP), interleukin-1 (IL-1), zymosan, or carrageenin.","PeriodicalId":17547,"journal":{"name":"Journal of Toxicology-cutaneous and Ocular Toxicology","volume":"22 1","pages":"191 - 202"},"PeriodicalIF":0.0,"publicationDate":"2002-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83189199","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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