Alterations of the tumor suppresser gene p53 have been found in ultraviolet radiation (UVR) related human skin cancers and in UVR-induced murine skin tumors. However, links between p53 gene alterations and the stages of carcinogenesis induced by UVR have not been clearly defined. We established a chronic UVR exposure-induced Sencar mouse skin carcinogenesis model to determine the frequency of p53 gene alterations in different stages of carcinogenesis, including UV-exposed skin, papillomas, squamous-cell carcinomas (SCCs), and malignant spindle-cell tumors (SCTs). A high incidence of SCCs and SCTs were found in this model. Positive p53 nuclear staining was found in 10/37 (27%) of SCCs and 12/24 (50%) of SCTs, but was not detected in normal skin or papillomas. DNA was isolated from 40 paraffin-embedded normal skin, UV-exposed skin, and tumor sections. The p53 gene (exons 5 and 6) was amplified from the sections by using nested polymerase chain reaction (PCR). Subsequent single-strand conformation polymorphism (SSCP) assay and sequencing analysis revealed one point mutation in exon 6 (coden 193, C-->A transition) from a UV-exposed skin sample, and seven point mutations in exon 5 (codens 146, 158, 150, 165, and 161, three C-->T, two C-->A, one C-->G, and one A-->T transition, respectively) from four SCTs, two SCCs and one UV-exposed skin sample. These experimental results demonstrate that alterations in the p53 gene are frequent events in chronic UV exposure-induced SCCs and later stage SCTs in Sencar mouse skin.
{"title":"Chronic ultraviolet exposure-induced p53 gene alterations in Sencar mouse skin carcinogenesis model.","authors":"Y. Tong, M. A. Smith, Stephen B. Tucker","doi":"10.1080/009841097160032","DOIUrl":"https://doi.org/10.1080/009841097160032","url":null,"abstract":"Alterations of the tumor suppresser gene p53 have been found in ultraviolet radiation (UVR) related human skin cancers and in UVR-induced murine skin tumors. However, links between p53 gene alterations and the stages of carcinogenesis induced by UVR have not been clearly defined. We established a chronic UVR exposure-induced Sencar mouse skin carcinogenesis model to determine the frequency of p53 gene alterations in different stages of carcinogenesis, including UV-exposed skin, papillomas, squamous-cell carcinomas (SCCs), and malignant spindle-cell tumors (SCTs). A high incidence of SCCs and SCTs were found in this model. Positive p53 nuclear staining was found in 10/37 (27%) of SCCs and 12/24 (50%) of SCTs, but was not detected in normal skin or papillomas. DNA was isolated from 40 paraffin-embedded normal skin, UV-exposed skin, and tumor sections. The p53 gene (exons 5 and 6) was amplified from the sections by using nested polymerase chain reaction (PCR). Subsequent single-strand conformation polymorphism (SSCP) assay and sequencing analysis revealed one point mutation in exon 6 (coden 193, C-->A transition) from a UV-exposed skin sample, and seven point mutations in exon 5 (codens 146, 158, 150, 165, and 161, three C-->T, two C-->A, one C-->G, and one A-->T transition, respectively) from four SCTs, two SCCs and one UV-exposed skin sample. These experimental results demonstrate that alterations in the p53 gene are frequent events in chronic UV exposure-induced SCCs and later stage SCTs in Sencar mouse skin.","PeriodicalId":17418,"journal":{"name":"Journal of Toxicology and Environmental Health, Part A","volume":"60 1","pages":"219-34"},"PeriodicalIF":0.0,"publicationDate":"1997-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83452092","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 subchronic toxicity of 2,2{prime},3,3{prime},4,4{prime}-hexachlorobiphenyl (PCB 128) was investigated in rats following dietary exposure at 0, 0.05, 0.5, 5, or 50 ppm for 13 wk. The growth rate was not affected by treatment and no apparent clinical signs of toxicity were observed. There was a significant increase in liver weight in the 50 ppm females. The liver ethoxy-resorufin deethylase (EROD) activity was increased by five- and fourfold in the highest dose males and females, respectively, while aminopyrine demethylase (ADPM) activity was significantly increased only in the highest dose females. Liver vitamin A was significantly reduced in the highest dose females. No other biochemical or hematological effects were observed. Treatment-related histopathological changes were seen in the thyroid and liver, and to a lesser extent in the bone marrow and thymus. Residue data showed a dose-dependent accumulation of PCB 128 in the following tissues: fat, liver, kidney, brain, spleen, and serum, with the highest concentration being found in fat followed by liver and kidney. Based on these data, the no-observable-adverse-effect level of PCB 128 was judged to be 0.5 ppm in diet or 42 {mu}g/kg body weight. 29 refs., 1 fig., 5 tabs.
{"title":"Subchronic toxicity of 2,2{prime},3,3{prime},4,4{prime}-hexachlorobiphenyl in rats","authors":"P. Lecavalier, I. Chu, M. Feeley","doi":"10.1080/009841097160069","DOIUrl":"https://doi.org/10.1080/009841097160069","url":null,"abstract":"The subchronic toxicity of 2,2{prime},3,3{prime},4,4{prime}-hexachlorobiphenyl (PCB 128) was investigated in rats following dietary exposure at 0, 0.05, 0.5, 5, or 50 ppm for 13 wk. The growth rate was not affected by treatment and no apparent clinical signs of toxicity were observed. There was a significant increase in liver weight in the 50 ppm females. The liver ethoxy-resorufin deethylase (EROD) activity was increased by five- and fourfold in the highest dose males and females, respectively, while aminopyrine demethylase (ADPM) activity was significantly increased only in the highest dose females. Liver vitamin A was significantly reduced in the highest dose females. No other biochemical or hematological effects were observed. Treatment-related histopathological changes were seen in the thyroid and liver, and to a lesser extent in the bone marrow and thymus. Residue data showed a dose-dependent accumulation of PCB 128 in the following tissues: fat, liver, kidney, brain, spleen, and serum, with the highest concentration being found in fat followed by liver and kidney. Based on these data, the no-observable-adverse-effect level of PCB 128 was judged to be 0.5 ppm in diet or 42 {mu}g/kg body weight. 29 refs., 1 fig., 5 tabs.","PeriodicalId":17418,"journal":{"name":"Journal of Toxicology and Environmental Health, Part A","volume":"54 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"1997-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75708262","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}
Interactions between arsenic (As) and selenium (Se) at the metabolic level are multifaceted and complex. These interactions are of practical significance because populations in various parts of the world are simultaneously exposed to inorganic As in drinking water and Se mainly in the diet at varying levels. The primary goal of this study was to investigate whether differing dietary Se status would alter the profile of urinary metabolites or their time course for elimination after exposure to arsenate [As(V)]. Weanling female 86C3F, mice were maintained for 28 d on either a control diet of powdered rodent meal sufficient in Se (A 0.2 ppm) or Torula yeast-based (TYB) diets deficient (B, 0.02 ppm Se), sufficient (C, 0.2 ppm Se), or excessive (D, 2.0 ppm Se) in Se; mice then received by oral gavage 5 mg (As)/kg as sodium [{sup 73}As] arsenate. The time course for elimination of total arsenic and metabolites in urine was measured over a 48-h period, and total arsenic was determined in feces and tissues at 48 h. Mice on the Se excess diet excreted a significantly higher percentage of urinary As as inorganic As, with a significantly decreased ratio of organic to inorganic As compared to Se-sufficientmore » mice, suggesting that As methylation was decreased. Mice on the Se-deficient diet appeared to eliminate As(V), arsenite, and dimethylarsinic acid (DMA) in urine more slowly than Se-sufficient mice; however, further studies are required to confirm this finding. Mice on the Se-sufficient meal diet (A) excreted significantly less (by percent) arsenate-derived radioactivity in urine and more in feces compared to mice on the Se-sufficient TYB diet (C), with total elimination being similar for both groups. This indicates that mice on the meal diet absorbed significantly less As(V) than mice on the TYB diet, and this may be due to more fiber or {open_quotes}bulk{close_quotes} in the meal diet. 35 refs., 6 figs., 6 tabs.« less
{"title":"Influence of dietary selenium on the disposition of arsenate in the female B6C3F{sub 1} mouse","authors":"E. Kenyon, M. Hughes, O. Levander","doi":"10.1080/009841097160078","DOIUrl":"https://doi.org/10.1080/009841097160078","url":null,"abstract":"Interactions between arsenic (As) and selenium (Se) at the metabolic level are multifaceted and complex. These interactions are of practical significance because populations in various parts of the world are simultaneously exposed to inorganic As in drinking water and Se mainly in the diet at varying levels. The primary goal of this study was to investigate whether differing dietary Se status would alter the profile of urinary metabolites or their time course for elimination after exposure to arsenate [As(V)]. Weanling female 86C3F, mice were maintained for 28 d on either a control diet of powdered rodent meal sufficient in Se (A 0.2 ppm) or Torula yeast-based (TYB) diets deficient (B, 0.02 ppm Se), sufficient (C, 0.2 ppm Se), or excessive (D, 2.0 ppm Se) in Se; mice then received by oral gavage 5 mg (As)/kg as sodium [{sup 73}As] arsenate. The time course for elimination of total arsenic and metabolites in urine was measured over a 48-h period, and total arsenic was determined in feces and tissues at 48 h. Mice on the Se excess diet excreted a significantly higher percentage of urinary As as inorganic As, with a significantly decreased ratio of organic to inorganic As compared to Se-sufficientmore » mice, suggesting that As methylation was decreased. Mice on the Se-deficient diet appeared to eliminate As(V), arsenite, and dimethylarsinic acid (DMA) in urine more slowly than Se-sufficient mice; however, further studies are required to confirm this finding. Mice on the Se-sufficient meal diet (A) excreted significantly less (by percent) arsenate-derived radioactivity in urine and more in feces compared to mice on the Se-sufficient TYB diet (C), with total elimination being similar for both groups. This indicates that mice on the meal diet absorbed significantly less As(V) than mice on the TYB diet, and this may be due to more fiber or {open_quotes}bulk{close_quotes} in the meal diet. 35 refs., 6 figs., 6 tabs.« less","PeriodicalId":17418,"journal":{"name":"Journal of Toxicology and Environmental Health, Part A","volume":"45 1","pages":"279-299"},"PeriodicalIF":0.0,"publicationDate":"1997-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90560480","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 applicability of PCNA as a tool for the analysis of germ cells in rats treated with 1,3,5-trinitrobenzene (TNB), a potent testicular toxicant, was evaluated. Male Fischer 344 (F344) rats were gavaged with TNB at 71 mg/kg or with corn oil (vehicle). Rats were killed after 10 daily oral doses or were allowed to recover for 10 or 30 d after the 10 doses. Testes from control rats, treated rats, and rats allowed to recover were immunohistochemically stained for PCNA. PCNA labeling in the control rats was confined to the nuclei of spermatogonia, pachytene spermatocytes, and nuclei of elongate spermatocytes. Conventional (hematoxylin and eosin) staining of testes from rats treated with TNB at 71 mg/kg for 10 d revealed loss of germ cells and cessation of spermatogenesis. Immunohistochemical staining of sections from these treated rats revealed only PCNA-positive spermatogonia. Rats allowed a 10-d recovery had both spermatogonial and spermatocytic staining, indicating partial restoration of germ-cell population. In rats allowed to recover for 30 d, the PCNA staining pattern was identical to the control rats. These results indicate that PCNA can be used to assess the proliferative status of spermatogonia (germ cells) in rodent testes exposed to testicular toxicants.
{"title":"Testicular effects of 1,3,5-trinitrobenzene (TNB). II. Immunolocalization of germ cells using proliferating cell nuclear antigen (PCNA) as an endogenous marker.","authors":"A. M. Chandra, C. Qualls, G. Campbell, G. Reddy","doi":"10.1080/009841097160410","DOIUrl":"https://doi.org/10.1080/009841097160410","url":null,"abstract":"The applicability of PCNA as a tool for the analysis of germ cells in rats treated with 1,3,5-trinitrobenzene (TNB), a potent testicular toxicant, was evaluated. Male Fischer 344 (F344) rats were gavaged with TNB at 71 mg/kg or with corn oil (vehicle). Rats were killed after 10 daily oral doses or were allowed to recover for 10 or 30 d after the 10 doses. Testes from control rats, treated rats, and rats allowed to recover were immunohistochemically stained for PCNA. PCNA labeling in the control rats was confined to the nuclei of spermatogonia, pachytene spermatocytes, and nuclei of elongate spermatocytes. Conventional (hematoxylin and eosin) staining of testes from rats treated with TNB at 71 mg/kg for 10 d revealed loss of germ cells and cessation of spermatogenesis. Immunohistochemical staining of sections from these treated rats revealed only PCNA-positive spermatogonia. Rats allowed a 10-d recovery had both spermatogonial and spermatocytic staining, indicating partial restoration of germ-cell population. In rats allowed to recover for 30 d, the PCNA staining pattern was identical to the control rats. These results indicate that PCNA can be used to assess the proliferative status of spermatogonia (germ cells) in rodent testes exposed to testicular toxicants.","PeriodicalId":17418,"journal":{"name":"Journal of Toxicology and Environmental Health, Part A","volume":"113 1","pages":"379-87"},"PeriodicalIF":0.0,"publicationDate":"1997-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79326682","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}
Hippuric acid is the most frequently used biomarker in the biological monitoring of occupational exposure to toluene. This product of solvent biotransformation may be also found in the urine of individuals who have not been exposed to the solvent. A smaller fraction of the absorbed toluene is oxidized to aromatic compounds including ortho-cresol, which is not found significantly in the urine of nonexposed individuals. An analytical methodology whereby gas chromatography with flame ionization detection is utilized for determination of o-cresol in urine of workers exposed to toluene is described. The levels obtained were subsequently compared to hippuric acid levels determined in the same urine samples. The analytical method has demonstrated an adequate precision (intra- and interassay coefficient of variation in the range of 2.4-5.4%) and average recovery of 98%. The samples for o-cresol determination were obtained from workers exposed to toluene in three different industrial activities. The concentration range found in exposed groups varied from < 0.21 to 2.8 micrograms/ml. The o-cresol values in the urine did not differ significantly among the exposed groups analyzed at the 5% level. The o-cresol and hippuric acid values found in the urine samples showed a significant correlation at the 1% level. These results may represent an additional contribution to studies for a definitive evaluation of the validity of o-cresol as a biomarker of exposure to toluene.
{"title":"Determination of o-cresol by gas chromatography and comparison with hippuric acid levels in urine samples of individuals exposed to toluene.","authors":"L. Amorim, Edna Maria Alvarez-Leite","doi":"10.1080/009841097160438","DOIUrl":"https://doi.org/10.1080/009841097160438","url":null,"abstract":"Hippuric acid is the most frequently used biomarker in the biological monitoring of occupational exposure to toluene. This product of solvent biotransformation may be also found in the urine of individuals who have not been exposed to the solvent. A smaller fraction of the absorbed toluene is oxidized to aromatic compounds including ortho-cresol, which is not found significantly in the urine of nonexposed individuals. An analytical methodology whereby gas chromatography with flame ionization detection is utilized for determination of o-cresol in urine of workers exposed to toluene is described. The levels obtained were subsequently compared to hippuric acid levels determined in the same urine samples. The analytical method has demonstrated an adequate precision (intra- and interassay coefficient of variation in the range of 2.4-5.4%) and average recovery of 98%. The samples for o-cresol determination were obtained from workers exposed to toluene in three different industrial activities. The concentration range found in exposed groups varied from < 0.21 to 2.8 micrograms/ml. The o-cresol values in the urine did not differ significantly among the exposed groups analyzed at the 5% level. The o-cresol and hippuric acid values found in the urine samples showed a significant correlation at the 1% level. These results may represent an additional contribution to studies for a definitive evaluation of the validity of o-cresol as a biomarker of exposure to toluene.","PeriodicalId":17418,"journal":{"name":"Journal of Toxicology and Environmental Health, Part A","volume":"25 1","pages":"401-7"},"PeriodicalIF":0.0,"publicationDate":"1997-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83464324","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. Dreher, R. Jaskot, J. Lehmann, J. Richards, J. Mcgee, A. Ghio, D. Costa
Identification of constituents responsible for the pulmonary toxicity of fugitive combustion emission source particles may provide insight into the adverse health effects associated with exposure to these particles as well as ambient air particulate pollution. Herein, we describe results of studies conducted to identify constituents responsible for the acute lung injury induced by residual oil fly ash (ROFA) and to assess physical-chemical factors that influence the pulmonary toxicity of these constituents. Biochemical and cellular analyses performed on bronchoalveolar lavage fluid obtained from rats following intratracheal instillation of ROFA suspension demonstrated the presence of severe inflammation, an indicator of pulmonary injury, which included recruitment of neutrophils, eosinophils, and monocytes into the airway. A leachate prepared from ROFA, containing predominantly Fe, Ni, V, Ca, Mg, and sulfate, produced similar lung injury to that induced by ROFA suspension. Depletion of Fe, Ni, and V from the ROFA leachate abrogated its pulmonary toxicity. Correspondingly, minimal lung injury was observed in animals exposed to saline-washed ROFA particles. A surrogate transition metal sulfate solution containing Fe, V, and Ni largely reproduced the lung injury induced by ROFA. Metal interactions and pH were found to influence the severity and kinetics of lung injury induced by ROFA and soluble transition metals. These findings provide direct evidence for the role of soluble transition metals in the pulmonary injury induced by the combustion emission source particulate, ROFA.
{"title":"Soluble transition metals mediate residual oil fly ash induced acute lung injury.","authors":"K. Dreher, R. Jaskot, J. Lehmann, J. Richards, J. Mcgee, A. Ghio, D. Costa","doi":"10.1080/009841097160492","DOIUrl":"https://doi.org/10.1080/009841097160492","url":null,"abstract":"Identification of constituents responsible for the pulmonary toxicity of fugitive combustion emission source particles may provide insight into the adverse health effects associated with exposure to these particles as well as ambient air particulate pollution. Herein, we describe results of studies conducted to identify constituents responsible for the acute lung injury induced by residual oil fly ash (ROFA) and to assess physical-chemical factors that influence the pulmonary toxicity of these constituents. Biochemical and cellular analyses performed on bronchoalveolar lavage fluid obtained from rats following intratracheal instillation of ROFA suspension demonstrated the presence of severe inflammation, an indicator of pulmonary injury, which included recruitment of neutrophils, eosinophils, and monocytes into the airway. A leachate prepared from ROFA, containing predominantly Fe, Ni, V, Ca, Mg, and sulfate, produced similar lung injury to that induced by ROFA suspension. Depletion of Fe, Ni, and V from the ROFA leachate abrogated its pulmonary toxicity. Correspondingly, minimal lung injury was observed in animals exposed to saline-washed ROFA particles. A surrogate transition metal sulfate solution containing Fe, V, and Ni largely reproduced the lung injury induced by ROFA. Metal interactions and pH were found to influence the severity and kinetics of lung injury induced by ROFA and soluble transition metals. These findings provide direct evidence for the role of soluble transition metals in the pulmonary injury induced by the combustion emission source particulate, ROFA.","PeriodicalId":17418,"journal":{"name":"Journal of Toxicology and Environmental Health, Part A","volume":"366 1","pages":"285-305"},"PeriodicalIF":0.0,"publicationDate":"1997-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91465654","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}
C. -. Yang, H. Chiu, J. Chiu, W. Kao, S. Tsai, S. Lan
An ecologic study design was used to investigate the relationship between cancer risks and residence in communities adjacent to petrochemical industrial counties (PICs). Directly age-adjusted mortality rates for cancer during 1982-1991 among 16 counties characterized by a heavy concentration of petrochemical industries were compared to rates among 16 matched counties with similar concentration of nonpetrochemical manufacturing industries, urbanization level, and demographic characteristics. An excess rate for liver cancer among males was found in the so-called PICs. The correlation could not be explained by confounding variables such as urbanization, socioeconomic class, or employment in nonpetrochemical industries. No other increased cancer risks were found to be associated with residence near petrochemical industries.
{"title":"Cancer mortality and residence near petrochemical industries in Taiwan.","authors":"C. -. Yang, H. Chiu, J. Chiu, W. Kao, S. Tsai, S. Lan","doi":"10.1080/009841097160474","DOIUrl":"https://doi.org/10.1080/009841097160474","url":null,"abstract":"An ecologic study design was used to investigate the relationship between cancer risks and residence in communities adjacent to petrochemical industrial counties (PICs). Directly age-adjusted mortality rates for cancer during 1982-1991 among 16 counties characterized by a heavy concentration of petrochemical industries were compared to rates among 16 matched counties with similar concentration of nonpetrochemical manufacturing industries, urbanization level, and demographic characteristics. An excess rate for liver cancer among males was found in the so-called PICs. The correlation could not be explained by confounding variables such as urbanization, socioeconomic class, or employment in nonpetrochemical industries. No other increased cancer risks were found to be associated with residence near petrochemical industries.","PeriodicalId":17418,"journal":{"name":"Journal of Toxicology and Environmental Health, Part A","volume":"28 1","pages":"265-73"},"PeriodicalIF":0.0,"publicationDate":"1997-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81329125","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}
D. Paustenbach, Y. Alarie, T. Kulle, Neil E. Schachter, Ralph G. Smith, J. Swenberg, H. Witschi, S. Horowitz
In recent years, several regulatory agencies and professional societies have recommended an occupational exposure limit (OEL) for formaldehyde. This article presents the findings of a panel of experts, the Industrial Health Foundation panel, who were charged to identify an OEL that would prevent irritation. To accomplish this task, they critiqued approximately 150 scientific articles. Unlike many other chemicals, a large amount of data is available upon which to base a concentration-response relationship for human irritation. A mathematical model developed by Kane et al. (1979) for predicting safe levels of exposure to irritants based on animal data was also evaluated. The panel concluded that for most persons, eye irritation clearly due to formaldehyde does not occur until at least 1.0 ppm. Information from controlled studies involving volunteers indicated that moderate to severe eye, nose, and throat irritation does not occur for most persons until airborne concentrations exceed 2.0-3.0 ppm. The data indicated that below 1.0 ppm, if irritation occurs in some persons, the effects rapidly subside due to "accommodation." Based on the weight of evidence from published studies, the panel found that persons exposed to 0.3 ppm for 4-6 h in chamber studies generally reported eye irritation at a rate no different than that observed when persons were exposed to clean air. It was noted that at a concentration of 0.5 ppm (8-h TWA) eye irritation was not observed in the majority of workers (about 80%). Consequently, the panel recommended an OEL of 0.3 ppm as an 8-h time-weighted average (TWA) with a ceiling value (CV) of 1.0 ppm (a concentration not to be exceeded) to avoid irritation. The panel believes that the ACGIH TLV of 0.3 ppm as a ceiling value was unnecessarily restrictive and that this value may have been based on the TLV Committee's interpretation of the significance of studies involving self-reported responses at concentrations less than 0.5 ppm. The panel concluded that any occupational or environmental guideline for formaldehyde should be based primarily on controlled studies in humans, since nearly all other studies are compromised by the presence of other contaminants. The panel also concluded that if concentrations of formaldehyde are kept below 0.1 ppm in the indoor environment (where exposures might occur 24 h/d) this should prevent irritation in virtually all persons. The panel could not identify a group of persons who were hypersensitive, nor was there evidence that anyone could be sensitized (develop an allergy) following inhalation exposure to formaldehyde. The panel concluded that there was sufficient evidence to show that persons with asthma respond no differently than healthy individuals following exposure to concentrations up to 3.0 ppm. Although cancer risk was not a topic that received exhaustive evaluation, the panel agreed with other scientific groups who have concluded that the cancer risk of formaldehyde is negligible at air
{"title":"A recommended occupational exposure limit for formaldehyde based on irritation.","authors":"D. Paustenbach, Y. Alarie, T. Kulle, Neil E. Schachter, Ralph G. Smith, J. Swenberg, H. Witschi, S. Horowitz","doi":"10.1080/009841097160465","DOIUrl":"https://doi.org/10.1080/009841097160465","url":null,"abstract":"In recent years, several regulatory agencies and professional societies have recommended an occupational exposure limit (OEL) for formaldehyde. This article presents the findings of a panel of experts, the Industrial Health Foundation panel, who were charged to identify an OEL that would prevent irritation. To accomplish this task, they critiqued approximately 150 scientific articles. Unlike many other chemicals, a large amount of data is available upon which to base a concentration-response relationship for human irritation. A mathematical model developed by Kane et al. (1979) for predicting safe levels of exposure to irritants based on animal data was also evaluated. The panel concluded that for most persons, eye irritation clearly due to formaldehyde does not occur until at least 1.0 ppm. Information from controlled studies involving volunteers indicated that moderate to severe eye, nose, and throat irritation does not occur for most persons until airborne concentrations exceed 2.0-3.0 ppm. The data indicated that below 1.0 ppm, if irritation occurs in some persons, the effects rapidly subside due to \"accommodation.\" Based on the weight of evidence from published studies, the panel found that persons exposed to 0.3 ppm for 4-6 h in chamber studies generally reported eye irritation at a rate no different than that observed when persons were exposed to clean air. It was noted that at a concentration of 0.5 ppm (8-h TWA) eye irritation was not observed in the majority of workers (about 80%). Consequently, the panel recommended an OEL of 0.3 ppm as an 8-h time-weighted average (TWA) with a ceiling value (CV) of 1.0 ppm (a concentration not to be exceeded) to avoid irritation. The panel believes that the ACGIH TLV of 0.3 ppm as a ceiling value was unnecessarily restrictive and that this value may have been based on the TLV Committee's interpretation of the significance of studies involving self-reported responses at concentrations less than 0.5 ppm. The panel concluded that any occupational or environmental guideline for formaldehyde should be based primarily on controlled studies in humans, since nearly all other studies are compromised by the presence of other contaminants. The panel also concluded that if concentrations of formaldehyde are kept below 0.1 ppm in the indoor environment (where exposures might occur 24 h/d) this should prevent irritation in virtually all persons. The panel could not identify a group of persons who were hypersensitive, nor was there evidence that anyone could be sensitized (develop an allergy) following inhalation exposure to formaldehyde. The panel concluded that there was sufficient evidence to show that persons with asthma respond no differently than healthy individuals following exposure to concentrations up to 3.0 ppm. Although cancer risk was not a topic that received exhaustive evaluation, the panel agreed with other scientific groups who have concluded that the cancer risk of formaldehyde is negligible at air","PeriodicalId":17418,"journal":{"name":"Journal of Toxicology and Environmental Health, Part A","volume":"69 1","pages":"217-63"},"PeriodicalIF":0.0,"publicationDate":"1997-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79468990","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. Feuston, C. Mackerer, C. Schreiner, C. E. Hamilton
Two crude oils, differing in viscosity (V) and nitrogen (N) and sulfur (S) content, were evaluated for systemic toxicity. In the Crude I (low V, low N, low S) study, the material was applied to the clipped backs of rats at dose levels of 0, 30, 125, and 500 mg/kg. In the Crude II (high V, high N, moderate S) study, the oil was applied similarly at the same dose levels. The crude oils were applied for 13 wk, 5 d/wk. Exposure sites were not occluded. Mean body weight gain (wk 1-14) was significantly reduced in male rats exposed to Crude II; body weight gain of all other animals was not adversely affected by treatment. An increase in absolute (A) and relative (R) liver weights and a decrease in A and R thymus weights were observed in male and female rats exposed to Crude II at 500 mg/kg; only liver weights (A and R) were adversely affected in male and female rats exposed to Crude I. In general, there was no consistent pattern of toxicity for serum chemistry endpoints; however, more parameters were adversely affected in Crude II-exposed female rats than in the other exposed groups. A consistent pattern of toxicity for hematology endpoints was observed among male rats exposed to Crude I and male and female rats exposed to Crude II. Parameters affected included: Crudes I and II, red blood cell count, hemoglobin, and hematocrit; Crude II, platelet count. Microscopic evaluation of tissues revealed the following treatment-related findings: Crude I, treated skin, thymus, and thyroid; Crude II, bone marrow, treated skin, thymus, and thyroid. The LOEL (lowest observable effect level) for skin irritation and systemic toxicity (based on marginal effects on the thyroid) for both crude oils was 30 mg/kg; effects were more numerous and more pronounced in animals exposed to Crude II. Systemic effects are probably related to concentrations of polycyclic aromatic compounds (PAC) found in crude oil.
{"title":"Systemic toxicity of dermally applied crude oils in rats.","authors":"M. Feuston, C. Mackerer, C. Schreiner, C. E. Hamilton","doi":"10.1080/009841097160005","DOIUrl":"https://doi.org/10.1080/009841097160005","url":null,"abstract":"Two crude oils, differing in viscosity (V) and nitrogen (N) and sulfur (S) content, were evaluated for systemic toxicity. In the Crude I (low V, low N, low S) study, the material was applied to the clipped backs of rats at dose levels of 0, 30, 125, and 500 mg/kg. In the Crude II (high V, high N, moderate S) study, the oil was applied similarly at the same dose levels. The crude oils were applied for 13 wk, 5 d/wk. Exposure sites were not occluded. Mean body weight gain (wk 1-14) was significantly reduced in male rats exposed to Crude II; body weight gain of all other animals was not adversely affected by treatment. An increase in absolute (A) and relative (R) liver weights and a decrease in A and R thymus weights were observed in male and female rats exposed to Crude II at 500 mg/kg; only liver weights (A and R) were adversely affected in male and female rats exposed to Crude I. In general, there was no consistent pattern of toxicity for serum chemistry endpoints; however, more parameters were adversely affected in Crude II-exposed female rats than in the other exposed groups. A consistent pattern of toxicity for hematology endpoints was observed among male rats exposed to Crude I and male and female rats exposed to Crude II. Parameters affected included: Crudes I and II, red blood cell count, hemoglobin, and hematocrit; Crude II, platelet count. Microscopic evaluation of tissues revealed the following treatment-related findings: Crude I, treated skin, thymus, and thyroid; Crude II, bone marrow, treated skin, thymus, and thyroid. The LOEL (lowest observable effect level) for skin irritation and systemic toxicity (based on marginal effects on the thyroid) for both crude oils was 30 mg/kg; effects were more numerous and more pronounced in animals exposed to Crude II. Systemic effects are probably related to concentrations of polycyclic aromatic compounds (PAC) found in crude oil.","PeriodicalId":17418,"journal":{"name":"Journal of Toxicology and Environmental Health, Part A","volume":"18 1","pages":"387-99"},"PeriodicalIF":0.0,"publicationDate":"1997-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75487326","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}
Craig C. Conrad, Christi A. Walter, Arlan Richardson, Martha A. Hanes, David T. Grabowski
To date, numerous correlative studies have implicated metallothionein in the detoxification of heavy metals and in the regulation of metal distribution within an organism. In the present study cadmium-binding proteins (metallothionein equivalents), cadmium acute toxicity, and cadmium distribution in tissues and subcellular fractions were compared in metallothionein-I and -II deficient (MT-/-) mice and the parental strain carrying intact metallothionein genes (MT+/+) to determine if the absence of metallothionein altered any of these parameters. In an uninduced state, MT-/- mice expressed lower levels of cadmium-binding proteins relative to MT+/+ mice in several tissues. Administration of zinc enhanced the levels of cadmium-binding proteins in liver, small intestine, kidney, pancreas, and male sex organs, but not in cecum or brain of MT+/+ mice compared to zinc pretreated MT-/- mice. The cadmium LD50 was similar for MT-/-, MT+/+, and zinc-pretreated MT-/- mice (15-17 mumol CdCl2/kg body weight delivered i.p.). However, zinc-pretreated MT+/+ mice had a cadmium LD50 of 58-63 mumol CdCl2/kg body weight. Over two-thirds of cadmium was found in liver, cecum, small intestine, and kidney in both MT+/+ and MT-/- mice; therefore, metallothionein levels do not appear to play a major role in the tissue distribution of cadmium. However, after zinc pretreatment, MT+/+ mice accumulated more cadmium in the liver and less in other tissues, whereas the amount of cadmium in the liver was not altered by zinc pretreatment in MT-/- mice. In general, the cytosolic/particulate ratio of cadmium was significantly higher in tissues of noninduced MT+/+ mice relative to MT-/- mice. This difference was accentuated after zinc pretreatment. Together these results indicate that basal levels of metallothionein do not protect from the acute toxicity of a single i.p. cadmium challenge. Furthermore, it does not appear that the cytosolic compartmentalization of cadmium is correlated with reduced toxicity.
{"title":"Cadmium toxicity and distribution in metallothionein-I and -II deficient transgenic mice.","authors":"Craig C. Conrad, Christi A. Walter, Arlan Richardson, Martha A. Hanes, David T. Grabowski","doi":"10.1080/009841097159502","DOIUrl":"https://doi.org/10.1080/009841097159502","url":null,"abstract":"To date, numerous correlative studies have implicated metallothionein in the detoxification of heavy metals and in the regulation of metal distribution within an organism. In the present study cadmium-binding proteins (metallothionein equivalents), cadmium acute toxicity, and cadmium distribution in tissues and subcellular fractions were compared in metallothionein-I and -II deficient (MT-/-) mice and the parental strain carrying intact metallothionein genes (MT+/+) to determine if the absence of metallothionein altered any of these parameters. In an uninduced state, MT-/- mice expressed lower levels of cadmium-binding proteins relative to MT+/+ mice in several tissues. Administration of zinc enhanced the levels of cadmium-binding proteins in liver, small intestine, kidney, pancreas, and male sex organs, but not in cecum or brain of MT+/+ mice compared to zinc pretreated MT-/- mice. The cadmium LD50 was similar for MT-/-, MT+/+, and zinc-pretreated MT-/- mice (15-17 mumol CdCl2/kg body weight delivered i.p.). However, zinc-pretreated MT+/+ mice had a cadmium LD50 of 58-63 mumol CdCl2/kg body weight. Over two-thirds of cadmium was found in liver, cecum, small intestine, and kidney in both MT+/+ and MT-/- mice; therefore, metallothionein levels do not appear to play a major role in the tissue distribution of cadmium. However, after zinc pretreatment, MT+/+ mice accumulated more cadmium in the liver and less in other tissues, whereas the amount of cadmium in the liver was not altered by zinc pretreatment in MT-/- mice. In general, the cytosolic/particulate ratio of cadmium was significantly higher in tissues of noninduced MT+/+ mice relative to MT-/- mice. This difference was accentuated after zinc pretreatment. Together these results indicate that basal levels of metallothionein do not protect from the acute toxicity of a single i.p. cadmium challenge. Furthermore, it does not appear that the cytosolic compartmentalization of cadmium is correlated with reduced toxicity.","PeriodicalId":17418,"journal":{"name":"Journal of Toxicology and Environmental Health, Part A","volume":"95 1","pages":"527-43"},"PeriodicalIF":0.0,"publicationDate":"1997-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73591448","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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