Pub Date : 1996-10-25DOI: 10.1080/00984108.1996.11667600
Hope E. Ratcliffe, G. Swanson, L. Fischer
The ubiquitous nature of mercury in the environment, its global atmospheric cycling, and its toxicity to humans at levels that are uncomfortably close to exposures experienced by a proportion of the population are some of the current concerns associated with this pollutant. The purpose of this review is to critically evaluate the scientific quality of published reports involving human exposures to mercury and associated health outcomes as an aid in the risk evaluation of this chemical. A comprehensive review of the scientific literature involving human exposures to mercury was performed and each publication evaluated using a defined set of criteria that are considered standards in epidemiologic and toxicologic research. Severe, sometimes fatal, effects of mercury exposure at high levels were primarily reported as case studies. The disasters in Minamata, Japan, in the 1950s and in Iraq in 1971-1972 clearly demonstrated neurologic effects associated with ingestion of methylmercury both in adults and in infants exposed in utero. The effects were convincingly associated with methylmercury ingestion, despite limitations of the study design. Several well-conducted studies have investigated the effects of methylmercury at levels below those in the Iraq incident but have not provided clear evidence of an effect. The lower end of the dose-response curve constructed from the Iraq data therefore still needs to be confirmed. The studies of mercury exposure in the workplace were mainly of elemental or inorganic mercury, and effects that were observed at relatively low exposure levels were primarily neurologic and renal. Several studies have investigated effects associated with dental amalgam but have been rated as inconclusive because of methodologic deficiencies. In our overall evaluation, 29 of 110 occupational studies and 20 of 54 studies where exposure occurred in the natural environment provided at least suggestive evidence of an exposure-related effect.
{"title":"Human exposure to mercury: a critical assessment of the evidence of adverse health effects.","authors":"Hope E. Ratcliffe, G. Swanson, L. Fischer","doi":"10.1080/00984108.1996.11667600","DOIUrl":"https://doi.org/10.1080/00984108.1996.11667600","url":null,"abstract":"The ubiquitous nature of mercury in the environment, its global atmospheric cycling, and its toxicity to humans at levels that are uncomfortably close to exposures experienced by a proportion of the population are some of the current concerns associated with this pollutant. The purpose of this review is to critically evaluate the scientific quality of published reports involving human exposures to mercury and associated health outcomes as an aid in the risk evaluation of this chemical. A comprehensive review of the scientific literature involving human exposures to mercury was performed and each publication evaluated using a defined set of criteria that are considered standards in epidemiologic and toxicologic research. Severe, sometimes fatal, effects of mercury exposure at high levels were primarily reported as case studies. The disasters in Minamata, Japan, in the 1950s and in Iraq in 1971-1972 clearly demonstrated neurologic effects associated with ingestion of methylmercury both in adults and in infants exposed in utero. The effects were convincingly associated with methylmercury ingestion, despite limitations of the study design. Several well-conducted studies have investigated the effects of methylmercury at levels below those in the Iraq incident but have not provided clear evidence of an effect. The lower end of the dose-response curve constructed from the Iraq data therefore still needs to be confirmed. The studies of mercury exposure in the workplace were mainly of elemental or inorganic mercury, and effects that were observed at relatively low exposure levels were primarily neurologic and renal. Several studies have investigated effects associated with dental amalgam but have been rated as inconclusive because of methodologic deficiencies. In our overall evaluation, 29 of 110 occupational studies and 20 of 54 studies where exposure occurred in the natural environment provided at least suggestive evidence of an exposure-related effect.","PeriodicalId":17418,"journal":{"name":"Journal of Toxicology and Environmental Health, Part A","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1996-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84402259","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}
{"title":"I. Chu D. C. Villeneuve A. Yagminas P. Lecavalier R. Poon H. Hakansson U. G. Ahlborg V. E. Valli S. W. Kennedy A. Bergman R. F. Seegal M. Feeley","authors":"I. Chu, D. Villeneuve, A. Yagminas","doi":"10.1080/009841096160844","DOIUrl":"https://doi.org/10.1080/009841096160844","url":null,"abstract":"","PeriodicalId":17418,"journal":{"name":"Journal of Toxicology and Environmental Health, Part A","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1996-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86904476","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}
Pub Date : 1996-10-01DOI: 10.1016/S0378-4274(96)80319-5
D. Moir, James Withey, A. Viau, Ih Chu, Ed. McMullen
{"title":"Pharmacokinetics of benzo[a]pyrene in the rat.","authors":"D. Moir, James Withey, A. Viau, Ih Chu, Ed. McMullen","doi":"10.1016/S0378-4274(96)80319-5","DOIUrl":"https://doi.org/10.1016/S0378-4274(96)80319-5","url":null,"abstract":"","PeriodicalId":17418,"journal":{"name":"Journal of Toxicology and Environmental Health, Part A","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1996-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78407899","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}
Pub Date : 1996-09-01DOI: 10.1080/00984108.1996.10662171
P. Hodson, S. Efler, J. Wilson, A. El-Shaarawi, M. Maj, T. G. Williams
A bioassay protocol was optimized for measuring the potency of effluents or waterborne chemicals for inducing mixed-function oxygenase (MFO) activity of rainbow trout (Oncorhynchus mykiss). Measurements of ethoxyresorufin O-deethylase (EROD) can be made with an established endpoint assay using large volumes of reagents and tissue. However, a new kinetic microplate assay offers significant savings in time, reagents, and sample volumes. Data are distributed lognormally and must be log transformed before statistical analyses. EROD activity increases with exposure time to pulp mill effluent, and a 4-d exposure provides a near-maximal response. Optimum fish size conforms to standard practices in fish toxicology; loading rates should not exceed 1 g of fish per liter of test solution per day. Feed should be withheld from test fish 48 h before testing to reduce the variance of measured activity, and anaesthetizing fish with MS-222 does not affect their response to MFO inducers. Pulp mill effluents do not lose their potency during 2-3 wk of exposure at temperatures ranging from -20 to 13 degrees C, whether stored in plastic or glass. Steel containers were associated with slight losses in potency. Bioassays of MFO induction in fish exposed to liquid effluents are practical and conform to standard practice for testing the lethality of waterbone chemicals. The results are sufficiently precise that differences among means based on live fish per treatment can be discriminated statistically when activity changes by threefold or more.
{"title":"Measuring the potency of pulp mill effluents for induction of hepatic mixed-function oxygenase activity in fish.","authors":"P. Hodson, S. Efler, J. Wilson, A. El-Shaarawi, M. Maj, T. G. Williams","doi":"10.1080/00984108.1996.10662171","DOIUrl":"https://doi.org/10.1080/00984108.1996.10662171","url":null,"abstract":"A bioassay protocol was optimized for measuring the potency of effluents or waterborne chemicals for inducing mixed-function oxygenase (MFO) activity of rainbow trout (Oncorhynchus mykiss). Measurements of ethoxyresorufin O-deethylase (EROD) can be made with an established endpoint assay using large volumes of reagents and tissue. However, a new kinetic microplate assay offers significant savings in time, reagents, and sample volumes. Data are distributed lognormally and must be log transformed before statistical analyses. EROD activity increases with exposure time to pulp mill effluent, and a 4-d exposure provides a near-maximal response. Optimum fish size conforms to standard practices in fish toxicology; loading rates should not exceed 1 g of fish per liter of test solution per day. Feed should be withheld from test fish 48 h before testing to reduce the variance of measured activity, and anaesthetizing fish with MS-222 does not affect their response to MFO inducers. Pulp mill effluents do not lose their potency during 2-3 wk of exposure at temperatures ranging from -20 to 13 degrees C, whether stored in plastic or glass. Steel containers were associated with slight losses in potency. Bioassays of MFO induction in fish exposed to liquid effluents are practical and conform to standard practice for testing the lethality of waterbone chemicals. The results are sufficiently precise that differences among means based on live fish per treatment can be discriminated statistically when activity changes by threefold or more.","PeriodicalId":17418,"journal":{"name":"Journal of Toxicology and Environmental Health, Part A","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1996-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86272602","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. Yokel, P. Ackrill, E. Burgess, J. Day, J. Domingo, T. Flaten, J. Savory
The prevention and treatment of aluminum (Al) accumulation and toxicity are reviewed. Recommendations to further our understanding of desferrioxamine (deferoxamine, DFO) treatment and to develop more effective chelation approaches are provided. Reduction of Al accumulation and toxicity may benefit end-stage renal disease (ESRD) patients and perhaps those suffering from specific neurodegenerative disorders as well as workers with Al-induced neurocognitive disorders. The clearance of Al may be increased by extracorporeal chelation, renal transplantation, perhaps complexation with simple ligands such as silicon (Si), and systemic chelation therapy. The abilities of extracorporeal chelation and Si to reduce Al accumulation require further evaluation. Although it may not be possible to design Al-specific chelators, chelators with greater Al selectivity are desired. Aluminum-selective chelation might be achieved by targeted chelator distribution or by the use of adjuvants with the chelator. The ability of carboxylic acids to facilitate Al elimination, under specific conditions, warrants further study. Desferrioxamine does not produce significant biliary Al excretion. A chelator with this property may be useful in ESRD patients. The necessity for an Al chelator to distribute extravascularly to be effective is unknown and should be determined to guide the selection of alternatives to DFO. The lack of oral efficacy and occasional side effects of DFO encourage identification of orally effective, safer Al chelators. The bidentate 3-hydroxypyridin-4-ones are currently the most encouraging alternatives to DFO. They have been shown to increase urinary Al excretion in rats and rabbits, but to have toxicity comparable to, or greater than, DFO. Their toxicity may relate to incomplete metal complexation. The ability of orally effective chelators to increase absorption of chelated metal from the gastrointestinal (Gl) tract needs to be evaluated. Orally effective, safe Al chelators would be of benefit to peritoneal dialysis patients and those with neurodegenerative disorders, if Al chelation therapy is indicated. The reduction of Alzheimer's disease (AD) progression and the reversal of Al-induced behavioral deficits and neurofibrillary tangles by DFO encourage further study of Al chelation therapy for selected neurodegenerative disorders.
{"title":"Prevention and treatment of aluminum toxicity including chelation therapy: status and research needs.","authors":"R. Yokel, P. Ackrill, E. Burgess, J. Day, J. Domingo, T. Flaten, J. Savory","doi":"10.1080/009841096161131","DOIUrl":"https://doi.org/10.1080/009841096161131","url":null,"abstract":"The prevention and treatment of aluminum (Al) accumulation and toxicity are reviewed. Recommendations to further our understanding of desferrioxamine (deferoxamine, DFO) treatment and to develop more effective chelation approaches are provided. Reduction of Al accumulation and toxicity may benefit end-stage renal disease (ESRD) patients and perhaps those suffering from specific neurodegenerative disorders as well as workers with Al-induced neurocognitive disorders. The clearance of Al may be increased by extracorporeal chelation, renal transplantation, perhaps complexation with simple ligands such as silicon (Si), and systemic chelation therapy. The abilities of extracorporeal chelation and Si to reduce Al accumulation require further evaluation. Although it may not be possible to design Al-specific chelators, chelators with greater Al selectivity are desired. Aluminum-selective chelation might be achieved by targeted chelator distribution or by the use of adjuvants with the chelator. The ability of carboxylic acids to facilitate Al elimination, under specific conditions, warrants further study. Desferrioxamine does not produce significant biliary Al excretion. A chelator with this property may be useful in ESRD patients. The necessity for an Al chelator to distribute extravascularly to be effective is unknown and should be determined to guide the selection of alternatives to DFO. The lack of oral efficacy and occasional side effects of DFO encourage identification of orally effective, safer Al chelators. The bidentate 3-hydroxypyridin-4-ones are currently the most encouraging alternatives to DFO. They have been shown to increase urinary Al excretion in rats and rabbits, but to have toxicity comparable to, or greater than, DFO. Their toxicity may relate to incomplete metal complexation. The ability of orally effective chelators to increase absorption of chelated metal from the gastrointestinal (Gl) tract needs to be evaluated. Orally effective, safe Al chelators would be of benefit to peritoneal dialysis patients and those with neurodegenerative disorders, if Al chelation therapy is indicated. The reduction of Alzheimer's disease (AD) progression and the reversal of Al-induced behavioral deficits and neurofibrillary tangles by DFO encourage further study of Al chelation therapy for selected neurodegenerative disorders.","PeriodicalId":17418,"journal":{"name":"Journal of Toxicology and Environmental Health, Part A","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1996-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85049769","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}
W. R. Harris, G. Berthon, J. Day, Christopher Exley, T. Flaten, W. Forbes, Tamás Kiss, Chris Orvig, P. Zatta
As a "hard", trivalent metal ion, Al3- binds strongly to oxygen-donor ligands such as citrate and phosphate. The aqueous coordination chemistry of Al is complicated by the tendency of many Al complexes to hydrolyze and form polynuclear species, many of which are sparingly soluble. Thus there is considerable variation among the Al stability constants reported for several important ligands. The complexity in the aqueous chemistry of Al has also affected Al toxicity studies, which have often utilized poorly characterized Al stock solutions. Serum fractionation studies show that most Al is protein bound, primarily to the serum iron transport protein transferrin. Albumin appears to play little, if any, role in serum transport. There is little agreement as to the speciation of the remaining low-molecular mass fraction of serum Al. The lability of the Al3+ion precludes the simple separation and identification of individual Al complexes. Computational methods are available for detailed computer calculations of the Al speciation in serum, but efforts in this area have been severely hampered by the uncertainties regarding the stability constants of the low molecular mass Al complexes with citrate, phosphate, and hydroxide. Specific recommendations for further research on Al speciation include: (1) Determine more accurate Al stability constants with critical low molecular mass ligands such as citrate and phosphate; (2) supplement traditional potentiometric studies on Al complexes with data from other techniques such as 27Al-NMR and accelerator mass spectrometry with 26Al; (3) develop new methods for generating reliable linear free energy relationships for Al complexation; (4) determine equilibrium and rate constants for Al binding to transferrin at 37 degrees C; (5) confirm the possible formation of low-molecular-mass Al-protein complexes following desferrioxamine therapy; (6) continue research efforts to incorporate kinetic considerations into the present equilibrium speciation calculations; (7) improve methods for preparing chemically well-defined stock solutions for toxicological studies; (8) incorporate more detailed speciation data into studies on Al toxicity and pharmacokinetics; and (9) incorporate more detailed speciation data into future epidemiological studies on the relationship between Al toxicity and various water quality parameters.
{"title":"Speciation of aluminum in biological systems.","authors":"W. R. Harris, G. Berthon, J. Day, Christopher Exley, T. Flaten, W. Forbes, Tamás Kiss, Chris Orvig, P. Zatta","doi":"10.1080/009841096161069","DOIUrl":"https://doi.org/10.1080/009841096161069","url":null,"abstract":"As a \"hard\", trivalent metal ion, Al3- binds strongly to oxygen-donor ligands such as citrate and phosphate. The aqueous coordination chemistry of Al is complicated by the tendency of many Al complexes to hydrolyze and form polynuclear species, many of which are sparingly soluble. Thus there is considerable variation among the Al stability constants reported for several important ligands. The complexity in the aqueous chemistry of Al has also affected Al toxicity studies, which have often utilized poorly characterized Al stock solutions. Serum fractionation studies show that most Al is protein bound, primarily to the serum iron transport protein transferrin. Albumin appears to play little, if any, role in serum transport. There is little agreement as to the speciation of the remaining low-molecular mass fraction of serum Al. The lability of the Al3+ion precludes the simple separation and identification of individual Al complexes. Computational methods are available for detailed computer calculations of the Al speciation in serum, but efforts in this area have been severely hampered by the uncertainties regarding the stability constants of the low molecular mass Al complexes with citrate, phosphate, and hydroxide. Specific recommendations for further research on Al speciation include: (1) Determine more accurate Al stability constants with critical low molecular mass ligands such as citrate and phosphate; (2) supplement traditional potentiometric studies on Al complexes with data from other techniques such as 27Al-NMR and accelerator mass spectrometry with 26Al; (3) develop new methods for generating reliable linear free energy relationships for Al complexation; (4) determine equilibrium and rate constants for Al binding to transferrin at 37 degrees C; (5) confirm the possible formation of low-molecular-mass Al-protein complexes following desferrioxamine therapy; (6) continue research efforts to incorporate kinetic considerations into the present equilibrium speciation calculations; (7) improve methods for preparing chemically well-defined stock solutions for toxicological studies; (8) incorporate more detailed speciation data into studies on Al toxicity and pharmacokinetics; and (9) incorporate more detailed speciation data into future epidemiological studies on the relationship between Al toxicity and various water quality parameters.","PeriodicalId":17418,"journal":{"name":"Journal of Toxicology and Environmental Health, Part A","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1996-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80473901","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}
Benzene is a known carcinogen and hematopoietic toxin in humans and experimental animals. The effect of acute, high-dose exposure to benzene on hepatic bioactivation and detoxication enzymes has been defined, while little is known about the effect of repeated, low-dose benzene exposure on these enzymes. Our objective was to determine whether repeated, oral benzene exposure alters enzymes involved in benzene metabolism. Specifically, we were concerned with cytochrome P-450-2E1, a bioactivation enzyme, and glutathione transferase and aldehyde dehydrogenase, two detoxifying enzymes. Female CD-1 mice were treated by gavage for 3 wk with benzene doses of 5 mg/kg (0.064 mmol/kg) or 50 mg/kg (0.646 mmol/kg) in corn oil. These doses of benzene produced 0.048 and 0.236 mumol muconic acid/d, respectively. We found that repeated exposure to 50 mg benzene/kg/d decreased P-450-2E1 activity by 34% and induced glutathione transferase activity by 30% without affecting aldehyde dehydrogenase activity. These changes in enzyme activities may serve a protective role against repeated exposure to benzene.
{"title":"Repeated oral benzene exposure alters enzymes involved in benzene metabolism.","authors":"D. Daiker, M. T. Moslen, J. Carr, J. Ward","doi":"10.1080/009841096161177","DOIUrl":"https://doi.org/10.1080/009841096161177","url":null,"abstract":"Benzene is a known carcinogen and hematopoietic toxin in humans and experimental animals. The effect of acute, high-dose exposure to benzene on hepatic bioactivation and detoxication enzymes has been defined, while little is known about the effect of repeated, low-dose benzene exposure on these enzymes. Our objective was to determine whether repeated, oral benzene exposure alters enzymes involved in benzene metabolism. Specifically, we were concerned with cytochrome P-450-2E1, a bioactivation enzyme, and glutathione transferase and aldehyde dehydrogenase, two detoxifying enzymes. Female CD-1 mice were treated by gavage for 3 wk with benzene doses of 5 mg/kg (0.064 mmol/kg) or 50 mg/kg (0.646 mmol/kg) in corn oil. These doses of benzene produced 0.048 and 0.236 mumol muconic acid/d, respectively. We found that repeated exposure to 50 mg benzene/kg/d decreased P-450-2E1 activity by 34% and induced glutathione transferase activity by 30% without affecting aldehyde dehydrogenase activity. These changes in enzyme activities may serve a protective role against repeated exposure to benzene.","PeriodicalId":17418,"journal":{"name":"Journal of Toxicology and Environmental Health, Part A","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1996-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89144856","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}
Trichothecene mycotoxins are a group of structurally similar fungal metabolites that are capable of producing a wide range of toxic effects. Deoxynivalenol (DON, vomitoxin), a trichothecene, is prevalent worldwide in crops used for food and feed production, including in Canada and the United States. Although DON is one of the least acutely toxic trichothecenes, it should be treated as an important food safety issue because it is a very common contaminant of grain. This review focuses on the ability of DON to induce toxicologic and immunotoxic effects in a variety of cell systems and animal species. At the cellular level, the main toxic effect is inhibition of protein synthesis via binding to the ribosome. In animals, moderate to low ingestion of toxin can cause a number of as yet poorly defined effects associated with reduced performance and immune function. The main overt effect at low dietary concentrations appears to be a reduction in food consumption (anorexia), while higher doses induce vomiting (emesis). DON is known to alter brain neurochemicals. The serotoninergic system appears to play a role in mediation of the feeding behavior and emetic response. Animals fed low to moderate doses are able to recover from initial weight losses, while higher doses induce more long-term changes in feeding behavior. At low dosages of DON, hematological, clinical, and immunological changes are also transitory and decrease as compensatory/adaptation mechanisms are established. Swine are more sensitive to DON than mice, poultry, and ruminants, in part because of differences in metabolism of DON, with males being more sensitive than females. The capacity of DON to alter normal immune function has been of particular interest. There is extensive evidence that DON can be immunosuppressive or immunostimulatory, depending upon the dose and duration of exposure. While immunosuppression can be explained by the inhibition of translation, immunostimulation can be related to interference with normal regulatory mechanisms. In vivo, DON suppresses normal immune response to pathogens and simultaneously induces autoimmune-like effects which are similar to human immunoglobulin A (IgA) nephropathy. Other effects include superinduction of cytokine production by T helper cells (in vitro) and activation of macrophages and T cells to produce a proinflammatory cytokine wave that is analogous to that found in lipopolysaccharide-induced shock (in vivo). To what extent the elevation of cytokines contributes to metabolic effects such as decreased feed intake remains to be established. Although these effects have been largely characterized in the mouse, several investigations with DON suggest that immunotoxic effects are also likely in domestic animals. Further toxicology studies and an assessment of the potential of DON to be an etiologic agent in human disease are warranted.
{"title":"Toxicology of deoxynivalenol (vomitoxin).","authors":"B. Rotter, D. Prelusky, J. Pestka","doi":"10.1080/713851046","DOIUrl":"https://doi.org/10.1080/713851046","url":null,"abstract":"Trichothecene mycotoxins are a group of structurally similar fungal metabolites that are capable of producing a wide range of toxic effects. Deoxynivalenol (DON, vomitoxin), a trichothecene, is prevalent worldwide in crops used for food and feed production, including in Canada and the United States. Although DON is one of the least acutely toxic trichothecenes, it should be treated as an important food safety issue because it is a very common contaminant of grain. This review focuses on the ability of DON to induce toxicologic and immunotoxic effects in a variety of cell systems and animal species. At the cellular level, the main toxic effect is inhibition of protein synthesis via binding to the ribosome. In animals, moderate to low ingestion of toxin can cause a number of as yet poorly defined effects associated with reduced performance and immune function. The main overt effect at low dietary concentrations appears to be a reduction in food consumption (anorexia), while higher doses induce vomiting (emesis). DON is known to alter brain neurochemicals. The serotoninergic system appears to play a role in mediation of the feeding behavior and emetic response. Animals fed low to moderate doses are able to recover from initial weight losses, while higher doses induce more long-term changes in feeding behavior. At low dosages of DON, hematological, clinical, and immunological changes are also transitory and decrease as compensatory/adaptation mechanisms are established. Swine are more sensitive to DON than mice, poultry, and ruminants, in part because of differences in metabolism of DON, with males being more sensitive than females. The capacity of DON to alter normal immune function has been of particular interest. There is extensive evidence that DON can be immunosuppressive or immunostimulatory, depending upon the dose and duration of exposure. While immunosuppression can be explained by the inhibition of translation, immunostimulation can be related to interference with normal regulatory mechanisms. In vivo, DON suppresses normal immune response to pathogens and simultaneously induces autoimmune-like effects which are similar to human immunoglobulin A (IgA) nephropathy. Other effects include superinduction of cytokine production by T helper cells (in vitro) and activation of macrophages and T cells to produce a proinflammatory cytokine wave that is analogous to that found in lipopolysaccharide-induced shock (in vivo). To what extent the elevation of cytokines contributes to metabolic effects such as decreased feed intake remains to be established. Although these effects have been largely characterized in the mouse, several investigations with DON suggest that immunotoxic effects are also likely in domestic animals. Further toxicology studies and an assessment of the potential of DON to be an etiologic agent in human disease are warranted.","PeriodicalId":17418,"journal":{"name":"Journal of Toxicology and Environmental Health, Part A","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1996-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83437452","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 development of drugs to combat diseases, chemicals to improve food production, or compounds to enhance the quality of life necessitates, by law, the use of laboratory animals to test their safety. In order to simulate the human condition it is necessary to choose a species in which pharmacokinetic and toxicokinetic mechanisms are established and resemble those of humans. The advantages of the use of the rat in drug and chemical toxicity testing include (a) metabolic pathway similarities to humans; (b) numerous similar anatomical and physiological characteristics; (c) a large database, which is extremely important for comparative purposes; and (d) the ease of breeding and maintenance of animals at relatively low cost. However, the choice of rat can be complicated, especially when over 200 different strains of rat are known to exist. The aim of this review is to summarize genetically determined differences in the responsiveness of rat strains to drugs and naturally occurring chemicals and to show that susceptibility is dependent on the target organ sensitivities, which may also be strain dependent. It is suggested that detailed studies of strain differences may help to clarify toxic mechanisms. Such studies are usually best conducted using inbred strains in which the genetic characteristics have been fixed, rather than in outbred stocks in which individual samples of animals may differ, the phenotype is variable, and the stocks are subject to substantial genetic drift. The fact that strains may differ also needs to be taken into account in assessing the potential hazard of the chemical, particularly when a study involves only a single strain and therefore provides no assessment of likely strain variation.
{"title":"Role of rat strain in the differential sensitivity to pharmaceutical agents and naturally occurring substances.","authors":"S. Kacew, M. Festing","doi":"10.1080/009841096161960","DOIUrl":"https://doi.org/10.1080/009841096161960","url":null,"abstract":"The development of drugs to combat diseases, chemicals to improve food production, or compounds to enhance the quality of life necessitates, by law, the use of laboratory animals to test their safety. In order to simulate the human condition it is necessary to choose a species in which pharmacokinetic and toxicokinetic mechanisms are established and resemble those of humans. The advantages of the use of the rat in drug and chemical toxicity testing include (a) metabolic pathway similarities to humans; (b) numerous similar anatomical and physiological characteristics; (c) a large database, which is extremely important for comparative purposes; and (d) the ease of breeding and maintenance of animals at relatively low cost. However, the choice of rat can be complicated, especially when over 200 different strains of rat are known to exist. The aim of this review is to summarize genetically determined differences in the responsiveness of rat strains to drugs and naturally occurring chemicals and to show that susceptibility is dependent on the target organ sensitivities, which may also be strain dependent. It is suggested that detailed studies of strain differences may help to clarify toxic mechanisms. Such studies are usually best conducted using inbred strains in which the genetic characteristics have been fixed, rather than in outbred stocks in which individual samples of animals may differ, the phenotype is variable, and the stocks are subject to substantial genetic drift. The fact that strains may differ also needs to be taken into account in assessing the potential hazard of the chemical, particularly when a study involves only a single strain and therefore provides no assessment of likely strain variation.","PeriodicalId":17418,"journal":{"name":"Journal of Toxicology and Environmental Health, Part A","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1996-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88456169","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}
Pub Date : 1994-09-01DOI: 10.1016/0165-1161(95)90119-1
H. Matsumura, Mie Watanabe, Kyomu Matsumoto, T. Ohta
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