Felbamate, 2-phenyl-l,3-propanediol dicarbamate, is a novel anticonvulsant that is effective agai... more Felbamate, 2-phenyl-l,3-propanediol dicarbamate, is a novel anticonvulsant that is effective against both chemically and electrically induced seizures in laboratory animals. Acute, subchronic, and chronic studies were conducted in mice, rats, and dogs to establish a preclinical safety profile for this drug. Clinical signs following single intraperitoneal doses included hypoactivity, tremors, decreased muscle tone, ataxia, prostration, and labored breathing. Death was observed after intraperitoneal but not oral administration. A consistent drug-related effect noted in all multiple-dose studies with this compound was decreased body weight and food consumption. The only other consistent change noted in multiple-dose studies with felbamate was an increase in liver weight (relative and absolute) in the rat and dog which was accompanied in some cases by increases in serum enzyme levels. No histopathological changes were observed in the liver that could explain these elevated serum enzyme levels. Based on the results of these studies it was concluded that long-term administration of felbamate in human clinical trials was warranted, o IWS soda; of Toxicology. Husbandry Acute Studies Mice and rats were housed five per cage in stainless-steel wire-mesh cages and fed Purina Certified Rodent Chow No. 5002. 225
Eisei Shikenjo hōkoku. Bulletin of National Institute of Hygienic Sciences, 1994
Tributoxyethyl phosphate (TBEP) is widely used in household materials such as plasticizer, floor ... more Tributoxyethyl phosphate (TBEP) is widely used in household materials such as plasticizer, floor polish and flame retardant in plastic resins and synthetic rubbers. This compound has been detected at ppb level in underground water. In order to elucidate the toxicity of TBEP, a 14-week oral toxicity study was conducted. Wistar rats (5-weeks old, male & female, 15 rats/group) were given diet containing 0, 0.03, 0.3 or 3.0% TBEP. Suppression of body weight gain was observed in both sexes of the 3.0% group. Serum cholinesterase activity was significantly decreased in both sexes of the 0.3 and 3.0% groups and serum gamma-glutamyl transferase activity was significantly increased in both sexes of the 3.0% group after 5 and 14 weeks exposure. Amylase in serum was also increased in 0.3 and 3.0% group males and 3.0% group females. Absolute and relative liver weights in both sexes were significantly increased in the 3.0% group after 5 and 14 weeks of exposure. Histopathological examination rev...
Eisei Shikenjo hōkoku. Bulletin of National Institute of Hygienic Sciences, 1993
As one of the projects in the safety evaluation of chemical constituents in common house-hold pro... more As one of the projects in the safety evaluation of chemical constituents in common house-hold products, effects of hexabromocyclododecane (HBCD) were evaluated by primary skin irritation, skin sensitization, phototoxicity and photosensitization using guinea pigs. Primary skin irritation was not observed in HBCD emulsified in distilled water by the Draize test method. Skin sensitization test was carried out according to the maximization test method of Magnusson and Kligman. For this test, HBCD was dissolved in olive oil to give 5, 0.5 and 0.05%. When induction of sensitization occurred, challenged doses of 0.005, 0.05, 0.5 and 5% of HBCD (dissolved in acetone) were applied to its respective sensitized groups. The results showed that the induction dose of greater than 0.5% and the challenge dose of greater than 0.05% elicited a positive response. The increase in the concentration of induction and challenge doses did not further increase the percentage of positive response or the inten...
Eisei Shikenjo hōkoku. Bulletin of National Institute of Hygienic Sciences, 1993
A proposal of test guidelines for identifying contact allergens in medical materials and devices ... more A proposal of test guidelines for identifying contact allergens in medical materials and devices and for evaluation of their potentials are described. The adjuvant tests, Maximization Test and Adjuvant and Patch Test, are recommended as a test method for identifying contact allergens in medical materials and devices. To evaluate the potency of the allergen, initially, it is necessary to determine the threshold contact allergenic dose (a lowest concentration at which a positive dermal response is attained). This approach gives an essential basis to predict risks of contact allergy in humans and to plan adequate strategies for reducing the risks.
Eisei Shikenjo hōkoku. Bulletin of National Institute of Hygienic Sciences, 1994
Cochineal (C), a scarlet material extracted from the powdered pregnant insect, Dactylopius Coceus... more Cochineal (C), a scarlet material extracted from the powdered pregnant insect, Dactylopius Coceus Costa, is used as a color food additive in the form of aluminum lakes. A 13 week subchronic toxicity study was conducted to investigate the effects of simultaneous administration of C and aluminum potassium sulfate (A). Male and female Wistar rats (5-weeks-old, 15 rats/group) were given diets containing 0.75%A and 0.75%C (1.5%AC), 1.5%A and 1.5%C (3%AC), 3%C alone or 3%A alone. The following results were obtained. 1) No toxic symptoms or death occurred in any treated group. Body weight gain in male rats of the 3%A group decreased significantly. 2) Serum levels of phospholipids, triglycerides (TG) and total cholesterol in male rats and TG in female rats fed 3%C, 3%A or 3%AC were significantly decreased at the 13th week. The serum level of glutamate dehydrogenase (GIDH) in male rats treated with 1.5% or 3%AC was increased at the 4th week but no difference from control was observed at the ...
lrOXICITY STUDIES OF A SYNTHETIC ANTIOXIDANT, 2, 2'-METHYLENEBIS (4-ETHYL･-6-･TERT-BUTYLPHENOL) I... more lrOXICITY STUDIES OF A SYNTHETIC ANTIOXIDANT, 2, 2'-METHYLENEBIS (4-ETHYL･-6-･TERT-BUTYLPHENOL) IN RATS ' be 171 mgfkg BXM'diay in rnale rats and 180 mglkg BWIday in female rats, Key words : 2, 2'-methylenebis (4-ethyl-6-tert-butylphenol), acute toxicity test, subchronic toxicity test, testicular texicity, parathyroid gland, rat.
The objective of this study was to assess the relationship between lipopolysaccharide (LPS)-induc... more The objective of this study was to assess the relationship between lipopolysaccharide (LPS)-induced elevation of nitric oxide (NO) levels and hematological changes. Twenty-four h following i.p. treatment of LPS (1 mg/kg body wt.), nitrite/nitrate (NO2-/NO3-) levels in the serum and urine of rats were, respectively, increased to 11 and 50 times those of control. Time-dependent decrease of white blood cells (80% of control), lymphocytes (40% of control), and platelets (35% of control) was also observed, while a significant increase of neutrophils (330% of control) and monocytes (650% of control) occurred during the 24-h post-treatment period. These results suggest that LPS-induced increase of NO2-/NO3- levels and coincident hematological changes may compromise immune functions.
Abstract The acute and subacute toxicity studies on 2,3-dichloropropionic acid and chlorinated po... more Abstract The acute and subacute toxicity studies on 2,3-dichloropropionic acid and chlorinated polyacrylamide, which are probably produced during the chlorination of a drinking water treatment system, were conducted in comparison with their original compounds, acrylamide and polyacrylamide using young Wistar rats in order to evaluate the safety of drinking water. The LD 50 (mg/kg body wt) values were found to be 177 and 141 for acrylamide, 470 and 289 for 2,3-dichloropropionic acid, > 1000 and > 1000 for polyacrylamide and > 1000 and > 1000 for chlorinated polyacrylamide, respectively, in male and female rats. The 28 day-toxicity tests on acrylamide, 2,3-dichloropropionic acid, polyacrylamide and chlorinated polyacrylamide were conducted using male rats. By feeding 340 ppm acrylamide, growth was delayed during the first 19 days and then ceased when paralysis of hindlimb was observed. Severe retardation of growth was observed from the onset when treated with 700 ppm. However, toxicity was weak when half doses of either acrylamide or 2,3-dichloropropionic acid were given. Feeding polyacrylamide or chlorinated polyacrylamide at doses of 2500 or 10,000 ppm did not induce any considerable toxicity on the growth, gross findings, hematological and biochemical parameters. Histopathological examination revealed inhibition of spermatogenesis in rats fed 340 ppm acrylamide.
ÐEYTEX TM is an in vitro test system for predicting the ocular irritation potential of chemicals ... more ÐEYTEX TM is an in vitro test system for predicting the ocular irritation potential of chemicals and formulations. This method was evaluated as an alternative method to the Draize eye irritation test (Draize test) for the eye irritation potential of several cosmetic ingredients in a three-phase validation study conducted at ®ve to seven laboratories. Thirty-nine test substances were used as coded samples. The test procedures were controlled under the same standard operating procedure (SOP) at all participating laboratories. The interlaboratory coecient of variation (CV) was 20.8%. The correlation coecient between EYTEX scores and the maximal average Draize total score (MAS) was 0.313. Irritancy classi®cations were established based on the results of 54 EYTEX tests and the EYTEX/Draize equivalent was calculated. Thirty-eight EYTEX test results concurred with the results of the Draize test, substantial equivalence was 70.4%. These results indicate that EYTEX provides a rough method of classi®cation rather than providing absolute values. The present results also indicate that EYTEX has the following characteristics: (1) intensely coloured substance may not be compatible; (2) some cationic surfactants may be underestimated; (3) EYTEX can be applied to most test substances under the same conditions as the in vivo tests.
In predicting human skin sensitization due to possible risky chemicals, it is not sufficient to e... more In predicting human skin sensitization due to possible risky chemicals, it is not sufficient to evaluate solely the minimum induction dose (MID) or the standard challenge dose (SCD) in the Guinea Pig Maximization Test (GPMT). Nakamura et al. (1994) (Nakamura, A., Momma, J., Sekiguchi, H., Noda, T., Yamano, T., Kaniwa, M., Kojima, S., Tsuda, M., Kurokawa, Y., 1994. A new protocol and criteria for quantitative determination of sensitization potencies of chemicals by guinea pig maximization test. Contact Dermatitis 31, 72-85) previously measured the residual dose of chemicals in the products implicated in human allergic accidents, and stated that '... the level of chemical in the products (direct exposure-dose = DED) was similar to or higher than value of sensitization potency.' However, several of the chemicals listed in their article, show an even lower value of sensitization potency than the DED, although a potential correlation between results of the GPMT and the DED was seemed to be evident; a key question about the essential rule of those parameters therefore remains open. Using the data of Nakamura et al. (1994), we analyzed the functional rules of the three independent parameters, the MID, the SCD, and the DED on which the GPMT is based. Calculations of the degree of allergic reactions elicited in humans provided a range of discrimination constants (D) using the formula; D = DED/(MID*SCD). Possible human allergic accidents may be predicted when the dose of a candidate chemical in a chemical product (equal to DED) exceeds the value; D*(MID*SCD), following the correct evaluation of the MID as well as the SCD.
Journal of the American College of Toxicology, 1989
Gelatin-starch syrup (food grade) microcapsulation was applied for toxicology studies of bromodic... more Gelatin-starch syrup (food grade) microcapsulation was applied for toxicology studies of bromodichloromethane (BDCM). BDCM concentrations were stable for 120 days in the microcapsules and for 9 months when incorporated in the powder diet. BDCM concentration in the blood following the administration of microcapsules in olive oil suspension was retained at higher levels than when BDCM was administered as olive oil solution. Subsequently, the microcapsules were mixed in powder diet and were given at concentrations of microcapsulated BDCM of 0, 0.024, 0.072, and 0.215% to groups of 7 male Wistar rats for 1 month. For comparison, BDCM dissolved in olive oil was administered by gavage to groups of 7 male rats for 1 month at dosage levels adjusted to those in the feeding study (0, 20, 60, and 180 mg/kg body weight). Suppression of body weight gain was seen in the high-dosage groups in both the feeding and the gavage studies and was more severe in the former. Similar histopathologic lesions...
The effects of 2,5-di(tert-butyl)-1,4-hydroquinone (DTBHQ) on the intracellular free Ca2+ level (... more The effects of 2,5-di(tert-butyl)-1,4-hydroquinone (DTBHQ) on the intracellular free Ca2+ level ([Ca2+]i) and histamine secretion of rat basophilic leukemia (RBL-2H3) cells were examined. DTBHQ (0.1-10 mumol/l) alone induced rapid and sustained increases in [Ca2+]i in a concentration-dependent manner. In cells sensitized with anti-dinitrophenyl IgE, DTBHQ (10 mumol/l) further increased the antigen (dinitrophenylated BSA)-induced Ca2+ response. In the absence of external Ca2+ with addition of 1 mmol/l EGTA, both DTBHQ (10 mumol/l) and the antigen (10 microgram/ml) induced transient increase in [Ca2+]i. In sensitized cells, both DTBHQ (10 mumol/l) and antigen (10 micrograms/ml) elicited histamine secretion, although the response was far stronger in the latter case. The DTBHQ-induced histamine secretion was markedly enhanced by addition of the protein kinase C activator, phorbol 12-myristate 13-acetate (TPA) (10 ng/ml) whereas TPA alone did not cause any increase. Moreover, DTBHQ enhanced the antigen-induced histamine secretion. The results suggest that DTBHQ increases [Ca2+]i and enhances antigen-induced histamine secretion while DTBHQ alone does not cause as much histamine secretion as antigen, which support the idea that calcium signals are necessary but are not sufficient for maximum histamine secretion in RBL-2H3 cells.
2-Mercaptobenzimidazole (2-MBI), a rubber antioxidant, is known to exhibit potent antithyroid tox... more 2-Mercaptobenzimidazole (2-MBI), a rubber antioxidant, is known to exhibit potent antithyroid toxicity in rats and is a candidate as an environmental endocrine disrupter. 2-Mercaptomethylbenzimidazoles (a 1:1 mixture of 4-methyl and 5-methyl isomers, MMBIs), are also employed industrially as rubber antioxidants and are suspected to exert antithyroid toxicity such as 2-MBI. In this investigation, acute and subacute oral toxicity studies of MMBIs in Wistar rats were conducted. The clinical signs of acute oral toxicity were observed including decreased spontaneous movement, a paralytic gait, salivation and lacrimation, and adoption of prone and lateral positions. The LD50 was estimated to be 330 mg/kg. In the subacute oral toxicity study, male and female rats were treated with MMBIs by gavage at doses of 0 (corn oil), 4, 20 and 100 mg/kg for 28 consecutive days followed by a 2-week recovery period for the control and highest dose groups. Body weight and food consumption, clinical signs, organ weights, clinical biochemistry and haematological parameters including clotting times and micronuclei induction in bone marrow erythropoeitic cells, and histopathology were examined. Relative organ weights of lung, liver and kidney, and serum cholesterol and phospholipid significantly increased in male rats treated with MMBIs at doses of 20 and 100 mg/kg. Male rats administered 100 mg/kg MMBIs exhibited a 1.8-fold increase in thyroid weight associated with histopathological changes but not altered serum thyroid hormone levels. Female rats administered 100 mg MMBIs/kg exhibited significant increases of liver and kidney but not thyroid weights, and serum cholesterol level. The antithyroid toxicity of MMBIs in rats was estimated to be one-tenth that of 2-MBI. No-observed-effect levels for male and female rats were found to be 4 and 20 mg/kg, respectively, in this subacute oral toxicity study.
Felbamate, 2-phenyl-l,3-propanediol dicarbamate, is a novel anticonvulsant that is effective agai... more Felbamate, 2-phenyl-l,3-propanediol dicarbamate, is a novel anticonvulsant that is effective against both chemically and electrically induced seizures in laboratory animals. Acute, subchronic, and chronic studies were conducted in mice, rats, and dogs to establish a preclinical safety profile for this drug. Clinical signs following single intraperitoneal doses included hypoactivity, tremors, decreased muscle tone, ataxia, prostration, and labored breathing. Death was observed after intraperitoneal but not oral administration. A consistent drug-related effect noted in all multiple-dose studies with this compound was decreased body weight and food consumption. The only other consistent change noted in multiple-dose studies with felbamate was an increase in liver weight (relative and absolute) in the rat and dog which was accompanied in some cases by increases in serum enzyme levels. No histopathological changes were observed in the liver that could explain these elevated serum enzyme levels. Based on the results of these studies it was concluded that long-term administration of felbamate in human clinical trials was warranted, o IWS soda; of Toxicology. Husbandry Acute Studies Mice and rats were housed five per cage in stainless-steel wire-mesh cages and fed Purina Certified Rodent Chow No. 5002. 225
Eisei Shikenjo hōkoku. Bulletin of National Institute of Hygienic Sciences, 1994
Tributoxyethyl phosphate (TBEP) is widely used in household materials such as plasticizer, floor ... more Tributoxyethyl phosphate (TBEP) is widely used in household materials such as plasticizer, floor polish and flame retardant in plastic resins and synthetic rubbers. This compound has been detected at ppb level in underground water. In order to elucidate the toxicity of TBEP, a 14-week oral toxicity study was conducted. Wistar rats (5-weeks old, male & female, 15 rats/group) were given diet containing 0, 0.03, 0.3 or 3.0% TBEP. Suppression of body weight gain was observed in both sexes of the 3.0% group. Serum cholinesterase activity was significantly decreased in both sexes of the 0.3 and 3.0% groups and serum gamma-glutamyl transferase activity was significantly increased in both sexes of the 3.0% group after 5 and 14 weeks exposure. Amylase in serum was also increased in 0.3 and 3.0% group males and 3.0% group females. Absolute and relative liver weights in both sexes were significantly increased in the 3.0% group after 5 and 14 weeks of exposure. Histopathological examination rev...
Eisei Shikenjo hōkoku. Bulletin of National Institute of Hygienic Sciences, 1993
As one of the projects in the safety evaluation of chemical constituents in common house-hold pro... more As one of the projects in the safety evaluation of chemical constituents in common house-hold products, effects of hexabromocyclododecane (HBCD) were evaluated by primary skin irritation, skin sensitization, phototoxicity and photosensitization using guinea pigs. Primary skin irritation was not observed in HBCD emulsified in distilled water by the Draize test method. Skin sensitization test was carried out according to the maximization test method of Magnusson and Kligman. For this test, HBCD was dissolved in olive oil to give 5, 0.5 and 0.05%. When induction of sensitization occurred, challenged doses of 0.005, 0.05, 0.5 and 5% of HBCD (dissolved in acetone) were applied to its respective sensitized groups. The results showed that the induction dose of greater than 0.5% and the challenge dose of greater than 0.05% elicited a positive response. The increase in the concentration of induction and challenge doses did not further increase the percentage of positive response or the inten...
Eisei Shikenjo hōkoku. Bulletin of National Institute of Hygienic Sciences, 1993
A proposal of test guidelines for identifying contact allergens in medical materials and devices ... more A proposal of test guidelines for identifying contact allergens in medical materials and devices and for evaluation of their potentials are described. The adjuvant tests, Maximization Test and Adjuvant and Patch Test, are recommended as a test method for identifying contact allergens in medical materials and devices. To evaluate the potency of the allergen, initially, it is necessary to determine the threshold contact allergenic dose (a lowest concentration at which a positive dermal response is attained). This approach gives an essential basis to predict risks of contact allergy in humans and to plan adequate strategies for reducing the risks.
Eisei Shikenjo hōkoku. Bulletin of National Institute of Hygienic Sciences, 1994
Cochineal (C), a scarlet material extracted from the powdered pregnant insect, Dactylopius Coceus... more Cochineal (C), a scarlet material extracted from the powdered pregnant insect, Dactylopius Coceus Costa, is used as a color food additive in the form of aluminum lakes. A 13 week subchronic toxicity study was conducted to investigate the effects of simultaneous administration of C and aluminum potassium sulfate (A). Male and female Wistar rats (5-weeks-old, 15 rats/group) were given diets containing 0.75%A and 0.75%C (1.5%AC), 1.5%A and 1.5%C (3%AC), 3%C alone or 3%A alone. The following results were obtained. 1) No toxic symptoms or death occurred in any treated group. Body weight gain in male rats of the 3%A group decreased significantly. 2) Serum levels of phospholipids, triglycerides (TG) and total cholesterol in male rats and TG in female rats fed 3%C, 3%A or 3%AC were significantly decreased at the 13th week. The serum level of glutamate dehydrogenase (GIDH) in male rats treated with 1.5% or 3%AC was increased at the 4th week but no difference from control was observed at the ...
lrOXICITY STUDIES OF A SYNTHETIC ANTIOXIDANT, 2, 2'-METHYLENEBIS (4-ETHYL･-6-･TERT-BUTYLPHENOL) I... more lrOXICITY STUDIES OF A SYNTHETIC ANTIOXIDANT, 2, 2'-METHYLENEBIS (4-ETHYL･-6-･TERT-BUTYLPHENOL) IN RATS ' be 171 mgfkg BXM'diay in rnale rats and 180 mglkg BWIday in female rats, Key words : 2, 2'-methylenebis (4-ethyl-6-tert-butylphenol), acute toxicity test, subchronic toxicity test, testicular texicity, parathyroid gland, rat.
The objective of this study was to assess the relationship between lipopolysaccharide (LPS)-induc... more The objective of this study was to assess the relationship between lipopolysaccharide (LPS)-induced elevation of nitric oxide (NO) levels and hematological changes. Twenty-four h following i.p. treatment of LPS (1 mg/kg body wt.), nitrite/nitrate (NO2-/NO3-) levels in the serum and urine of rats were, respectively, increased to 11 and 50 times those of control. Time-dependent decrease of white blood cells (80% of control), lymphocytes (40% of control), and platelets (35% of control) was also observed, while a significant increase of neutrophils (330% of control) and monocytes (650% of control) occurred during the 24-h post-treatment period. These results suggest that LPS-induced increase of NO2-/NO3- levels and coincident hematological changes may compromise immune functions.
Abstract The acute and subacute toxicity studies on 2,3-dichloropropionic acid and chlorinated po... more Abstract The acute and subacute toxicity studies on 2,3-dichloropropionic acid and chlorinated polyacrylamide, which are probably produced during the chlorination of a drinking water treatment system, were conducted in comparison with their original compounds, acrylamide and polyacrylamide using young Wistar rats in order to evaluate the safety of drinking water. The LD 50 (mg/kg body wt) values were found to be 177 and 141 for acrylamide, 470 and 289 for 2,3-dichloropropionic acid, > 1000 and > 1000 for polyacrylamide and > 1000 and > 1000 for chlorinated polyacrylamide, respectively, in male and female rats. The 28 day-toxicity tests on acrylamide, 2,3-dichloropropionic acid, polyacrylamide and chlorinated polyacrylamide were conducted using male rats. By feeding 340 ppm acrylamide, growth was delayed during the first 19 days and then ceased when paralysis of hindlimb was observed. Severe retardation of growth was observed from the onset when treated with 700 ppm. However, toxicity was weak when half doses of either acrylamide or 2,3-dichloropropionic acid were given. Feeding polyacrylamide or chlorinated polyacrylamide at doses of 2500 or 10,000 ppm did not induce any considerable toxicity on the growth, gross findings, hematological and biochemical parameters. Histopathological examination revealed inhibition of spermatogenesis in rats fed 340 ppm acrylamide.
ÐEYTEX TM is an in vitro test system for predicting the ocular irritation potential of chemicals ... more ÐEYTEX TM is an in vitro test system for predicting the ocular irritation potential of chemicals and formulations. This method was evaluated as an alternative method to the Draize eye irritation test (Draize test) for the eye irritation potential of several cosmetic ingredients in a three-phase validation study conducted at ®ve to seven laboratories. Thirty-nine test substances were used as coded samples. The test procedures were controlled under the same standard operating procedure (SOP) at all participating laboratories. The interlaboratory coecient of variation (CV) was 20.8%. The correlation coecient between EYTEX scores and the maximal average Draize total score (MAS) was 0.313. Irritancy classi®cations were established based on the results of 54 EYTEX tests and the EYTEX/Draize equivalent was calculated. Thirty-eight EYTEX test results concurred with the results of the Draize test, substantial equivalence was 70.4%. These results indicate that EYTEX provides a rough method of classi®cation rather than providing absolute values. The present results also indicate that EYTEX has the following characteristics: (1) intensely coloured substance may not be compatible; (2) some cationic surfactants may be underestimated; (3) EYTEX can be applied to most test substances under the same conditions as the in vivo tests.
In predicting human skin sensitization due to possible risky chemicals, it is not sufficient to e... more In predicting human skin sensitization due to possible risky chemicals, it is not sufficient to evaluate solely the minimum induction dose (MID) or the standard challenge dose (SCD) in the Guinea Pig Maximization Test (GPMT). Nakamura et al. (1994) (Nakamura, A., Momma, J., Sekiguchi, H., Noda, T., Yamano, T., Kaniwa, M., Kojima, S., Tsuda, M., Kurokawa, Y., 1994. A new protocol and criteria for quantitative determination of sensitization potencies of chemicals by guinea pig maximization test. Contact Dermatitis 31, 72-85) previously measured the residual dose of chemicals in the products implicated in human allergic accidents, and stated that '... the level of chemical in the products (direct exposure-dose = DED) was similar to or higher than value of sensitization potency.' However, several of the chemicals listed in their article, show an even lower value of sensitization potency than the DED, although a potential correlation between results of the GPMT and the DED was seemed to be evident; a key question about the essential rule of those parameters therefore remains open. Using the data of Nakamura et al. (1994), we analyzed the functional rules of the three independent parameters, the MID, the SCD, and the DED on which the GPMT is based. Calculations of the degree of allergic reactions elicited in humans provided a range of discrimination constants (D) using the formula; D = DED/(MID*SCD). Possible human allergic accidents may be predicted when the dose of a candidate chemical in a chemical product (equal to DED) exceeds the value; D*(MID*SCD), following the correct evaluation of the MID as well as the SCD.
Journal of the American College of Toxicology, 1989
Gelatin-starch syrup (food grade) microcapsulation was applied for toxicology studies of bromodic... more Gelatin-starch syrup (food grade) microcapsulation was applied for toxicology studies of bromodichloromethane (BDCM). BDCM concentrations were stable for 120 days in the microcapsules and for 9 months when incorporated in the powder diet. BDCM concentration in the blood following the administration of microcapsules in olive oil suspension was retained at higher levels than when BDCM was administered as olive oil solution. Subsequently, the microcapsules were mixed in powder diet and were given at concentrations of microcapsulated BDCM of 0, 0.024, 0.072, and 0.215% to groups of 7 male Wistar rats for 1 month. For comparison, BDCM dissolved in olive oil was administered by gavage to groups of 7 male rats for 1 month at dosage levels adjusted to those in the feeding study (0, 20, 60, and 180 mg/kg body weight). Suppression of body weight gain was seen in the high-dosage groups in both the feeding and the gavage studies and was more severe in the former. Similar histopathologic lesions...
The effects of 2,5-di(tert-butyl)-1,4-hydroquinone (DTBHQ) on the intracellular free Ca2+ level (... more The effects of 2,5-di(tert-butyl)-1,4-hydroquinone (DTBHQ) on the intracellular free Ca2+ level ([Ca2+]i) and histamine secretion of rat basophilic leukemia (RBL-2H3) cells were examined. DTBHQ (0.1-10 mumol/l) alone induced rapid and sustained increases in [Ca2+]i in a concentration-dependent manner. In cells sensitized with anti-dinitrophenyl IgE, DTBHQ (10 mumol/l) further increased the antigen (dinitrophenylated BSA)-induced Ca2+ response. In the absence of external Ca2+ with addition of 1 mmol/l EGTA, both DTBHQ (10 mumol/l) and the antigen (10 microgram/ml) induced transient increase in [Ca2+]i. In sensitized cells, both DTBHQ (10 mumol/l) and antigen (10 micrograms/ml) elicited histamine secretion, although the response was far stronger in the latter case. The DTBHQ-induced histamine secretion was markedly enhanced by addition of the protein kinase C activator, phorbol 12-myristate 13-acetate (TPA) (10 ng/ml) whereas TPA alone did not cause any increase. Moreover, DTBHQ enhanced the antigen-induced histamine secretion. The results suggest that DTBHQ increases [Ca2+]i and enhances antigen-induced histamine secretion while DTBHQ alone does not cause as much histamine secretion as antigen, which support the idea that calcium signals are necessary but are not sufficient for maximum histamine secretion in RBL-2H3 cells.
2-Mercaptobenzimidazole (2-MBI), a rubber antioxidant, is known to exhibit potent antithyroid tox... more 2-Mercaptobenzimidazole (2-MBI), a rubber antioxidant, is known to exhibit potent antithyroid toxicity in rats and is a candidate as an environmental endocrine disrupter. 2-Mercaptomethylbenzimidazoles (a 1:1 mixture of 4-methyl and 5-methyl isomers, MMBIs), are also employed industrially as rubber antioxidants and are suspected to exert antithyroid toxicity such as 2-MBI. In this investigation, acute and subacute oral toxicity studies of MMBIs in Wistar rats were conducted. The clinical signs of acute oral toxicity were observed including decreased spontaneous movement, a paralytic gait, salivation and lacrimation, and adoption of prone and lateral positions. The LD50 was estimated to be 330 mg/kg. In the subacute oral toxicity study, male and female rats were treated with MMBIs by gavage at doses of 0 (corn oil), 4, 20 and 100 mg/kg for 28 consecutive days followed by a 2-week recovery period for the control and highest dose groups. Body weight and food consumption, clinical signs, organ weights, clinical biochemistry and haematological parameters including clotting times and micronuclei induction in bone marrow erythropoeitic cells, and histopathology were examined. Relative organ weights of lung, liver and kidney, and serum cholesterol and phospholipid significantly increased in male rats treated with MMBIs at doses of 20 and 100 mg/kg. Male rats administered 100 mg/kg MMBIs exhibited a 1.8-fold increase in thyroid weight associated with histopathological changes but not altered serum thyroid hormone levels. Female rats administered 100 mg MMBIs/kg exhibited significant increases of liver and kidney but not thyroid weights, and serum cholesterol level. The antithyroid toxicity of MMBIs in rats was estimated to be one-tenth that of 2-MBI. No-observed-effect levels for male and female rats were found to be 4 and 20 mg/kg, respectively, in this subacute oral toxicity study.
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