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1.
Food Chem Toxicol ; 77: 120-31, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25592784

RESUMO

A toxicity/toxicokinetic swine-adapted infant formula feeding study was conducted in Domestic Yorkshire Crossbred Swine from lactation day 3 for 28 consecutive days during the preweaning period at carrageenan concentrations of 0, 300, 1000 and 2250 ppm under GLP guidelines. This study extends the observations in newborn baboons (McGill et al., 1977) to piglets and evaluates additional parameters: organ weights, clinical chemistry, special gastrointestinal tract stains (toluidine blue, Periodic Acid-Schiff), plasma levels of carrageenan; and evaluation of potential immune system effects. Using validated methods, immunophenotyping of blood cell types (lymphocytes, monocytes, B cells, helper T cells, cytotoxic T cells, mature T cells), sandwich immunoassays for blood cytokine evaluations (IL-6, IL-8, IL1ß, TNF-α), and immunohistochemical staining of the gut for IL-8 and TNF-α were conducted. No treatment-related adverse effects at any carrageenan concentration were found on any parameter. Glucosuria in a few animals was not considered treatment-related. The high dose in this study, equivalent to ~430 mg/kg/day, provides an adequate margin of exposure for human infants, as affirmed by JECFA and supports the safe use of carrageenan for infants ages 0-12 weeks and older and infants with special medical needs.


Assuntos
Carragenina/farmacocinética , Trato Gastrointestinal/efeitos dos fármacos , Sistema Imunitário/efeitos dos fármacos , Fórmulas Infantis/química , Animais , Animais Recém-Nascidos , Peso Corporal/efeitos dos fármacos , Carragenina/efeitos adversos , Carragenina/sangue , Relação Dose-Resposta a Droga , Feminino , Interleucina-1beta/sangue , Interleucina-6/sangue , Interleucina-8/sangue , Masculino , Tamanho do Órgão/efeitos dos fármacos , Suínos , Testes de Toxicidade , Fator de Necrose Tumoral alfa/sangue
2.
Food Chem Toxicol ; 39(8): 759-86, 2001 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-11434984

RESUMO

Inorganic phosphate salts are widely used as food ingredients and in a variety of commercial applications. The United States Food and Drug Administration (FDA) considers inorganic phosphates "Generally Recognized As Safe" (GRAS) (FDA, 1973a, 1979) [FDA: Food and Drug Administration 1973a. GRAS (Generally Recognized as Safe) food ingredients-phosphates. NTIS PB-221-224, FDA, Food and Drug Administration, 1979. Phosphates; Proposed Affirmation of and Deletion From GRAS Status as Direct and Human Food Ingredients. Federal Register 44 (244). 74845-74857, 18 December (1979)] and the European Union (EU) allows inorganic phosphates to be added directly to food (EU Directive 95/2/EC as amended by 98/72/EC). In this review, data on the acute, subchronic and chronic toxicity, genotoxicity, teratogenicity and reproductive toxicity from the published literature and from unpublished studies by the manufacturers are reviewed. Based on the toxicity data and similar chemistry, the inorganic phosphates can be separated into four major classes, consisting of monovalent salts, divalent salts, ammonium salts and aluminum salts. The proposed classification scheme supports the use of toxicity data from one compound to assess the toxicity of another compound in the same class. However, in the case of eye and skin irritation, the proposed classification scheme cannot be used because a wide range of responses exists within each class. Therefore, the eye and skin hazards associated with an individual inorganic phosphate should be assessed on a chemical-by-chemical basis. A large amount of toxicity data exists for all four classes of inorganic phosphates. The large and comprehensive database allows an accurate assessment of the toxicity of each class of inorganic phosphate. Overall, all four classes of inorganic phosphates exhibit low oral, inhalation and dermal toxicities. Based on these data, humans are unlikely to experience adverse effects when the daily phosphorus consumption remains below 70 mg/kg/day (JECFA, 1964, 1982a) [JECFA (Joint FAO/WHO Expert Committee on Food Additives 1964. Specifications for the Identity and Purity of Food Additives and their Toxicological Evaluation) Emulsifiers, Stabilizers, Bleaching, and Maturing Agents. Technical Report Series of the World Health Organization 281; ECFA (Joint FAO/WHO Expert Committee on Food Additives 1982a. Phosphoric Acid and Phosphate Salts. ICS/FA/82)].


Assuntos
Aditivos Alimentares/toxicidade , Fosfatos/toxicidade , Animais , Cricetinae , Bases de Dados Factuais , Aditivos Alimentares/classificação , Cobaias , Humanos , Camundongos , Testes de Mutagenicidade , Fosfatos/classificação , Política Pública , Ratos , Teratogênicos/toxicidade , Testes de Toxicidade
3.
Food Chem Toxicol ; 38(7): 607-15, 2000 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-10942322

RESUMO

A GLP OECD guideline study was conducted to evaluate the subchronic toxicity of hydrogen peroxide (HP) when administered continuously in the drinking water of catalase-deficient (C57BL/6N) mice and reversibility of toxic effects. Groups of mice (15/sex/group) received solutions of 0, 100, 300, 1000 or 3000 ppm HP in distilled water for 13 weeks; five/sex/group continued on untreated distilled water for an additional 6 weeks. Animals drinking 3000 ppm HP exhibited depressed water and food consumption and body weight. Females drinking 1000 ppm HP had reduced water consumption with intermittent effects on food consumption, but no body weight effects. HP administration did not produce any mortality, clinical signs, hematological effects or organ weight effects on brain, liver, kidneys, adrenals, testes, heart or spleen. Total protein and globulin were depressed among high dose males. Mild to minimal duodenal mucosal hyperplasia was noted in animals receiving 1000 and 3000 ppm HP and one male receiving 300 ppm for 13 weeks. There were no other histopathological findings. All effects noted during the treatment period, including the duodenal hyperplasia, were reversible during the 6-week recovery period. Females dosed with 300-3000 ppm HP during the treatment period showed increased water consumption during the recovery period. The no-observed-effect level (NOEL), based on duodenal mucosal hyperplasia, is 100 ppm in drinking water or 26 and 37 mg/kg/day HP, respectively, for males and females.


Assuntos
Acatalasia , Peróxido de Hidrogênio/toxicidade , Animais , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ingestão de Líquidos/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Peróxido de Hidrogênio/análise , Hiperplasia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Masculino , Camundongos , Nível de Efeito Adverso não Observado , Fatores Sexuais , Água/análise
4.
Neurotoxicology ; 20(4): 653-73, 1999 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-10499364

RESUMO

This paper reviews the characteristics of organophosphate-induced delayed neurotoxicity, its mechanism, lesions, species sensitivities and structure activity-relationships as they relate to the class of compounds known as triaryl phosphates. The triaryl phosphates have been widely used in commerce for over thirty years as flame retardants in fluids and plastics. Concern has been raised regarding their potential to cause organophosphate-induced delayed neurotoxicity (OPIDN), due to structural similarities to the potent neurotoxicant, tri-ortho cresyl phosphate (TOCP). Based on research on many pure isomers, Johnson (1975a, 1975b) found that certain structural features are required for a triaryl phosphate to react with the enzyme, neuropathy target enzyme (NTE), in a manner which induces OPIDN. Results of acute hen OPIDN studies, the experimental model of choice, support his findings as regards the structure-activity relationships for commercial triaryl phosphates. Thus, standard acute hen OPIDN studies on triphenyl phosphate and butylated triaryl phosphates fail to demonstrate a potential to elicit OPIDN by these products after a single dose. Studies on the mixed isopropyl phenyl phosphates indicate that, while some are neurotoxic, they are much less potent than tricresyl phosphate (TCP) and TOCP in the induction of OPIDN. Most commercial isopropylated triaryl phosphates lacked the potential to induce acute OPIDN using a limit dose of 2000 mg/kg. Although in early studies these compounds appeared to be neurotoxic, they were generally tested at excessively high doses, often exceeding 10,000 mg/kg in acute hen OPIDN studies. In contrast to the isopropylated and butylated triaryl phosphate products, TCP, and especially its ortho substituted isomer, TOCP, were found to be neurotoxic in both acute and subchronic hen OPIDN studies. Recent advances in the synthesis of commercial TCP products have resulted in products with reduced neurotoxic potential (McCormick et al, 1993). As an example, when 3% TCP in aviation oil was dosed acutely at 5000 mg/kg, or for 90 days at 1000 mg/kg/day, no delayed neurotoxicity was noted (Daughtrey et al., 1990, 1996). These data are indicative of the safety of these aviation lubricants at use levels currently employed.


Assuntos
Esterases/metabolismo , Doenças do Sistema Nervoso/induzido quimicamente , Doenças do Sistema Nervoso/genética , Compostos Organofosforados/toxicidade , Animais , Galinhas , Lubrificação , Doenças do Sistema Nervoso/patologia , Especificidade da Espécie , Relação Estrutura-Atividade
5.
Toxicology ; 128(2): 125-34, 1998 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-9710153

RESUMO

Tri-n-butyl phosphate (TBP, CAS No. 126-73-8), an industrial chemical, was administered in the diet at concentrations of 0, 200, 700 and 3000 ppm to groups of 50 male and 50 female Sprague-Dawley rats for 2 years. Body weights and food consumption were measured weekly for the first 13 weeks and monthly thereafter. Hematology was performed at 12, 18 and 24 months; urinalyses were performed at 3 weeks and 3, 6, 12 and 18 months. All surviving animals were euthanized after 24 months of treatment. Macroscopic postmortem examinations were performed on all animals; complete histopathological evaluation was performed on control and high dose animals; target organs were examined in all dose groups. Significant decreases in body weight gain occurred in males and females receiving the 3000 ppm concentration and a slight decrease in weight gain occurred in females receiving the 700 ppm concentration. The only clinical sign attributed to TBP was an increased incidence of red discoloration of the urine in some high-dose males. Survival, hematology and urinalysis parameters were unaffected by treatment at any concentration. A dose-related increase in the incidence and severity of urinary bladder hyperplasia and the incidence of urinary bladder papillomas was evident in male and female rats receiving the 700 and 3000 ppm concentrations. Transitional cell carcinomas were present in six of 49 males and two of 50 females and a squamous cell carcinoma was present in one of 49 males in the group which received 3000 ppm. The oncogenic effects showed a clear threshold of 700 ppm in the diet. The NOEL (no observable effect level) for chronic toxicity was 200 ppm. Mean intake of TBP was 9 and 12 mg/kg/day for males and females, respectively, receiving 200 ppm; 33 and 42 mg/kg/day for males and females, respectively, receiving 700 ppm, and 143 and 182 mg/kg/day for males and females, respectively, receiving 3000 ppm. TBP was negative in genotoxicity tests, suggesting that the tumors are induced by nongenotoxic mechanisms.


Assuntos
Carcinógenos/toxicidade , Organofosfatos/toxicidade , Neoplasias da Bexiga Urinária/induzido quimicamente , Bexiga Urinária/efeitos dos fármacos , Administração Oral , Animais , Carcinoma de Células Escamosas/induzido quimicamente , Carcinoma de Células de Transição/induzido quimicamente , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Hiperplasia/induzido quimicamente , Masculino , Nível de Efeito Adverso não Observado , Organofosfatos/administração & dosagem , Papiloma/induzido quimicamente , Ratos , Ratos Sprague-Dawley , Fatores Sexuais , Análise de Sobrevida , Bexiga Urinária/patologia , Urina/química , Aumento de Peso/efeitos dos fármacos
6.
J Anat ; 189 ( Pt 3): 531-5, 1996 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-8982827

RESUMO

A subchronic toxicity study was conducted to evaluate the potential toxicological effects associated with intestinal translocation of a special fine particle size (median particle size 6 microns) microcrystalline cellulose (MCC). Four groups of Sprague-Dawley rats (20/sex/group) received either 0 (control), 500, 2500 or 5000 mg/kg/day MCC (25% w/v in tap water) daily by oral gavage for 90 d. At study termination, organs and tissues from high-dose and control animals, including multiple sections of intestine with gut-associated lymphoid tissue, were processed for light microscopy with subsequent examination under polarised light for the presence of birefringent MCC particles. None were observed in any tissue examined. No toxicologically significant effects or lesions were found in any other parameter or organ evaluated. The 'no observed adverse effect level' (NOAEL) for toxicological effects was greater than 5000 mg/kg/day MCC, which was the highest dosage tested. These results further verify the safety of commercial MCC products for use in food and pharmaceutical applications.


Assuntos
Celulose/toxicidade , Absorção Intestinal/fisiologia , Administração Oral , Animais , Transporte Biológico , Celulose/administração & dosagem , Celulose/análise , Feminino , Íleo/química , Masculino , Microesferas , Nível de Efeito Adverso não Observado , Nódulos Linfáticos Agregados/química , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual
7.
Regul Toxicol Pharmacol ; 24(2 Pt 1): 149-54, 1996 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-8933628

RESUMO

This article presents a set of proposed guidelines for the safety assessment of new pharmaceutical excipients. These guidelines were developed by the Safety Committee of the International Pharmaceutical Excipients Council and represent a new, scientifically based approach to establishing conditions for the safe use of proposed pharmaceutical excipients utilizing various routes of human exposure. They are based upon the best currently available toxicological science and have taken the deliberations of the International Conference on Harmonization into consideration. These guidelines were developed because there are no regulatory agency guidelines currently available which specifically address the toxicological testing of a material intended for use as an excipient in pharmaceutical preparations. Only materials which have been previously permitted for use in a pharmaceutical preparation or which have been permitted for use in foods may be considered safe under current practices. If implemented, these guidelines should expedite the review of a proposed new excipient by regulatory agencies.


Assuntos
Química Farmacêutica/normas , Excipientes/efeitos adversos , Química Farmacêutica/legislação & jurisprudência , Excipientes/administração & dosagem , Guias como Assunto , Humanos , Medição de Risco
8.
JAMA ; 271(2): 146-50, 1994 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-8031346

RESUMO

OBJECTIVE: To reevaluate the risk associated with in utero exposure to lithium. DATA SOURCES AND STUDY SELECTION: Data were obtained from all published studies, in multiple languages, referenced in MEDLINE, Toxline, and the Lithium Information Center databases. Unpublished studies were not included. The search terms were lithium, pregnancy, teratogen, abnormalities (drug induced), Ebstein's anomaly, and adverse effects. DATA EXTRACTION AND SYNTHESIS: In the 1970s a very strong association was suggested between maternal lithium treatment during pregnancy and Ebstein's anomaly of the heart in the offspring. The relative risk for Ebstein's anomaly among such children was estimated to be 400 on the basis of data collected from a registry of voluntarily submitted cases. More recent controlled epidemiologic studies have consistently shown a lower risk. No women who took lithium during pregnancy were found among four case-control studies of Ebstein's anomaly involving 25, 34, 59, and 89 affected children, respectively. In two cohort studies, risk ratios of 3.0 (95% confidence interval [CI], 1.2 to 7.7) and 1.5 (95% CI, 0.4 to 6.8) for all congenital anomalies have been observed. The risk ratios for cardiac malformations in these studies were 7.7 (95% CI, 1.5 to 41.2) and 1.2 (95% CI, 0.1 to 18.3), respectively. CONCLUSION: While initial information regarding the teratogenic risk of lithium treatment was derived from biased retrospective reports, more recent epidemiologic data indicate that the teratogenic risk of first-trimester lithium exposure is lower than previously suggested. The clinical management of women with bipolar disorder who have childbearing potential should be modified with this revised risk estimate.


Assuntos
Anormalidades Induzidas por Medicamentos , Anomalia de Ebstein/induzido quimicamente , Lítio/efeitos adversos , Complicações na Gravidez/tratamento farmacológico , Anormalidades Induzidas por Medicamentos/epidemiologia , Animais , Estudos de Casos e Controles , Estudos de Coortes , Anomalia de Ebstein/epidemiologia , Feminino , Humanos , Lactente , Lítio/uso terapêutico , Gravidez , Resultado da Gravidez/epidemiologia , Fatores de Risco
9.
Agents Actions ; 32(1-2): 46-51, 1991 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-2058470

RESUMO

Food-grade carrageenan is a safe natural product prepared from seaweed. Its addition to food imparts many desirable characteristics which have allowed it to be used continuously for centuries. The long safe history of this natural food additive is confirmed by negative results in subchronic and chronic feeding studies in many animal species, mutagenicity studies and reproductive toxicity studies.


Assuntos
Carragenina/toxicidade , Aditivos Alimentares/toxicidade , Animais , Carragenina/farmacocinética , Carragenina/farmacologia , Imunidade/efeitos dos fármacos , Mutagênese , Neoplasias Experimentais/induzido quimicamente , Reprodução/efeitos dos fármacos
10.
Toxicology ; 65(1-2): 1-22, 1990 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-2274961

RESUMO

Lithium hypochlorite (LiOCl), the pool and spa sanitizer/algicide, was evaluated for genotoxicity in a battery of studies designed to evaluate potential mutagenicity, DNA damage and chromosome aberrations. LiOCl was not mutagenic in the Ames test when tested in Salmonella typhimurium strains TA98, TA100, TA1535, TA1537, TA1538 or in the hypoxanthine-guanine phosphoribosyl transferase (HGPRT) mutation assay in Chinese hamster ovary (CHO) cells without metabolic activation. LiOCl did not induce DNA damage in the unscheduled DNA synthesis assay using rat primary hepatocytes. Effects on metaphase chromosomes were evaluated in vitro in CHO cells at 12 and 18 h exposure without S9 and at 12 and 22 h following a 2 h exposure with S9. LiOCl induced a statistically significant increase in chromosome aberrations at the high dose only at both harvest times without S9 and at the late harvest time with S9. There were significant increases in chromosome aberrations at the low dose, low-mid and high doses, but not at the high mid-dose at the early harvest time with S9. However, LiOCl did not increase chromosome aberrations when tested orally in rats at maximally tolerated doses. Bone marrow cells, collected 6, 24 and 48 h after a single oral dose of LiOCl to rats (100, 500, 1000 mg/kg in males; 50, 250, 500 mg/kg in females) showed no increase in the incidence of aberrations. In general, the weight of the evidence indicates that LiOCl is not genotoxic.


Assuntos
Compostos de Lítio , Lítio/toxicidade , Mutagênicos , Animais , Biotransformação , Sobrevivência Celular/efeitos dos fármacos , Aberrações Cromossômicas , Cricetinae , Cricetulus , Dano ao DNA , Reparo do DNA , Feminino , Hipoxantina Fosforribosiltransferase/genética , Lítio/farmacocinética , Fígado/metabolismo , Masculino , Testes de Mutagenicidade , Mutagênicos/farmacocinética , Ratos , Ratos Endogâmicos
11.
Food Chem Toxicol ; 26(10): 867-80, 1988 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-3065162

RESUMO

This review focuses on the intestinal transport of macromolecules in food. Although it is known that neonates have the ability to absorb proteins from the intestine as a means of passive immunization, it has generally been assumed that adults do not retain this capability. A number of studies have shown that the adult mammalian small intestine is capable of transporting a variety of macromolecules in food to a very limited extent. The evidence demonstrating the transport of test substances in the micron-size range across the adult intestinal epithelial barrier is examined for a number of food substances and environmental contaminants. It will be shown that macromolecules can be transported across this barrier by endocytosis; by uptake into the gut-associated lymphoid tissue, and possibly by uptake into the goblet cells. It is considered highly unlikely that large micron-sized particles pass between intestinal cells due to the integrity of the tight junctions between cells that exclude particles in this size range. Quantitative estimates for macromolecular uptake are included along with a discussion of the physiological parameters influencing macromolecular transport.


Assuntos
Mucosa Intestinal/metabolismo , Animais , Amianto/farmacocinética , Transporte Biológico , Carragenina/farmacocinética , Celulose/farmacocinética , Proteínas Alimentares/farmacocinética , Humanos , Látex/farmacocinética , Substâncias Macromoleculares
15.
J Gen Physiol ; 59(4): 462-75, 1972 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-4260495

RESUMO

The relationship between active extrusion of Ca(++) from red cell ghosts and active uptake of Ca(++) by isolated red cell membrane fragments was investigated by studying the Ca(++) uptake activities of inside-out and right side-out vesicles. Preparations A and B which had mainly inside-out and right side-out vesicles, respectively, were isolated from red cell membranes and were compared with respect to Ca(++) adenosine triphosphatase (ATPase) and ATP-dependent Ca(++) uptake activities. Preparation A had nearly eight times more inside-out vesicles and took up eight times more (45)Ca in the presence of ATP compared to preparation B. Separation of the (45)Ca-labeled membrane vesicles by density gradient centrifugation showed that the (45)Ca label was localized to the inside-out vesicle fraction. In addition, the (45)Ca taken up in the presence of ATP was lost during a subsequent incubation in the absence of ATP. The rate of (45)Ca loss was not influenced by the presence of EGTA, but was slowed in the presence of La(+8) (0.1 mM) in the efflux medium. The results presented here support the thesis that the active uptake of Ca(++) by red cell membrane fragments is due to the active transport of Ca(++) into inside-out vesicles.


Assuntos
Cálcio/sangue , Membrana Celular/metabolismo , Eritrócitos/metabolismo , Adenosina Trifosfatases/metabolismo , Isótopos de Cálcio , Membrana Celular/efeitos dos fármacos , Membrana Celular/enzimologia , Centrifugação com Gradiente de Concentração , Cloretos/farmacologia , Humanos , Lantânio/farmacologia , Magnésio/farmacologia
16.
Appl Opt ; 8(6): 1225-8, 1969 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-20072410

RESUMO

The rationale, development, and experimental test of a new process for producing three-dimensional photographic projections and movies are described; the process has application to 3-D photographic prints and television, as well.

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