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Biomedical subjects

J F Borzelleca

Publications and source records attributed to J F Borzelleca.

At least 19 recordsLinked to original sources
PubMed1992

Macronutrient substitutes: safety evaluation.

Macronutrient substitutes, reduced-calorie substances used to replace organoleptic and/or functional properties of fats and sugars in the diet, may become a significant part of the diet as the trend toward lower fat and lower calorie diets continues. Procedures currently used to evaluate the safety of traditional food additives (microadditives) may be inadequate to properly assess the safety of macronutrient substitutes (macroadditives) because of the unique nature of these substances and the potentially large intakes. An evaluation procedure is proposed that recognizes the benefits to be derived from the test material, uses a structured approach to obtain animal and human nutritional and toxicological (including kinetic and dispositional) data that are critically evaluated and that provide a basis for further testing, encourages consultation with the regulatory agency (FDA), and recommends postmarketing surveillance of the macronutrient substitute. The proposed scheme differs from the traditional approach in many respects, such as using dispositional and kinetic data, assessing nutritional status, using human data collected under carefully controlled conditions early in the process, and consulting with the FDA. A case-by-case approach is recommended for safety evaluation of these macroadditives.

Animals↗
PubMed1992

Alcohol and cancer.

Explore the source record for details and available documents.

Alcohol Drinking↗
PubMed1991

A CCl4/CHCl3 interaction study in isolated hepatocytes: non-induced and phenobarbital-pretreated cells.

The purpose of this study was to evaluate an isolated hepatocyte model for predicting the in vivo hepatotoxicity of carbon tetrachloride (CCl4) and chloroform (CHCl3), alone and in combination. Response surface methodology (RSM) was used to analyze and describe the data. The interaction was evaluated for % initial K+ (cell injury) and % LDH leakage (cell death) in non-induced (untreated) and phenobarbital-pretreated suspended hepatocytes. CCl4 and CHCl3 were delivered alone and in combination in dimethyl sulfoxide (DMSO) to suspended hepatocytes. The maximum observed no-effect level (MONEL) for CCl4 in non-induced cells was 1.0 mM (LDH and K+). In induced cells, the MONEL was 0.25 mM (K+) and 0.5 mM (LDH). The MONEL for CHCl3 in non-induced cells was 5.0 mM (LDH and K+) and in induced cells was 0.5 mM (K+) and 1.0 mM (LDH). Phenobarbital pretreatment enhanced the toxicity of both CCl4 and CHCl3, alone and in combination. RSM analysis of the % initial K+ and % LDH for CCl4 and CHCl3 in combination in noninduced and induced cells showed a greater than additive interaction. The isolated hepatocyte model appears to be a promising system for evaluating the toxicity of chemical mixtures and predicting their in vivo effects.

Animals↗
PubMed1991

Lifetime toxicity/carcinogenicity studies of FD & C red no. 40 (allura red) in mice.

FD & C Red No. 40 (allura red) was fed to Charles River HaM/ICR (CD-1) (study A) and CD-1 outbred (study B) mice as a dietary admixture in two separate lifetime toxicity/carcinogenicity studies. Each study included an in utero exposure phase during which the colouring was fed at dietary concentrations of 0.0, 0.37, 1.39 or 5.19% throughout the mating, gestation and lactation periods. After random selection, the lifetime exposure phase was initiated using the same dietary concentrations with 50 mice/sex/group in study A and 100 mice/sex/group in study B. Exposure was for 104 wk in study A and 109 wk in study B. No compound-related adverse effects were observed. The no-observable-adverse-effect level in these studies was 5.19%; approximately 7300 and 8300 mg/kg body weight/day for male and female mice, respectively.

Administration, Oral↗
PubMed1990

Interactions of water contaminants. I. Plasma enzyme activity and response surface methodology following gavage administration of CCl4 and CHCl3 or TCE singly and in combination in the rat.

The joint hepatotoxicity of CCl4 and CHCl3 or TCE in male CD rats following simultaneous oral administration has been investigated. Rats with chronic indwelling arterial cannulas were administered a single oral dose of CCl4 and CHCl3 or CCl4 and TCE in 5% Emulphor at doses of 0 to 700 mg/kg. Hepatotoxicity was evaluated by measuring the activity of AST, ALT, and SDH in plasma at 0, 3, 6, 12, 24, 36, 48, and 72 hr postgavage. Response data were analyzed for interaction using response surface methodology. CCl4 alone displayed dose-dependent toxicity. TCE demonstrated little evidence of hepatotoxicity. In combination, both CCl4/CHCl3 and CCl4/TCE displayed a synergistic (supraadditive) response for peak plasma enzyme activity.

Alanine Transaminase↗
PubMed1990

Lifetime toxicity/carcinogenicity studies of FD & C Blue No. 1 (brilliant blue FCF) in rats and mice.

FD & C Blue No. 1 was fed to Charles River CD rats and CD-1 mice as a dietary admixture in lifetime toxicity/carcinogenicity studies. The rat study was conducted with an in utero phase in which the compound was administered to the F0 generation rats (60/sex/group) at dietary concentrations of 0.0%, 0.0%, 0.1%, 1.0% or 2.0%. After randomly selecting the F1 animals, the lifetime phase was initiated at the same levels with 70 rats/sex/group, including two control groups. The maximum exposure times were 116 and 111 wk for males and females, respectively. The no-observed-adverse-effect levels are dietary concentrations of 2.0% for males (1072 mg/kg body weight/day), and 1.0% for females (631 mg/kg/day) based on a 15.0% decrease in terminal body weight and decreased survival in the high-dose females compared with the combined control groups. Charles River CD-1 mice (60/sex/group) were fed FD & C Blue No. 1 as a dietary admixture at levels of 0.0%, 0.0%, 0.5%, 1.5% or 5.0% in a lifetime toxicity/carcinogenicity study. The maximum exposure time was 104 wk for both males and females. No consistent, significant compound-related adverse effects were noted. The no-observed-adverse-effect level established in this study is a dietary concentration of 5.0% (7354 mg/kg/day and 8966 mg/kg/day for male and female mice, respectively.

Animals↗
PubMed1990

Multigeneration study of FD & C Red No. 3 (erythrosine) in Sprague-Dawley rats.

Sprague-Dawley rats received dietary admixtures containing 0.0, 0.25, 1.0 or 4.0% FD & C Red No. 3 (25 rats/sex/group) in a three-generation reproduction study. Each generation was bred twice and breeders for subsequent generations were selected after weaning of the second mating from each generation. There were no compound-related adverse effects on reproductive indices and no gross anomalies were observed. The body weights of parents and pups were significantly reduced (P less than 0.05) in all generations at the 4.0% dietary concentration. Maternal body-weight gain during gestation was frequently reduced in the 1.0 and 4.0% groups. The conservative no-observed-adverse-effect level established in this study was 0.25% (approximately 149 and 255 mg/kg body weight/day for males and females, respectively).

Animals↗
PubMed1990

Comprehensive Health Effects Testing Program for Denver's Potable Water Reuse Demonstration Project.

The Comprehensive Health Effects Testing Program for the Denver Water Department's Potable Water Reuse Demonstration Project is designed to evaluate the relative health effects of highly treated reclaimed water derived from secondary wastewater compared to Denver's present high-quality drinking water. The 1 million gallon per day (1 mgd) demonstration plant provides water to be evaluated in the studies treating unchlorinated secondary treated wastewater with the following additional processes: high pH lime clarification, recarbonation, filtration, ultraviolet irradiation, activated carbon adsorption, reverse osmosis, air stripping, ozonation, and chloramination. An additional sample is obtained from the identical treatment process substituting ultrafiltration for reverse osmosis. The toxicology tests to evaluate the possible long-term health effects are chronic toxicity and oncogenicity studies in Fischer 344 rats and B6C3F1 mice and reproductive/teratology in Sprague-Dawley rats. The results of these evaluations will be correlated with microbiological, chemical, and physical test results to establish the relative quality of reclaimed water compared to all established health standards as well as Denver's pristine drinking water.

Animals↗
PubMed1989

Toxic interactions between carbon tetrachloride and chloroform in cultured rat hepatocytes.

Primary cultures of adult rat hepatocytes were incubated (1.5-16 hr) with various concentrations of CCl4 (less than or equal to 0.5 mM) and/or CHCl3 (less than or equal to 2.5 mM). Agent-dependent alterations in hepatocyte functions were assessed by measuring (1) [3H]choline incorporation into phosphatidylcholine (endoplasmic reticulum), (2) MTT (tetrazolium salt) reduction (mitochondria), and (3) AST release into medium (plasma membrane). Cultured hepatocytes incubated with 0.5 mM CCl4 displayed a significant (p less than or equal to 0.001) and rapid (1.5 hr) reduction (40%) in endoplasmic reticulum function that preceded significant (p less than or equal to 0.001) alterations in mitochondria (6-16 hr) and plasma membrane (6-16 hr) functions. CCl4-dependent alterations in liver cell functions are a result of CCl4 bioactivation since metyrapone inhibits the CCl4-mediated changes in cell functions. Response surface methods (RSM) were used to determine the influence of combinations of CCl4 and CHCl3 on liver cell MTT reduction and [3H]choline incorporation. Regression coefficients were determined for CCl4, CHCl3, and CCl4-CHCl3. All results were significant (p less than 0.0001) and implied that CCl4 was a more potent hepatotoxin in vitro than CHCl3. The RSM analysis also suggested that combinations of CHCl3 and CCl4 have greater than additive effects on MTT reduction and [3H]choline incorporation. These effects of CCl4 and/or CHCl3 on liver cell functions in vitro are consistent with liver alterations observed in vivo. Therefore, primary cultures of adult rat hepatocytes may be an appropriate model in vitro to assess the hepatotoxic potential of agents alone or in combination.

Animals↗
PubMed1989

Lifetime toxicity/carcinogenicity study of FD & C Red No. 40 (allura red) in Sprague-Dawley rats.

FD & C Red No. 40 was fed to Charles River CD (Sprague-Dawley) rats as a dietary admixture in a lifetime toxicity/carcinogenicity study. The study included a phase during which the colouring was administered to parental rats (30 of each sex per group) at concentrations of 0.0, 0.37, 1.39 and 5.19%, throughout the mating, gestation and lactation periods. The concurrent control group received the basal diet. After random selection of the first-generation rats, the lifetime phase was initiated using the same dietary concentrations with 50 rats of each sex per group. The maximum durations of exposure to the colouring were 118 and 121 for males and females, respectively. No compound-related adverse effects were observed, except for a reduction in body weight in high-dose females at the end of the study. The no-adverse-effect levels in this study were 5.19% (2829 mg/kg/day) for male rats, and 1.39% (901 mg/kg/day) for female rats.

Animals↗
PubMed1989

A CCl4/CHCl3 interaction study in isolated hepatocytes: selection of a vehicle.

Emulphor, ethanol, and dimethyl sulfoxide (DMSO) were evaluated as vehicles in studying the toxicity of CCl4 and CHCl3 in isolated hepatocytes. The appropriateness of the vehicle was determined by evaluating the following parameters: solubility of CCl4 and CHCl3 in the vehicle, cell injury (intracellular K+), cell death (LDH leakage), and lack of interaction (protection or enhanced toxicity) with CCl4 and CHCl3. The relative toxicity of the vehicles according to maximum no effect levels (v/v) was: emulphor (0.125%) greater than ethanol (1.0%) greater than DMSO (5.0%). Emulphor at toxic levels was inadequate to dissolve enough CCl4 to evaluate in this system. Ethanol (5.0, 2.5, 1.0, 0.5%) was more toxic than DMSO and interacted with both CCl4 and CHCl3 to enhance toxicity. DMSO (15.0, 5.0, 2.5%) did not significantly alter the toxicity of CCl4 and CHCl3; no interaction. These data suggest that DMSO should be the vehicle for evaluating the toxicity of CCl4 and CHCl3 and their mechanisms of action in the isolated hepatocyte.

Animals↗
PubMed1988

Chronic toxicity/carcinogenicity studies of FD & C Yellow No. 5 (tartrazine) in rats.

FD & C Yellow No. 5 was fed to Charles River CD rats as a dietary admixture in two long-term toxicity/carcinogenicity studies. The studies were conducted with an in utero phase in which the compound was administered to the F0 generation rats (60/sex/group) at levels of 0.0, 0.0, 0.1, 1.0 or 2.0% ('original study') and 0.0 or 5.0% ('high-dose study'). The concurrent control groups received the basal diet. After random selection of the F1 animals, the long-term phase was initiated using the same dietary levels with 70 rats of each sex/group, including the three control groups. The maximum exposure to the colouring was 113 and 114 wk for males and females, respectively, in the 'original' study and 122 and 125 wk for males and females, respectively, in the 'high-dose' study. No compound-related effects were noted. The no-adverse-effect level found in this study was 5.0% in the diet providing an average intake of 2641 and 3348 mg/kg/day for male and female rats, respectively.

Animals↗
PubMed1988

A chronic toxicity/carcinogenicity study of FD & C Yellow No. 5 (tartrazine) in mice.

Charles River CD-1 mice were fed FD & C Yellow No. 5 in the diet at levels of 0.0, 0.0, 0.5, 1.5 or 5.0% in a long-term toxicity/carcinogenicity study. Each group consisted of 60 males and 60 females. Maximum exposure was 104 wk for both males and females. No consistent, significant compound-related adverse effects were noted. The no-observed-adverse effect level established in this study was 5.0% (8103 mg/kg/day and 9735 mg/kg/day for male and female mice, respectively.)

Animals↗
PubMed1988

Oral toxicology studies with xylene isomers and mixed xylenes.

Xylene isomers and mixed xylenes were administered to male and female Sprague-Dawley rats to evaluate their effects on standard toxicological parameters which included body and organ weights, hematology, serum chemistries, urinalysis and histopathological examination. In the initial study, m, o- or p-xylene were administered in corn oil by gavage for 10 consecutive days at dose levels of 250, 1000 and 2000 mg/kg/day. The most noteworthy changes were increased liver weight in both sexes for all three isomers while decreases in spleen and thymus weights were seen less frequently. Rats were subsequently exposed to mixed xylenes by gavage in corn oil for 90 consecutive days at dose levels of 150, 750 and 1500 mg/kg/day. The most significant findings of the subchronic study were enlarged livers and kidneys. Histopathological evaluation of liver and kidney tissues revealed an increased incidence of minimal chronic renal disease in only female rats, while treatment related hepatic histopathological changes were not detected in either sex.

Administration, Oral↗
PubMed1987

Evaluation of the potential teratogenicity of FD & C Blue No. 2 in rats and rabbits.

Charles River CD rats (20 pregnant rats/group) received by gavage on days 6-15 of gestation 0.5% Methocel (controls, A, B and C), retinoic acid at 7.5 mg/kg/day or FD & C Blue No. 2 in doses of 25, 75 or 250 mg/kg/day. Pregnant Dutch belted rabbits (ten pregnant does/group) received by gavage on days 6-18 of gestation 0.5% Methocel (controls A, B and C), thalidomide at 150 mg/kg/day or FD & C Blue No. 2 in doses of 25, 75 or 250 mg/kg/day. All animals were observed twice daily during gestation for signs of toxicity. The animals were killed 1 day before term and appropriate maternal and foetal parameters were evaluated. There were no consistent, significant compound-related adverse effects on any of these parameters. Foetal malformations occurred in both positive control groups. Under the conditions of this study, FD & C Blue No. 2 did not exert any teratogenicity or other developmental toxicity in either rats or rabbits.

Animals↗
PubMed1987

Lifetime toxicity/carcinogenicity study of FD & C Red No. 3 (erythrosine) in rats.

FD & C Red No. 3 was fed to Charles River CD rats as a dietary admixture in two long-term toxicity/carcinogenicity studies. The studies consisted of an in utero and an F1 phase. In the former, the compound was administered to five groups of the F0 generation rats (60 of each sex/group) at levels of 0.0, 0.0, 0.1, 0.5 or 1.0% ('original study') and 0.0 or 4.0% ('high-dose study'). The concurrent control groups received the basal diet. After random selection of the F1 animals, the long-term phase was initiated using the same dietary levels and 70 rats of each sex/group, including the three control groups. Rats were exposed for a maximum of 30 months. No compound-related effects were noted in the in utero phase. Mean body weights of the female F1 rats on 4.0% FD & C Red No. 3 (3029 mg/kg/body weight/day) were significantly lower than those of controls (P less than 0.01) throughout the study. Food consumption increased in all treated groups in a dose-related manner. There were no significant effects on the haematology, serum chemistry and urinalysis and no compound-related effects on survival. In male rats receiving 4.0% FD & C Red No. 3 (2464 mg/kg/day) thyroid weights were increased, with a mean weight of 92 mg compared to 44 mg for controls, and statistically significant increases in the incidence of thyroid follicular cell hypertrophy, hyperplasia and adenomas were recorded. A numerically increased incidence of thyroid follicular adenomas in female rats given 0.5, 1.0 or 4.0% FD & C Red No. 3 was not statistically significant. The no-observed-adverse-effect levels established in these studies were 0.5% (251 mg/kg/day) for male rats and 1.0% (641 mg/kg/day) for females.

Animals↗