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D J Fort

Publications and source records attributed to D J Fort.

At least 37 records · Page 2Linked to original sources
PubMed1991

Altered developmental toxicity caused by three carrier solvents.

Many aquatic bioassays rely on chemical solvents to solubilize water-insoluble test materials. Interactions between solvents and test materials can lead to false positive or negative results. For this reason, tests for interactions between solvents and test materials were performed. The Frog Embryo Teratogenesis Assay--Xenopus (FETAX) was chosen because of its capacity to assess three different endpoints; mortality, malformation and embryo growth. Three solvents--dimethylsulfoxide (DMSO), acetone and triethylene glycol (TG)--were tested with two teratogens--methylmercury chloride (MMC) and trichloroethylene (TCE). DMSO potentiated the lethal effect of both teratogens but did not alter significantly the rate of malformation. Acetone increased the mortality for both teratogens, but only increased the MMC malformation greater than the additive effects. TG only increased the mortality and malformation with TCE. There were additive effects for growth for all solvents with the teratogens. The carrier solvents caused interactions even at their no-observable-effect concentration (NOEC). Therefore, the choice of carrier solvent should be made with caution. This study shows that different results can occur depending on the solvent used, and that a difference in one endpoint does not necessarily change the other endpoints.

Acetone↗
PubMed1991

Assessment of the developmental toxicity of ascorbic acid, sodium selenate, coumarin, serotonin, and 13-cis retinoic acid using FETAX.

The developmental toxicity of five compounds was evaluated with the Frog Embryo Teratogenesis Assay: Xenopus (FETAX) and the results were compared to mammalian literature. Small cell Xenopus laevis blastulae were exposed to ascorbic acid, sodium selenate, coumarin, serotonin and 13-cis retinoic acid for 96 hr. Three separate static-renewal assays were conducted for each compound. Teratogenic potential of the test materials was determined based on Teratogenic Index values [TI = LC50/EC50 (malformation)], types and severity of induced malformations and embryo growth. Ascorbic acid had little or no teratogenic potential. Sodium selenate and coumarin tested as having moderately positive teratogenic potential. Serotonin scored as having moderately strong teratogenic potential and 13-cis retinoic acid scored as having strong teratogenic potential. Results were consistent with mammalian data and support the use of FETAX for the screening of developmental toxicants.

Abnormalities, Drug-Induced↗
PubMed1991

Assessing the efficacy of an Aroclor 1254-induced exogenous metabolic activation system for FETAX.

The developmental toxicity of N-nitrosodimethylamine (NDMA) and trichloroethylene (TCE) was assessed with Frog Embryo Teratogenesis Assay: Xenopus (FETAX). Late Xenopus laevis blastulae were exposed to NDMA and TCE for 96-h in two separate static-renewal tests with and without the presence of three differently induced exogenous metabolic activation systems (MAS). The MAS consisted of Aroclor 1254-induced (Aroclor 1254 MAS), isoniazid-induced (INH MAS), and a post-isolation mixture (mixed MAS) of Aroclor 1254- and isoniazid-induced rat liver microsomes. Addition of the INH MAS and the mixed MAS increased the Teratogenic Index [TI = LC50/EC50 (malformation)] of NDMA and TCE nearly 2.0- and 2.1-fold and 2.1- and 1.7-fold, respectively. Inclusion of the Aroclor 1254 MAS did not alter the developmental toxicity of either compound. Based on TI values, embryo growth, and types and severity of induced malformations, both NDMA and TCE were developmentally toxic. Use of post-microsome isolation mixtures from differentially induced rat livers increased the efficacy of the exogenous MAS routinely used by FETAX.

Abnormalities, Drug-Induced↗
PubMed1990

Analysis of the mechanism of isoniazid-induced developmental toxicity with frog embryo teratogenesis assay: Xenopus (FETAX).

The developmental toxicity of isoniazid (INH) and the metabolites acetylhydrazide (AH) and isonicotinic acid (INA) were examined with the frog embryo teratogenesis assay-Xenopus (FETAX). Late Xenopus laevis blastulae were exposed to INH, AH, and INA for 96 h in two separate static-renewal tests with and without the presence of three differently induced metabolic activation systems (MAS). The MAS consisted of uninduced, Aroclor 1254-induced, and INH-induced rat liver microsomes. Addition of the INH-induced MAS decreased the 96 h LC50 of INH and AH approximately 1.6-fold and 7.9-fold, respectively. The 96 h EC50 (malformation) of INH was virtually unaffected; however, the INH-MAS decreased the teratogenic index (TI) [96 h LC50/96 h EC50 (malformation)] nearly 1.8-fold. The 96 h EC50 (malformation) of AH increased approximately 2.0-fold, decreasing the teratogenic index value 15.8-fold. INA yielded a teratogenic index value of 2.5. Neither the uninduced MAS nor the Aroclor 1254-induced MAS had an effect on any of the compounds tested and none of the MAS affected the developmental toxicity of INA. Results from this study suggest that mixed functional oxidase metabolism may alter the developmental toxicity of INH in vitro by producing a more embryolethal, but less teratogenic metabolite(s) than INH or AH themselves. Results are indicative of the utility and versatility of FETAX in evaluating toxicological mechanisms of teratogenesis in vitro.

Animals↗
PubMed1990

Use of Frog Embryo Teratogenesis Assay-Xenopus and an exogenous metabolic activation system to evaluate the developmental toxicity of diphenylhydantoin.

The teratogenic potential of diphenylhydantoin (DPH) and hydroxylated metabolites (HPPH) was evaluated with the Frog Embryo Teratogenesis Assay--Xenopus (FETAX). Embryos of the South African clawed frog, Xenopus laevis were exposed to DPH and HPPH in two separate static-renewal experiments with and without the presence of an exogenous metabolic activation system (MAS) for 96 hr. Two separate dose-response tests were also conducted with DPH and HPPH with a MAS modulated by various mixed functional oxidase inhibitors [carbon monoxide (CO) (broad spectrum cytochrome P450), cimetidine (mainly cytochrome P450), and ellipticine (cytochrome P448)] and an epoxide hydrolase inhibitor (cyclohexene oxide). Assessment of the potential teratogenic hazard was based on teratogenic indices [TI = 96-hr LC50/96-hr EC50 (malformation)], types and severity of malformations, and embryo growth endpoints. Addition of the intact MAS to DPH increased the 96-hr LC50 and EC50 (malformation) from approximately 74.5 and 32.4 mg/liter to 126.4 and 62.9 mg/liter, respectively. The TI was reduced 1.2-fold. Both p-HPPH and m-HPPH were much less developmentally toxic than DPH. CO and cimetidine inhibition of cytochrome P450 maintained much of the developmental toxicity of DPH, whereas ellipticine inhibition of cytochrome P448 was much less effective in maintaining the developmental toxicity of DPH. Cyclohexene oxide inhibition of epoxide hydrolase markedly increased DPH-induced embryotoxicity decreasing the 96-hr LC50 from approximately 74.5 to 38.6 mg/liter. These results suggest that unmetabolized DPH and an embryotoxic epoxide intermediate may serve as the teratogenic species in FETAX.

Abnormalities, Drug-Induced↗
PubMed1990

Further validation of FETAX: evaluation of the developmental toxicity of five known mammalian teratogens and non-teratogens.

The developmental toxicity of five compounds was evaluated with the Frog Embryo Teratogenesis Assay: Xenopus (FETAX). Late Xenopus laevis blastulae were exposed to 5-azacytidine, methotrexate, pseudoephedrine, aspartame, and amaranth for 96 h. Three separate static-renewal assays were conducted for each compound. Based on Teratogenic Index [LC50/EC50 (malformation)] values, types and severity of induced malformations, and embryo growth, 5-azacytidine and methotrexate tested as having strong teratogenic potential. Pseudoephedrine scored as having moderate teratogenic potential, but amaranth and aspartame had little or no teratogenic potential. Results support the use of FETAX for the screening of developmental toxicants.

Abnormalities, Drug-Induced↗
PubMed1989

Evaluation of the developmental toxicity of five compounds with the frog embryo teratogenesis assay: Xenopus (FETAX) and a metabolic activation system.

The potential teratogenic hazard of five compounds was evaluated using the Frog Embryo Teratogenesis Assay--Xenopus (FETAX) and a metabolic activation system. Embryos of the South African clawed frog, Xenopus laevis, were exposed to (i) three compounds suspected to be proteratogenic in mammalian test systems--[2-acetylaminofluorene (2-AAF), rifampicin (RA) and benzo[a]pyrene (BP)] for 96 h; (ii) one compound unaffected by mixed-functional oxidase (MFO) metabolism--ZnSO4; (iii) one compound thought to be inactivated by cytochrome P-450--cytochalasin D (CD). Two separate static renewal tests were conducted with and without the presence of an exogenous metabolic activation system (MAS). The metabolic activation system consisted of Aroclor 1254-induced rat liver microsomes. The teratogenic potential of each compound and the effects of metabolic activation were based on teratogenic indices [TI = 96 h LC50/96 h EC50 (malformation)], types and severity of malformation, and effects on embryo growth. Metabolic activation increased the potential teratogenic hazard of 2-AAF, RA and BP by TI factors of 1.3, 2.8 and 6.8, respectively. The teratogenic potential of ZnSO4 was virtually unaffected by the MAS. The MAS significantly reduced the teratogenic potential of CD by a TI factor of 2.7. These results demonstrate the utility and importance of a MAS for in vitro developmental toxicity screens such as FETAX. Consistent use of a MAS with FETAX should reduce the number of potential false-positive and false-negative test results.

Animals↗
PubMed1989

Developmental toxicity testing with FETAX: evaluation of five compounds.

The teratogenic potential of five compounds was evaluated with FETAX (Frog Embryo Teratogenesis Assay: Xenopus). Early embryos of Xenopus laevis were exposed for 96 h to 6-aminonicotinamide (6-AN), isoniazid (INH), urethane, nitrilotriacetate (NTA) or sodium cyclamate, in two separate static-renewal tests of each compound. Based on Teratogenic Index values, growth endpoints and the types and severity of the induced malformations, 6-AN, INH and urethane scored as having strong teratogenic potential. NTA and sodium cyclamate had little or no teratogenic potential. The results support continued evaluation of FETAX as a screening assay for chemical teratogens.

Abnormalities, Drug-Induced↗
PubMed1988

Development of a metabolic activation system for the frog embryo teratogenesis assay: Xenopus (FETAX).

FETAX (frog embryo teratogenesis assay: Xenopus) is a 96-hr teratogenesis screening assay using embryos of the South African clawed frog, Xenopus laevis. Since Xenopus embryos have limited xenobiotic metabolism through 96 hr of development, we have developed an in vitro metabolic activation system employing Aroclor 1254-induced rat liver microsomes. By adding an exogenous source of mixed functional oxidase (MFO) activity, we may more accurately assess the teratogenic risk of proteratogenic compounds. Xenopus embryos were cocultured with varying concentrations of cyclophosphamide (CP), Aroclor 1254-induced microsomal protein, an NADPH-generating system, and antibiotics in a static renewal fashion for 96 hr. Residual Aroclor 1254 remaining in the microsomes was successfully reduced during purification to levels that had no significant effect on embryo survival and development. The results of three definitive dose-response tests performed with CP revealed that activation reduced the 96 hr LC50 from 8.0 to 1.4 mg/ml (5.7-fold). The 96-hr EC50 (malformation) was reduced from 6.2 to 0.4 mg/ml (15.5-fold). Activation also increased the types and severity of malformation and reduced embryonic growth. Aroclor 1254-induced rat liver microsomes may be used as an acceptable in vitro metabolic activation system for FETAX.

Animals↗
PubMed1988

Evaluation of the developmental toxicity of nicotine and cotinine with frog embryo teratogenesis assay: Xenopus.

The teratogenic potential of nicotine and a primary metabolite, cotinine, was examined with FETAX (Frog Embryo Teratogenesis Assay: Xenopus). Early embryos of Xenopus laevis were exposed for 96 hr to nicotine or cotinine in two separate static renewal tests of each compound without addition of the metabolic activation system (MAS). Two static renewal tests of nicotine with the MAS were also conducted. Addition of the MAS to nicotine reduced the LC50 from an average of 136 to 20 mg/L. However, the EC50 (malformation) was increased from 0.4 to 5.8 mg/L upon activation. The LC50 and EC50 values for cotinine averaged 4,340 and 720 mg/L, respectively. Based on mortality/malformation index values, growth end points, and the types and severity of the induced malformations, nicotine and cotinine scored as potential teratogens. Metabolism of nicotine to more polar metabolites increased the nicotine concentration required to induce terata. The results are indicative of the versatility of FETAX in developmental toxicity testing.

Animals↗
PubMed1985

The beneficial effect of amrinone on acute drug-induced heart failure in the anaesthetised dog.

Amrinone, a positive inotropic-vasodilator agent, was administered to anaesthetised dogs in an attempt to reverse heart failure induced by drugs possessing negative inotropic properties. Propranolol, a beta-adrenergic blocker; verapamil, a calcium slow-channel blocker procainamide, a type 1 antiarrhythmic agent; or sodium pentobarbital, a barbituate; administered as a bolus injection and/or infusion, produced a sustained depression in canine cardiac function. Cardiac depression was characterised by a greater than 40% reduction in cardiac contractile force (CF) and maximum left ventricular pressure development (LV dp/dtmax), a 30 to 50% reduction in cardiac output (CO) and concomitant increases in mean central venous or mean right atrial blood pressures (CVP, RAP, respectively). Amrinone, when administered intravenously as a bolus injection (1 or 3 mg X kg-1) plus an infusion (0.03 or 0.1 mg X kg-1 X min-1) reversed the depression in cardiac function by increasing CF, CO and LV dp/dtmax and decreasing preload CVP or RAP in all four drug-induced failure models. Due to the vasodilator properties of amrinone, afterload, total peripheral resistance (TPR), was reduced in verapamil and procainamide failures as well as in propranolol failure, the only model where TPR increases. In another model of heart failure, in which ouabain-induced arrhythmias preceded procainamide toxicity, amrinone was also an effective cardiotonic agent. Ouabain's inotropic effect was studied in propranolol-induced heart failure. Although an increase in LV dp/dtmax and a decrease in CVP were noted, ouabain (40 micrograms X kg-1 iv) increased TPR and had little effect on the depression in CF and CO. Drug-induced models of heart failure were useful pharmacological tools for evaluating the cardiotonic agent's ability to overcome severe cardiac depression. In propranolol-, verapamil-, procainamide-, and pentobarbital-induced cardiac toxicity, amrinone could be of therapeutic value.

Aminopyridines↗
PubMed1978

A method of evaluating the impact of services at a comprehensive community mental health center.

Efforts of one community mental health center to develop a system of program evaluation designed to meet criteria mandated by recent Federal legislation are described. This approach represents a comprehensive evaluation system with the capability of objectively assessing: (a) patterns of utilization of services, (b) satisfaction with services as well as the availability, accessibility, and acceptability of services, and (c) the quality of direct mental health services as measured by attainment of individualized treatment goals. A rationale for the development of this system as well as a description of the modifications and automatization of the procedure are included. Initial results are presented which pertain to 2,900 goals written for 1,250 clients receiving treatment within five of the Center's direct service elements.

Attitude of Health Personnel↗
PubMedDate not supplied

FETAX interlaboratory validation study: phase III--Part 1 testing.

The Frog Embryo Teratogenesis Assay-Xenopus (FETAX) is a 96-h whole embryo developmental toxicity screening assay that can be used in ecotoxicology and in detecting mammalian developmental toxicants when an in vitro metabolic activation system is employed. A standardized American Society for Testing and Materials (ASTM) guide for the conduct of FETAX has been published, along with a companion atlas that aids in embryo staging and identifying malformations. As part of the ASTM process, a three-phase interlaboratory validation study was undertaken to evaluate the repeatability and reliability of FETAX. Seven different participants collaborated in the study. In Phase I, FETAX proved to be more repeatable and reliable than many bioassays. However, some excessive variation was observed in a few laboratories. An initial lack of assay experience by some technicians caused variation. Phase II showed far less intra- and interlaboratory variability than Phase I. Non-teratogens showed the most consistent results, while more variability was observed for the two teratogens tested. Interlaboratory coefficient of variation values for all endpoints ranged from 7.3 to 54.7. Phase III--Part 1, using coded samples and test concentration ranges selected by each laboratory, showed results similar to Phase I. Analysis of the causes of variation suggested that some technicians judged some embryos to be malformed while others consistently judged similar embryos as normal. Concentration ranges tested by some of the laboratories varied greatly and a new protocol for selecting concentrations for initial testing was written to reduce variation from this source. Testing to date suggests that FETAX is as repeatable and reliable as other standard bioassays.

Aminopropionitrile↗
PubMedDate not supplied

Phase III interlaboratory study of FETAX. Part 3. FETAX validation using 12 compounds with and without an exogenous metabolic activation system.

FETAX (Frog Embryo Teratogenesis Assay-Xenopus) is a 96-h whole-embryo developmental toxicity screening assay that can be used in ecotoxicology and in detecting mammalian developmental toxicants when an in vitro metabolic activation system is employed. A standardized American Society for Testing and Materials (ASTM) guide for the conduct of FETAX has been published, along with a companion atlas that helps in embryo staging and in identifying malformations. As part of the ASTM process, an interlaboratory validation study was undertaken to evaluate the repeatability and reliability of FETAX and to evaluate the potential teratogenic hazard of 12 compounds. Three different laboratories participated in the study. All three participating laboratories had extensive experience with the assay. FETAX intralaboratory and interlaboratory variability, as judged by coefficients of variation, were very low. Potential teratogenic hazard was evaluated using two major criteria from FETAX experiments employing metabolic activation systems (MAS). These were the teratogenic index TI (TI = 96-h lc(50)/96-h ec(50) (malformation)) and the minimum concentration that inhibits growth (MCIG). A compound was considered teratogenic by this criterion when the MCIG was significantly different from controls at concentrations below the 30% level of the MAS 96-h lc(50). Based on the results of this and other studies, a decision table was constructed in order to evaluate additional studies. Severity of malformations caused, especially near the MAS 96-h ec(50) (malformation), were also evaluated. Four compounds were non-teratogenic but two compounds were clearly teratogenic. The remaining six compounds were ranked as equivocal teratogens. The results were discussed in light of the difficulty of producing an adequate decision table. FETAX proved to yield repeatable and reliable data as long as care was taken during range-finding and technicians were adequately trained. The MAS was essential in using FETAX to predict developmental hazard in mammals, and still requires further development.

Acetates↗
PubMedDate not supplied

Preliminary validation of a short-term morphological assay to evaluate adverse effects on amphibian metamorphosis and thyroid function using Xenopus laevis.

Short-term static-renewal studies were performed on Xenopus laevis embryos with 16 selected test materials from day 50 (stage 60) to day 64 (stage 66) (14-day test) to evaluate effects on tail resorption and thyroid function. Of the 16 test materials, nine were found to inhibit significantly the rate of tail resorption, four were found to stimulate metamorphosis and three had no appreciable effect on the rate of metamorphosis. In an effort to determine if the morphological effects observed were related to alteration in thyroid activity, measurement of triiodothyronine (T3) in the test organisms and coadministration studies using thyroxine (agonist) or propylthiouracil (antagonist) were performed based on the morphological response noted during tail resorption. Of the nine compounds found to inhibit the rate of tail resorption, six were found to reduce the levels of T3. In each case, the inhibitory response could be at least partially alleviated by the co-administration of thyroxine. Larvae exposed to the four stimulatory agents had somewhat elevated levels of T3 and were responsive to propylthiouracil antagonism. These results suggest that 12 of the 14 compounds tested in this study that altered the rate of tail resorption did so via the thyroid axis. Overall, the X. laevis model appeared to be a suitable system for evaluating the impact of environmental agents and chemical products on thyroid function.

Animals↗