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B Ekwall

Publications and source records attributed to B Ekwall.

At least 19 recordsLinked to original sources
PubMed2001

In vitro long-term cytotoxicity testing of 27 MEIC chemicals on Hep G2 cells and comparison with acute human toxicity data.

Within the framework of the EDIT (Evaluation guided Development of In vitro Toxicity and toxicokinetic tests) programme, the long-term cytotoxicity of 27 chemicals was investigated on Hep G2 cells. The first step in the experiments was to determine the PI50(24h) of the chemicals. This is the concentration of compound needed to reduce the total protein content by 50% after 24 h of treatment. In the long-term experiments the chemicals were tested in six different concentrations, using the PI50(24h) as maximum concentration. The cells were treated twice a week with the same concentration of test compound and were trypsinised and counted once a week (dynamic culture). The number of cells was compared to the number of cells of the control. Three major long-term cytotoxicity patterns could be distinguished. After 6 weeks, the EC50(6w)s were determined. This is the concentration of compound needed to reduce the number of cells by 50% after 6 weeks of treatment. These values were compared with the PI50(24h). A good correlation was found for the 27 chemicals (r(2)=0.860). After 6 weeks, the concentration of test compound needed to reduce the total cell protein content by 50% after 24 h after 6 weeks of pretreatment of the cells with a particular concentration of test compound was measured: the PI50(24h-6w). For the majority of compounds there is no difference between the PI50(24h) and the PI50(24h-6w). For ethanol, arsenic (III) oxide, verapamil hydrochloride and orphenadrine, the PI50(24h-6w) increased in comparison to the PI50(24h). For some compounds a doseresponse was observed, indicating that the cells have become more resistant or more sensitive. Linear regression analysis revealed a good correlation (r(2)=0.709) between the EC50(6w) and the human acute toxicity. All these data indicate that a good alternative test may be found for predicting the long-term human toxicity.

Carcinoma, Hepatocellular↗
PubMed1989

MEIC--a new international multicenter project to evaluate the relevance to human toxicity of in vitro cytotoxicity tests.

A new international project to evaluate the relevance for human systemic and local toxicity of in vitro tests of general toxicity of chemicals has been organized by the Scandinavian Society of Cell Toxicology under the title Multicenter Evaluation of In Vitro Cytotoxicity (MEIC). The basic assumptions underlying the project, as well as the practical goals and the design of the program are outlined. The list of the first 50 reference chemicals is presented. The chemicals are an otherwise unbiased selection of compounds with known human acutely lethal dosage and blood concentrations, including LD50-values in the rat or mouse. Most agents also have other data on human toxicity and toxicokinetics, including more extensive animal toxicity data. International laboratories already using or developing in vitro tests of various partial aspects of general toxicity are invited to test the substances, the results of which will be evaluated by us. The predictivity of the in vitro results for both partial and gross human toxicity data will be determined with combined use of univariate regression analysis and soft multivariate modeling. The predictivity of the in vitro results will be compared with the predictivity of conventional animal tests for the same chemicals. Finally, batteries of tests with optimal prediction power for various types of human toxicity will be selected. The need for and possible uses of such batteries are discussed.

Animals↗
PubMed1983

Screening of toxic compounds in mammalian cell cultures.

The cytotoxic concentrations of about 100 randomly selected drugs and chemicals, tested on HeLa cells in the MIT-24 system and/or in primary cultures of fetal chicken cells, were compared with the lethal doses and/or concentrations of the agents in the mouse and in man. Most agents (80%) had a similar toxicity in vitro and in vivo, suggesting a lethal interference in man with basal functions common to all specialized human tissues as well as cultured cells, i.e., basal cytotoxicity. This high frequency of basally cytotoxic agents opens possibilities for screening chemicals for toxicity and for studying cytotoxic mechanisms with a standard battery of a few appropriate cell tests. This battery may be used in three ways: (1) to study cytotoxic mechanisms of all chemicals, and apply the resulting knowledge to understanding toxicity in man of basally cytotoxic agents; (2) to supplement conventional animal tests in acute toxicity test programs; (3) to screen chemicals and extracts for their potential basal cytotoxicity. To validate these ideas and to select suitable tests for the battery, results from cytotoxicity tests on a wide variety of chemicals in several in vitro systems must be compared with one another and with the toxicity of the agents in animals and man.

Animals↗
PubMed1982

Toxicity of 29 plasticizers to HeLa cells in the MIT-24 system.

The toxicity to HeLa cells of 29 plasticizers was determined in the MIT-24 test system. The 7-day IC50 for HeLa cells varied from 260 to 1.5 g/l. Phthalates, adipates, sebacates, azelates and phosphates with long carbon chain alcohols were very non-toxic to the cells, probably due to insolubility in water of the compounds, while the citrates, some phosphates and the 2 polymer plasticizers had a higher toxicity to the cells. A comparison of the HeLa cytotoxicity with the toxicity in vitro to other cells for 7 plasticizers showed a similarity of the cytotoxicity to all cell types. A comparison of the HeLa cytotoxicity for 20 plasticizers with i.p. lethal dosage in rodents demonstrated a rough similarity of values, suggesting a toxicity in rodents of the compounds by toxic interference of the agents with basal functions and structures of tissues (basal cytotoxicity). Tissue culture studies of the cytotoxic mechanisms of the plasticizers therefore could reveal modes of toxic action in vivo.

Animals↗
PubMed1982

In vitro comparative toxicity of selected drugs and chemicals in HeLa cells, Chang liver cells, and rat hepatocytes.

The cytotoxicity of 16 agents was compared in four different in vitro cellular systems: HeLa cells, Chang liver cells, freshly isolated rat hepatocytes in suspension, and primary monolayer cultures of postnatal rat hepatocytes. The compared cytotoxicity values had been obtained by different techniques: inhibition of spreading of HeLa cells by 50% after 24 hr incubation and leakage of lactate dehydrogenase (LDH) by 50% in Chang liver cells, isolated rat hepatocytes in suspension, and primary cultures of rat hepatocytes after 4, 1, and 3 or 24 hr incubation with the chemicals. Carbon tetrachloride, halothane, acetaminophen, and tetracycline were more toxic to the hepatocytes compared with the two cell lines. Alcohol, sodium salicylate, caffeine, papaverine, nitrofurantoin, and five tricyclic antidepressants showed similar toxicity in all compared cellular systems. Thus, the agents with a known or suspected metabolism-mediated liver toxicity indeed had a high differential hepatotoxicity in vitro.

Animals↗
PubMed1981

Preliminary studies on the validity of in vitro measurement of drug toxicity using HeLa cells. IV. Therapeutic effects and side effects of 50 drugs related to the HeLa toxicity of the therapeutic concentrations.

As a measure of the relevance to human drug effects of drug cytotoxicity in vitro, calculated and actual therapeutic blood concentrations of 50 drugs were divided by their 50% inhibitory concentrations for HeLa cells in vitro to make up three types of cytotoxic quotients (CQTv, CQTd, and CQTr). When the various quotients were compared with known cytotoxic effects of the drugs the parameters correlated well. While most drugs at single dosage reached concentrations with low quotients (CQTv and CQTd) corresponding to few reported cytotoxic effects and side effects, a substantial number of drugs at repeated dosage reached concentrations with high quotients (CQTr) corresponding to known or suspected cytotoxic action in man.

Cell Survival↗
PubMed1980

Toxicity to HeLa cell of 205 drugs as determined by the metabolic inhibition test supplemented by microscopy.

The toxicity of 205 drugs to HeLa cells was evaluated by the Metabolic Inhibition Test supplemented by microscopy. Two end points of cyto-inhibition were estimated; total and partial inhibition after 24 h, based on absence or scarcity of spindle-shaped cells, respectively, and total and partial inhibition after 7 days, based on different degrees of basic pH change of the phenol red included in the cell medium. Direct drug-induced pH changes and precipitates in the cultures were also recorded. Many drugs were found to induce a culture zone with a particularly low pH after 7 days of incubation, at concentrations below the cyto-inhibitory concentration. Forty-three drugs regularly caused this hyperacid reaction, while 44 drugs caused the reaction irregularly. Since the reaction was always continuous with the cyto-inhibitory zone, it was provisionally judged to represent excitatory cell injury. Since many of the drugs which regularly induced the reaction are also known to induce proliferation of the endoplasmic reticulum in various cells, the reaction may be related to this and allied effects. Many drugs that are known to accumulate in cells displayed a high inhibitory toxicity, which might have been due to the paucity of cells in the test system. However, the high 7-day inhibitory toxicity shown by antineoplastic and some anti-inflammatory drugs, including triamterene and disulfiram, may constitute a genuine antimetabolic drug action. Seven grand mal antiepileptics were only very slightly toxic as compared with their precipitating tendency, which may be of significance in their therapeutic action.

Drug Evaluation, Preclinical↗
PubMed1980

Screening of toxic compounds in tissue culture.

To screen toxicity of chemicals most often easily manageable cultures of less differentiated cells have been used. This work includes 3 fields: (i) Screening of chemicals and fermentation broths for their cytoinhibitory effect, to predict antineoplastic activity. A related practical approach is to achieve optimal antitumour drug therapy by testing drugs on cultures of tumour cells from the patient. (ii) Screening of metal and plastic materials used in medicine, surgery and dentistry for their cytoinhibitory effect to predict local irritation. (iii) Screening of the mutagenicity or transformation capacity of chemicals in tissue culture, to predict their carcinogenicity. In addition, organ-specific cultures of most specialized cells (hepatocytes, ova, nerve cells, heart cells, skin cells, respiratory mucosa, and macrophages) have also been used to predict drug action on corresponding targets in the body. The author's group has focused on 2 new uses of standard cells for screening chemical toxicity: (i) Comparisons of in vitro cytotoxicity with in vivo toxicity of 85 randomly selected drugs indicated that for most drugs a systemic lethal action was brought about by cytotoxicity. A screening model is advocated by which results of cytotoxicity tests are compared with systemic toxicity in vivo to evaluate the systemic cytotoxicity of chemicals. (ii) Combinations of compounds with a cytotoxic lethal action in man indicated by the previous method have been screened in vitro for their combined systemic toxicity. By systematic comparison of results from standardized in vitro tests with in vivo toxicity, steps have been taken to resolve the question of the relevance of screening in tissue culture and to contribute to the development of an emerging subdiscipline to toxicology -- in vitro cytotoxicology.

Animals↗
PubMed1980

Preliminary studies on the validity of in vitro measurement of drug toxicity using HeLa cells. I. Comparative in vitro cytotoxicity of 27 drugs.

Combined drug toxicity to HeLa cells was studied in vitro with use of the microtitre MIT-24 test system. Whether drug toxicity to HeLa cells is representative of drug toxicity to other cultivated cells was investigated by a comparison of the MIT-24 toxicity of 27 drugs to HeLa cells with their toxicity to various permanent cell lines and more differentiated primary cell cultures as reported in the literature, together with original recordings of the MIT-24 toxicity of 9 of the drugs to human fetal kidney cells. A similarity of drug toxicity to all cell types was found. Thus the MIT-24 recordings may be representative of a basal drug cytotoxicity, probably corresponding to local drug irritation and to causal systemic drug toxicity.

Cell Survival↗
PubMed1980

Preliminary studies on the validity of in vitro measurement of drug toxicity using HeLa cells. II. Drug toxicity in the MIT-24 system compared with mouse and human lethal dosage of 52 drugs.

By a comparison of the 50% inhibitory concentration to HeLa cells in the microtitre Metabolic Inhibition Test supplemented by microscopy of cells after 24 h incubation (the MIT-24 test), of 52 drugs with their mouse i.v. LD50 and available approximate human lethal dosage, 7 were found to have a human LD considerably lower than HeLa IC50, indicating a lethal action to specialized functions of the human body not found in vitro, while 39 were found to have a gross similarity between the human LD and HeLa IC50.

Animals↗
PubMed1980

Preliminary studies on the validity of in vitro measurement of drug toxicity using HeLa cells. III. Lethal action to man of 43 drugs related to the HeLa cell toxicity of the lethal drug concentrations.

The human lethal plasma concentrations of 46 drugs were divided by their IC50 for HeLa cells in vitro to make up a series of cytotoxic quotients (CQLv). CQLv was then compared with the recorded lethal action to man of 43 of the drugs. While the 7 drugs with the lowest CQLv values produce a non-cytotoxic interference with neuro-transmission, most of the remaining 36 drugs have a known local or systemic cytotoxicity to man. A majority of the 36 drugs induces a non-specific central nervous system (CNS)-depression at lethal dosage, intermingled with function loss from organs outside CNS in proportion to decreasing drug accumulation in CNS cells and increasing CQLv. The remaining drugs which do not penetrate CNS cells and at lethal dosage induce a widespread injury and function loss of tissues outside the CNS, have a CQLv near unity. Non-specific CNS-depression may thus be the primary human reaction to lethal systemic drug cytotoxicity, while widespread drug injury to various tissues outside CNS--conventionally considered to be cytotoxic in origin--may be the obligatory human reaction to drugs that do not penetrate cells well. The present findings indicate a relevance to human toxicity of the HeLa toxicity for most drugs.

Cell Survival↗
PubMedDate not supplied

Comparison of in vivo acute lethal potency and in vitro cytotoxicity of 48 chemicals.

The cytotoxicity of 48 compounds included in the MEIC (Multicenter Evaluation of In Vitro Cytotoxicity) list was determined in cultures of rat hepatocytes, McCoy, and MDBK cells. The average minimum concentration of each compound inducing cytotoxicity was measured in each cell type. The cytotoxicity values were then compared with published oral LD50 values for rats and mice. The logarithmic transformation of in vivo toxic doses and the corresponding in vitro cytotoxic concentrations showed a statistically significant correlation between the in vitro and in vivo values. The results show that an accurate in vivo LD50 dose could be predicted from in vitro data for at least 75% of the selected compounds. It is hoped that this finding will not only stimulate others to pursue in vitro technique but will eventually lead to elimination of the in vivo LD50 test.

Animal Testing Alternatives↗