clinical toxicology

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MEIC Evaluation of Acute Systemic Toxicity

Björn Ekwall, Cecilia Clemedson, Balcarras Crafoord

The Multicenter Evaluation of In Vitro Cytotoxicity (MEIC) programme was set up to evaluate the relevance for acute human systemic toxicity of in vitro cytotoxicity tests. At the end of the programme in the summer of 1996, 29 laboratories had tested all 50 reference chemicals in 61 cytotoxicity assays. As a necessary prerequisite to the forthcoming evaluation papers of this series, this paper presents the animal and human toxicity data of the programme. This database contains tabulated handbook data for the 50 chemicals, on: a) oral rat and mouse LD50 values; b) acute oral lethal doses in humans; c) clinically measured acute lethal serum concentrations in humans; d) acute lethal blood concentrations in humans measured postmortem; e) peaks from curves of an approximate 50% lethal blood/serum concentration over time after ingestion (LC50 curves), derived from a compilation of human acute poisoning case reports; f) human kinetics of single doses, including absorption, peak time, distribution/elimination curve, plasma half-life, distribution volume, distribution to organs (notably brain), and blood protein binding; and g) qualitative human acute toxicity data, including lethal symptoms, main causes of death, average time to death, target organs, presence of histopathological injury in target organs, presence of toxic metabolites, and known or hypothetical mechanisms for the lethal toxicity. The rationales for selection of the human toxicity data are also noted. The methods used to compile the in vivo toxicity data are described, including a presentation of a new method of constructing LC50 curves. Finally, the merits and shortcomings of the various human toxicity data for evaluation purposes are discussed.
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MEIC Evaluation of Acute Systemic Toxicity

Björn Ekwall, Frank A. Barile, Argelia Castano, Cecilia Clemedson, Richard H. Clothie, Paul Dierickx, Barbro Ekwall, Margherita Ferro, Geirid Fiskesjö, Lourdes Garza-Ocañas, Maria José Gómez-Lechón, Michael Gülden, Tony Hall, Boris Isomaa, Anne Kahru, Gustaw Kerszman, Udo Kristen, Manabu Kunimoto, Sirpa Kärenlampi, Lillemor Lewan, Anatoly Loukianov, Tadao Ohno, Guido Persoone, Lennart Romert, Thomas W. Sawyer, Ravi Shrivastava, Helmut Segner, Annalaura Stammati, Noriho Tanaka, Matteo Valentino, Erik Walum and Flavia Zucco

The Multicenter Evaluation of In Vitro Cytotoxicity (MEIC) programme was set up to evaluate the relevance for human acute toxicity of in vitro cytotoxicity tests. At the end of the project in 1996, 29 laboratories had tested all 50 reference chemicals in 61 cytotoxicity assays. Five previous articles have presented the in vitro data and the human database to be used in the evaluation. This article presents three important parts of the final evaluation: a) a comparison of rat and mouse oral LD50 with human acute lethal doses for all 50 chemicals; b) a display of the correlations between IC50 (concentration causing 50% inhibition) values from all 61 assays and three independent sets of human acute lethal blood concentrations, i.e. clinical lethal concentrations, forensic lethal concentrations, and peak concentrations; and c) a series of comparisons between average IC50 values from ten human cell line 24-hour assays and human lethal blood concentrations. In the latter comparisons, results from correlations were linked with known human toxicity data for the chemicals, to provide an understanding of correlative results. This correlative/mechanistic approach had the double purpose of assessing the relevance of the in vitro cytotoxicities, and of testing a series of hypotheses connected with the basal cytotoxicity concept. The results of the studies were as follows. Rat LD50 predictions of human lethal dosage were only relatively good (R2 = 0.61), while mouse LD50s gave a somewhat better prediction (R2 = 0.65). Comparisons performed between IC50 values from the 61 assays and the human lethal peak concentrations demonstrated that human cell line tests gave the best average results (R2 = 0.64), while mammalian and fish cell tests correlated less well (R2 = 0.52–0.58), followed by non-fish ecotoxicological tests (R2 = 0.36). Most of the 61 assays underpredicted human toxicity for digoxin, malathion, carbon tetrachloride and atropine sulphate. In the correlative/mechanistic study, the 50 chemicals were first separated into three groups: A = fast-acting chemicals with a restricted passage across the blood–brain barrier; B = slow-acting chemicals with a restricted passage across the blood–brain barrier; and C = chemicals which cross the blood–brain barrier freely, while inducing a non-specific excitation/depression of the central nervous system (CNS). The IC50 values for chemicals in group C were divided by a factor of ten to compensate for a hypothetical extra vulnerability of the CNS to cytotoxicity. Finally, the average human cell line IC50 values (24-hour IC50 for groups A and C, and after 48-hour for group B) were compared with relevant human lethal blood concentrations (peak concentrations for groups A and C, and 48-hour concentrations for group B). As a result, in vitro toxicity and in vivo toxicity correlated very well for all groups (R2 = 0.98, 0.82 and 0.85, respectively). No clear overprediction of human toxicity was made by the human cell tests. The human cell line tests underpredicted human toxicity for only four of the 50 chemicals. These outlier chemicals were digoxin, malathion, nicotine and atropine sulphate, all of which have a lethal action in man through interaction with specific target sites not usually found in cell lines. Potassium cyanide has a cellular human lethal action which cannot be measured by standard anaerobic cell lines. The good prediction of the human lethal whole-blood concentration of this chemical was not conclusive, i.e. was probably a “false good correlation”. Another two chemicals in group C resulted in “false good correlations”, i.e. paracetamol and paraquat. The comparisons thus indicated that human cell line cytotoxicities are relevant for the human acute lethal action for 43 of the 50 chemicals. The results strongly support the basal cytotoxicity concept, and further point to the non-specific CNS depression being the obligatory reaction of humans to cytotoxic concentrations of chemicals, provided that the chemicals are able to pass the blood–brain barrier.
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Haematotoxicology: Scientific Basis and Regulatory Aspects

Laura Gribaldo

Haematopoietic tissues are the targets of numerous xenobiotics. The purpose of in vitro haematotoxicology is the prediction of adverse haematological effects from toxicants on human haematopoietic targets under controlled experimental conditions in the laboratory. Building on its foundations in experimental haematology and the wealth of haematotoxicological data found in experimental oncology, this field of alternatives toxicology has developed rapidly during the past decade. Preclinical and clinical drug development for anti-cancer drugs differs from that for other pharmaceuticals, because of the life-threatening nature of the disease. Treatment with anti-cancer drugs at clinically efficacious doses usually induces serious side-effects. The design of preclinical toxicology studies for anti-cancer drugs is intended to identify a safe clinical starting dose, characterise toxicities that could be encountered in human clinical trials, and determine whether these toxicities are reversible, manageable, and predictable. Although the myeloid colony-forming unit (CFU-GM) progenitor is most frequently evaluated, other defined progenitors and stem cells, as well as cell types found in the bone-marrow stroma, can now be evaluated in vitro. Genetic damage to haematopoietic cells can occur in the absence of any overt haematological signs. The development of tissue-specific screening systems that are able to give information about the toxic effects of chemicals, drugs and environmental hazards on target genes is needed, in order to make preliminary decisions or to set priorities for selection among large groups of chemicals and possible drugs.
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