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At least 73 records · Page 4Linked to original sources
PubMed1998

Validated determination of total arsenic species of toxicological interest (arsenite, arsenate and their metabolites) by atomic absorption spectrometry after separation from dietary arsenic by liquid extraction: toxicological applications.

A validated method for the selective extraction of total As species of toxicological interest (arsenite, arsenate and mono- and dimethylated arsenic species) from urine, followed by atomic absorption spectrometric determination, is described. The mechanisms involved in extraction were studied and the extraction method was optimized. The urine sample was acidified with concentrated HCl and KI and sodium hypophosphite were added. Under these conditions, As species were reduced to their corresponding iodide arsines, extracted with toluene and back-extracted with 1 mmol l-1 NaOH solution. Only inorganic arsenic and its metabolites in humans (monomethylarsonic and dimethylarsinic acid) were extracted. Arsenobetaine of dietary origin was not extracted. This method can detect if any As increase in urine originates from inorganic As intoxication or only from dietary non-toxic As species such as arsenobetaine.

Arsenates↗
PubMed2005

Studies of the toxicological potential of tripeptides (L-valyl-L-prolyl-L-proline and L-isoleucyl-L-prolyl-L-proline): IV. Assessment of the repeated-dose toxicological potential of synthesized L-valyl-L-prolyl-L-proline in male and female rats and dogs.

The objective of these repeated-dose, 8-week studies was to assess the toxicological potential of a synthetic tripeptide, L-valyl-L-prolyl-L-proline (VPP), when administered to Charles River rats and Beagle dogs. Groups of 20 male and 20 female rats were fed powdered diets containing sufficient VPP to afford daily doses of 0, 2, 8, or 16 mg/kg body weight (BW)/day. Groups of five male and five female dogs were administered 0, 2, 8, or 16 mg/kg BW/day in hard gelatin capsules. Antemortem evaluative parameters for both species included grossly observable clinical signs, body weight and food consumption, clinical pathology (hematology, clinical chemistry, urinalysis), and ophthalmological examinations. Dogs also received electrocardiographic examinations. Postmortem evaluations in both species included complete necropsy, determination of major organ weights, and histopathological examination of specimens from approximately 50 organs and tissues. All rats and dogs survived to the scheduled termination of the studies and neither species exhibited evidence of VPP effects on appetite or body weight gain/maintenance. Ophthalmic examinations revealed occasional lens clouding in rats, but this occurred in all groups and was not attributable to VPP. Some clinical pathology parameters in both species were occasionally altered, but there was no evidence that this was dose-related. Electrocardiographic examinations in dogs revealed no VPP-associated changes. Mid- and high-dose male rats (but not females) had slightly reduced mean pituitary and kidney weight parameters, whereas mid- and high-dose females had slightly increased mean uterus:body weight ratios. There were no microscopic correlates for these minor changes. Ten percent to 20% of all female rats (but not males) exhibited corticomedullary mineralization of the kidney and gliosis of the optic nerve, and 10% to 20% of males (but not females) had thymic hemorrhage. Postmortem evaluations of dogs revealed no VPP-related effects on organ weights or either macro- or microscopic appearances of organs. The results of these studies provided no evidence of either local or systemic toxicity. Similarly, there was no evidence of neurotoxicity that might have been detected by the appearance of physical or behavioral changes during gross observations of animals. Although these results do not identify target organs for VPP toxicity, the no-observable-effect level and maximally tolerated dose are both greater than 16 mg/kg/day when administered to male and female rats and dogs for 8 consecutive weeks. Based upon food enhancement levels of VPP currently being evaluated, the resultant margin of safety (160) is substantial.

Administration, Oral↗
PubMed2003

Evaluating the genetic toxicology of DNA-based products using existing genetic toxicology assays.

Unlike the development of drugs based on small chemical entities there are no conventional regulatory toxicity studies established for DNA-based products. As the potential for insertional mutagenesis is of particular concern for gene therapy, we have investigated the mutagenicity of model non-viral DNA-based products at the HPRT locus in Chinese hamster V79 cells. Cultures were transfected with a pL3112BSKS plasmid in combination with a number of non-viral transfection facilitators: Effectene, Lipofectamine 2000 and ExGen 500. The plasmid contains a green fluorescent protein gene, which was used as a reporter of transfection efficiency. Flow cytometry was used to analyse large numbers of cells. Small scale transient transfection efficiencies (7-90%) were obtained at low cytotoxicity, however, scaling up the process led to decreased transfection and increased cytotoxicity. Stable transfection (chromosomal) was observed, but only at very low levels (<1.5%). Two of the non-viral delivery facilitators (Effectene and ExGen 500) themselves induced mutation at the HPRT locus, although they were considerably less potent than the positive control ethyl methanesulphonate. In transfection experiments, neither of the non-viral delivery facilitators (Effectene and Lipofectamine 2000) had a mutagenic effect, whereas with ExGen 500 there was evidence of a mutagenic effect, consistent with the mutagenicity observed with the non-viral transfection facilitator alone. Moreover, treatment with the plasmid pL3112BSKS itself was able to induce a 3- to 7-fold increase in the mutation frequency at the HPRT locus. Our studies highlight some of the problems associated with using exisiting genetic toxicology testing procedures for the assessment of DNA-based products used in novel gene therapy approaches. However, given the limited level of sophistication of the current approach, the data suggest that non-viral gene therapy may present a detectable mutation risk and more appropriate testing strategies are needed to evaluate the nature of the risk.

Animals↗
PubMed2005

Developmental toxicology evaluations--issues with including neurotoxicology and immunotoxicology assessments in reproductive toxicology studies.

Developmental and reproductive toxicology (DART) has routinely been a part of safety assessment. Attention is now focused on the effects of chemicals on the developing nervous and immune systems. This focus on developmental neurotoxicology (DNT) and developmental immunotoxicology (DIT) is based on the premise that children differ from adults in some aspects of their biology and, thus, may also differ in their responses to chemicals. This session's objective was to discuss issues common to DNT and DIT as they relate to DART protocols, including high dose selection and maternal toxicity, adequacy of pup exposure during lactation, use of a different dosing paradigm for DART versus DNT or DIT studies, and whether DIT and DNT endpoints can be incorporated into a single DART study for hazard identification purposes. Consensus was achieved on all topics except the adequacy for risk assessment purposes of the use of a limited number of endpoints for DIT and DNT, with the DNT endpoints being the primary focus of disagreement. Panelists indicated that a combination study design for hazard identification was feasible, though flexibility to meet the scientific needs of the project was emphasized. The adequacy of existing triggers for additional developmental studies was also questioned. Panelists iterated the importance of understanding pup exposure during the various life stages and the use of toxicokinetic data in designing these studies. The group agreed to consider the HESI ACSA Life Stages Task Force recommendations as a next step to address some of the issues and challenges raised during this session.

Abnormalities, Drug-Induced↗
PubMed1992

The clinical toxicology of chlordecone as an example of toxicological risk assessment for man.

Safety assessment procedures still rely heavily if not exclusively on the results of tests carried out in laboratory animals, then extrapolated to man. There are few examples of environmental compounds examined extensively enough in both man and animals to permit a critical comparison of the accuracy of such risk assessment procedures. Chlordecone (Kepone) is a lipophilic, rodent liver carcinogen which now stands among the most extensively studied environmental agents in humans. More than five years of clinical investigations of workers heavily exposed to organochlorine pesticide have established the spectrum of human toxicity of Chlordecone, its dose-response relationships, tissue distribution, metabolic pathways, half-time for elimination, and the concentration at which its major toxic manifestations involving the central nervous system, the liver, and the testes are not observed (no observable effect level, NOEL). Taking advantage of this unique opportunity to proximately compare humans with experimental animals for a single compound administered at comparable doses, we find that none of the toxic effects produced in humans were unrepresented in animal testing. However, the animal testing produced numerous "false positive" results. Hence, accurately predicting the qualitative toxicity of chlordecone in man based on studies in rats would have been impossible. Indeed, proteinuria observed in rats fed small amounts of chlordecone for two years was chosen as a sensitive endpoint by the United States Environmental Protection Agency as the basis for establishing acceptable levels of human exposure. However, we never observed proteinuria even in humans whose dose of chlordecone was hundreds of times higher than that given to the rats. We conclude that greater emphasis should be placed on clinical investigation of humans exposed to environmental agents. A better understanding of the strength and also of the limitations of animal toxicity testing will improve the reliability of extrapolating results of animal testing to human exposure conditions.

Animals↗