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PubMed2002

Data collection in clinical toxicology: are there too many variables?

The evidence base of clinical toxicology suffers in comparison to other clinical disciplines. There is an excess of case reports and case series with little in the way of case control or cohort studies, and very few randomized controlled trials. While randomized controlled trials are rightly regarded as the gold standard for interventional studies, they have limitations that are particularly evident in the practice of clinical toxicology. Properly conducted observational studies using quantitative, epidemiological methods [nonrandomized trials, cohort studies (prospective and retrospective), case control methods] can provide answers that may be impossible to obtain from randomized controlled trials. Development of a strong evidence base is essential for progress in clinical toxicology. Whether that evidence base is derived from randomized controlled trials or observational studies, it is essential to collect data. Important observations can be made from basic clinical data and systematic collection of those data into some form of electronic database has siginificant advantages. A clinical database provides accurate information in the areas of clinical practice, quality assurance (audit), and research. In the area of research, an appropriately designed database can be both a source of hypotheses as well as a vehicle to test them. It can also serve as a repository of research data in subsequent randomized controlled trials.

Confounding Factors, Epidemiologic↗
PubMed2000

Military deployment toxicology: a program manager's perspective.

The Persian Gulf War drew attention to the potential hazards of chemicals that personnel may encounter during military operations and deployments overseas. During the War, the oil well fires of Kuwait highlighted the military threat of industrial chemicals in the area of operations. Following the War, the occurrence of Gulf War Illnesses brought home concerns and suspicions regarding "low level" and "mixed" exposures to chemicals. The public's concern and attention resulted in numerous institutional responses to the real and perceived problems of health risks during military deployments. These institutional responses ranged in scope from a Presidential Review Directive to the initiative known as the Deployment Toxicology Research, Development, Testing and Evaluation (RDT&E) Program. Most institutions, however, seem to agree that additional research is needed to assess the health risks from chemical exposures during military deployments. Establishing and managing an effective RDT&E program in risk assessment for deployed forces is a challenging enterprise. The Deployment Toxicology RDT&E Program was conceived utilizing the military's acquisition framework, an effective methodology with a proven record of fielding of new technologies. Based on a series of structured meetings with military representatives that would utilize new risk assessment tools, a hierarchical set of plans was developed to identify and prioritize end products. The challenge ahead for the Deployment Toxicology RDT&E Program is to execute these plans, provide the necessary oversight, and transition the results into successful product development.

Animals↗
PubMed2003

Statistical evaluation of the Predictive Toxicology Challenge 2000-2001.

MOTIVATION: The development of in silico models to predict chemical carcinogenesis from molecular structure would help greatly to prevent environmentally caused cancers. The Predictive Toxicology Challenge (PTC) competition was organized to test the state-of-the-art in applying machine learning to form such predictive models. RESULTS: Fourteen machine learning groups generated 111 models. The use of Receiver Operating Characteristic (ROC) space allowed the models to be uniformly compared regardless of the error cost function. We developed a statistical method to test if a model performs significantly better than random in ROC space. Using this test as criteria five models performed better than random guessing at a significance level p of 0.05 (not corrected for multiple testing). Statistically the best predictor was the Viniti model for female mice, with p value below 0.002. The toxicologically most interesting models were Leuven2 for male mice, and Kwansei for female rats. These models performed well in the statistical analysis and they are in the middle of ROC space, i.e. distant from extreme cost assumptions. These predictive models were also independently judged by domain experts to be among the three most interesting, and are believed to include a small but significant amount of empirically learned toxicological knowledge. AVAILABILITY: PTC details and data can be found at: http://www.predictive-toxicology.org/ptc/.

Algorithms↗
PubMed2004

Tailored gene array databases: applications in mechanistic toxicology.

MOTIVATION: The development of an annotated global database suitable for a wide range of investigations is a challenging and labor-intensive task. Thus, the development of databases tailored for specific applications remains necessary. For example, in the field of toxicology, no annotated gene array databases are now available that may assist in the correlation of changes in gene activity to cellular functions and processes associated with the toxic response. RESULTS: As an example of a tailored annotated database, an attempt was made to systematize available biological information on genes present on the Affymetrix Rat Toxicology U34 GeneChip, with a focus on how the gene products relate to liver cells and their response to chemical toxins. The information collected was imbedded in a local relational database to analyze data obtained in toxicological gene array experiments with hydrazine-exposed hepatocytes. The advantages and benefits of the tailored database in the biological interpretation of the results are demonstrated.

Abstracting and Indexing↗
PubMedDate not supplied

Survey of admission toxicology panels in patients with multiple hospitalizations.

Of 1309 different patients with toxicology panels performed on admission to our university medical center during 1978-79, 65 (5.0%) had more than one hospitalization or emergency-room visit. The average patient with multiple admission panels performed during the year was an alert 32-year-old man who presented to the emergency room a mean of 2.2 times, following an episode of suspected drug abuse. The visits were separated by a mean time interval of 2.5 months. An average 1.7 different drugs per patient were found on the admission toxicology screening (usually ethanol, a barbiturate, an opiate, or a phenothiazine). One third of the drugs per patient were positive again on subsequent hospitalizations of the patient. In more than a third of the instances in which repeated drugs were quantitated, the "repeat level" on the subsequent admission was within +/- 17% of that found on the first admission. Laboratory recognition of patients with repetitive admission toxicology screening may facilitate analysis by permitting specific-drug-oriented searches.

Adolescent↗
PubMed2000

The practice of structure activity relationships (SAR) in toxicology.

Both qualitative and quantitative modeling methods relating chemical structure to biological activity, called structure-activity relationship analyses or SAR, are applied to the prediction and characterization of chemical toxicity. This minireview will discuss some generic issues and modeling approaches that are tailored to problems in toxicology. Different approaches to, and some facets and limitations of the practice and science of, SAR as they pertain to current toxicology analyses, and the basic elements of SAR and SAR-model development and prediction systems are discussed. Other topics include application of 3-D SAR to understanding of the propensity of chemicals to cause endocrine disruption, and the use of models to analyze biological activity of metal ions in toxicology. An example of integration of knowledge pertaining to mechanisms into an expert system for prediction of skin sensitization to chemicals is also discussed. This minireview will consider the utility of modeling approaches as one component for better integration of physicochemical and biological properties into risk assessment, and also consider the potential for both environmental and human health effects of chemicals and their interactions.

Animals↗
PubMed2002

Analysis of rodent growth data in toxicology studies.

To evaluate compound-related effects on the growth of rodents, body weight and food consumption data are commonly collected either weekly or biweekly in toxicology studies. Body weight gain, food consumption relative to body weight, and efficiency of food utilization can be derived from body weight and food consumption for each animal in an attempt to better understand the compound-related effects. These five parameters are commonly analyzed in toxicology studies for each sex using a one-factor analysis of variance (ANOVA) at each collection point. The objective of this manuscript is to present an alternative approach to the evaluation of compound-related effects on body weight and food consumption data from both subchronic and chronic rodent toxicology studies. This approach is to perform a repeated-measures ANOVA on a selected set of parameters and analysis intervals. Compared with a standard one-factor ANOVA, this approach uses a statistical analysis method that has greater power and reduces the number of false-positive claims, and consequently provides a succinct yet comprehensive summary of the compound-related effects. Data from a mouse carcinogenicity study are included to illustrate this repeated-measures ANOVA approach to analyzing growth data in contrast with the one-factor ANOVA approach.

Analysis of Variance↗
PubMed2003

The future of regulatory toxicology: impact of the biotechnology revolution.

The molecular biology revolution and the advent of genomic and proteomic technologies are facilitating rapid advances in our understanding of the molecular details of cell and tissue function. These advances have the potential to transform toxicological and clinical practice, and are likely to lead to the supplementation or replacement of traditional biomarkers of cellular integrity, cell and tissue homeostasis, and morphological alterations that result from cell damage or death. New technologies that permit simultaneous monitoring of many hundreds, or thousands, of macro- and small molecules ("-omics" technologies) promise to allow functional monitoring of multiple (or perhaps all) key cellular pathways simultaneously. Elucidation of cellular responses to molecular damage, including evolutionarily conserved inducible molecular defense systems, suggests the possibility of new biomarkers based on molecular responses to functional perturbations and cellular damage. Our improved understanding of the molecular basis of various pathologies suggests that monitoring specific molecular responses may provide improved prediction of human outcomes. Responses that can be monitored directly in the human should provide "bridging biomarkers" that may eliminate much of the current uncertainty in extrapolating from laboratory models to human outcome. Another aspect of genomics is our enhanced ability to associate DNA sequence variations with biological outcomes and individual sensitivity. The human genome sequence has revealed that sequence variations are very common, and may be an important determinant of variation in biological outcomes. The impending availability of a complete human haplotype map linked to standard genetic markers greatly facilitates identification of genetic variations that convey sensitivity or resistance to chemical exposures. Genetic approaches have already linked a large number of genetic variants (polymorphisms) with human diseases and adverse reactions from exposure to drugs or toxicants, suggesting an important role in sensitivity to drugs and environmental agents, disease susceptibilities, and therapeutic responses. As these opportunities are transformed into reality, regulatory toxicological practice is likely to be shaped in the future by the combination of conventional pathology, toxicology, molecular genetics, biochemistry, cell biology, and computational bio-informatics-resulting in the broad application of molecular approaches to monitoring functional disturbances.

Animals↗
PubMed2003

Thioredoxin and its role in toxicology.

Thioredoxins (Trx) are members of an evolutionarily conserved family of redox-active proteins containing a conserved active site dithiol motif. Trx supports diverse reduction reactions, including several of direct toxicologic interest, but relatively little information is available concerning the roles of Trx under specific toxicologic conditions. Accumulating evidence suggests that Trx serves a partially overlapping and highly complementary role to the glutathione (GSH) system in protecting against toxicity. GSH and Trx both function in the reduction of peroxides through the action of multiple GSH peroxidases and Trx peroxidases (peroxiredoxins), respectively. However, GSH is a small molecule that is present at millimolar concentrations, thereby providing a potential mechanism for elimination of alkylating electrophiles. In contrast, even though Trx is only present at micromolar or submicromolar concentrations, its dithiol motif makes it suited to reverse oxidative changes to proteins, including reduction of protein disulfides, methioninyl sulfoxides, and cysteinyl sulfenic acids. Moreover, Trx functions in redox-sensitive signal transduction, transcriptional activation of stress response genes, ribonucleotide reduction in synthesis of deoxyribonucleotides for DNA repair, and post-injury cell proliferation. Molecular studies show that the predominant cytoplasmic/nuclear form, Trx-1, and the mitochondrial form, Trx-2, both protect against oxidative stress, that both are essential for embryonic development, and that Trx-1 is inducible in response to oxidative stress. Because of the differences between GSH and Trx in distribution, catalytic activities and reactivities with electrophiles, particularly with the important role to be played by glutathione S-transferases, considerable research is needed to clarify their respective roles in protection against specific toxicologic conditions.

Animals↗
PubMed2004

Use and application of stem cells in toxicology.

In recent years, stem cells have been the subject of increasing scientific interest because of their utility in numerous biomedical applications. Stem cells are capable of renewing themselves; that is, they can be continuously cultured in an undifferentiated state, giving rise to more specialized cells of the human body such as heart, liver, bone marrow, blood vessel, pancreatic islet, and nerve cells. Therefore, stem cells are an important new tool for developing unique, in vitro model systems to test drugs and chemicals and a potential to predict or anticipate toxicity in humans. The following review provides an overview of the applications of stem cell technology in the area of toxicology. Specifically, this review addresses core technologies that are emerging in the field and how they could fulfill critical safety issues such as QT prolongation and hepatotoxicity, two leading causes of failures in preclinical development of new therapeutic drugs. We report how adult stem cells derived from various sources, such as human bone marrow and placenta, can potentially generate suitable models for cardiotoxicity, hepatotoxicity, genotoxicity/epigenetic and reproductive toxicology screens. Additionally, this review addresses the role and advantages of embryonic stem cells in the aforementioned models for toxicity and how genetic selection is employed to overcome major limitations to the implementation of stem cell-based in vitro models for toxicology.

Adult↗
PubMed1999

The utility of toxicologic analysis in children with suspected ingestions.

OBJECTIVE: To evaluate the usefulness of toxicologic studies on the management of children with suspected ingestions. DESIGN: Prospective, consecutive case series. SETTING: Two tertiary care children's hospital emergency departments. PATIENTS: All children < or =18 years of age presenting with a suspected ingestion. STUDY DESIGN: Pediatric emergency physicians completed a 14-point questionnaire on each identified patient that included demographics, signs, and symptoms, and if applicable, the extent of drug analysis performed. Pre-test and post-test utility values were determined by the ordering physician using an 11-point scale (0 = least valuable, 10 = most valuable). Physicians also assessed how positive or negative drug analyses affected patient management. RESULTS: Two hundred twenty patients met study criteria. Median age was 5 years, with males making up 53% of patients. Drug analysis was ordered in 72% (158/220) of cases, with 59% of these tests obtained for a history of ingestion and 27% obtained for altered mental status (AMS). The most common suspected ingestions were acetaminophen and cold preparations. Seventy-eight of 158 (49%) patients had positive toxicology tests, with 17 unsuspected findings. Patient management was affected in 53/158 (34%; 95% CI, 27-41%) cases. Unsuspected findings affecting management were found in only 4/158 (3%; 95% CI, 1-6%) cases. Significant differences in pre-test and post-test utility values occurred for serum assays (mean difference +0.4, P = 0.008), patients presenting with AMS (mean difference -0.8, P = 0.005), and patients having a negative drug test (mean difference -0.5, P = 0.003). Although negative drug analysis gave the physician reassurance in 39/80 (49%; 95% CI, 38-60%) cases, patient management was altered in only 8/80 (10%; 95% CI, 5-18%) cases. CONCLUSIONS: Seventy-two percent of children presenting with suspected drug ingestions had toxicologic analysis performed as part of their evaluation. Analysis was most valuable to physicians when evaluation of overdoses required serum drug levels. Qualitative urine drug screens provided minimal useful information. Unexpected findings on urine drug screening leading to changes in management were uncommon.

Adolescent↗
PubMed1995

Molecular approaches in toxicology: change in perspective.

Molecular approaches have attained a central position in modern experimental and human toxicology by providing the means to study basic underlying mechanisms. Molecular methods can be used to identify causal associations that would otherwise be obscure and to make better quantitative estimates of those associations at relevant levels of exposure. They may also make it possible to identify susceptible groups or individuals who are at risk of suffering the toxic effects of certain types of environmental and occupational agents. The use of transgenic animals in toxicology will improve our understanding of the role of toxic chemicals, such as carcinogens and mutagens, and their dosimetry and target organs. The use of molecular approaches in toxicology should thus result in better estimates of risks to human health.

Animals↗
PubMed2005

Veterinary pharmacovigilance. Part 6. Predictability of adverse reactions in animals from laboratory toxicology studies.

Toxicological studies are conducted on constituents of veterinary medicinal products for a number of reasons. Aside from being a requirement of legislation, they are carried out for predictive purposes in the assessment of user safety or for the determination of consumer safety, for example, in the elaboration of maximum residue limits or tolerances. Alternatively, the results of toxicology studies may be available as they have been generated for registration of the drug for human medicinal purposes. This paper examines if the results of such studies have any predictive value for adverse reactions, which might occur during clinical use in animals. A number of adverse reactions, notably the Type A (toxicology or pharmacology dependent) should be predictable from these laboratory studies. However, as with human pharmaceutical products, they have less utility in predicting Type-B reactions (idiosyncratic in nature).

Animals↗
PubMedDate not supplied

Illumination of therapeutics by toxicology: a personal view.

1. My specialties are therapeutics and toxicology. When we think in classical terms about drugs, therapeutics refers to curative healing, toxicology to the capacity to produce harm. However, they are not opposite disciplines, but rather reflect a continuum along the dose-response curve of a drug or toxin. Since antiquity, the study of toxicology has underpinned and illuminated therapeutics. Even the most potent toxins, such as botulinum and ricin, are used for therapeutic purposes. 2. In the case of one of my favourite research topics, the herbicide paraquat, I illustrate how investigating methods to treat patients poisoned by it has led to important advances in knowledge in medicine and therapeutics. Studying paraquat has launched my own research group on a path towards elucidating the mechanisms of the chronic neurological side effects of the antipsychotic drug, haloperidol, which is used widely to treat schizophrenia. In tracing these tortuous paths, the roles that serendipity and creativity play in research and their implications for education and funding policies are high-lighted.

Dose-Response Relationship, Drug↗
PubMed2006

Within-animal variation as an indication of the minimal magnitude of the critical effect size for continuous toxicological parameters applicable in the benchmark dose approach.

In this study, the within-animal variation in routinely studied continuous toxicological parameters was estimated from temporal fluctuations in individual healthy nonexposed animals. Assuming that these fluctuations are nonadverse, this within-animal variation may be indicative of the minimal magnitude of the critical effect size (CES). The CES is defined as the breaking point between adverse and nonadverse changes in a continuous toxicological parameter, at the level of the individual organism. The total variation in the data from individual nonexposed animals was divided in variation parts due to known factors (differences in sex, animal, and day) and a residual variation, by means of analysis of variance. Using the residual variation and the estimated analytical measurement error of a toxicological parameter, the within-animal variation can be estimated. The data showed within-animal variations ranging between 0.6% and 34% for different clinical chemistry and hematological parameters in 90-day rat studies. This indicates that different (minimal) CES values may be applicable for different parameters.

Analysis of Variance↗
PubMed2003

Zebrafish as a novel experimental model for developmental toxicology.

It is widely believed that embryos and infants during development are highly sensitive to chemicals that cause serious damage to growth. However, knowledge on the mechanisms of developmental toxicity is scarce. One reason for this is limited convenient model system other than organ cultures using rodents to study the various aspects of developmental toxicology. Cultured cells are not always adequate for this purpose, since events in morphogenesis are processed through interactions with other tissues. We focused on zebrafish embryo (Danio rerio), one of the most important organisms in developmental biology. Saturation mutagenesis, applied to drosophila and nematode to define the functions of genes, has been carried out in zebrafish but almost no other vertebrate, and several thousand lines are available due to the rapid growth and transparent body of this embryo. Enhanced databases for the genome and ESTs are available at websites with abundant genetic and biological background. By targeted gene knock-down with morpholino-modified antisense oligonucleotieds (morpholinos), the translation of a specific protein can be transiently blocked for several days. Many reporter systems in vivo have been established mainly as GFP-transgenic fish for environmental chemicals. Although several excellent studies have been performed with zebrafish embryos on the effects of chemicals, the developmental toxicology of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been most extensively studied to date. We have found that TCDD induces apoptosis in dorsal midbrain with a concomitant decrease in local blood flow, using developing zebrafish. TCDD seems to produce oxidative stress through CYP1A induction in vascular endothelium, resulting in local circulation failure and apoptosis in the dorsal midbrain. In addition to applications in toxicology, an experimental system with zebrafish embryos could help to clarify the mechanism of congenital anomaly, which arises from genetic mutation.

Animals↗
PubMed2000

From developmental biology to developmental toxicology.

Progress derived from the human genome project will have tremendous impact on toxicology. Questions concerning genetic susceptibility or resistance to toxic compound exposure and the dissection of the molecular mechanisms involved will be at the forefront of future toxicological research. In recent years, it was recognized that many of the molecular control mechanisms of embryogenesis have been conserved during evolution. The relevance of these observations for toxicology and the application of genetic approaches using mouse mutants as a tool for functional genome analysis are discussed.

Animals↗
PubMedDate not supplied

Environmental Protection Agency risk assessment--process and toxicologic pathology.

Risk assessment of a pesticide includes the identification of hazard, dose-response, exposure assessment, and risk characterization. Toxicology study reports undergo several levels of scientific and regulatory review in the Environmental Protection Agency's (EPA's) Office of Pesticide Programs. A Health Effects Division (HED) scientist reviews the reports. The resulting Data Evaluation Records are presented to several internal HED Peer Review committees to ensure consistency across chemicals in establishing which hazard end points to use when determining the reference dose and carcinogenicity potential for use in dietary and nondietary risk assessments. There may also be external reviews. The toxicologic pathologist can impact many steps in this process. The noncancer end points are just as important as the cancer end points when evaluating the hazard component of a pesticide. The toxicologic pathologist can assist in the hazard and risk characterization by being clear and concise, carefully defining terms and relating individual lesions to the animal, study, and database as a whole. The preceding will assist the HED in fulfilling EPA Administrator Carol Browner's guidance for risk characterizations that are transparent, clear, concise, and reasonable.

Animals↗