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PubMed2005

Diagnosis: toxic!--trying to apply approaches of clinical diagnostics and prevalence in toxicology considerations.

The assessment of relevance of toxicological testing was compared with approaches of diagnostic medicine, a discipline that faces a comparable situation. Considering the work of a toxicologist as setting a diagnosis for compounds, assessment tools for diagnostic tests were transferred to toxicological tests. In clinical diagnostics, test uncertainty is well accepted and incorporated in this assessment. Furthermore, prevalence information is considered to evaluate the gain in information resulting from the application of a test. Several common toxicological scenarios, in which test uncertainty and prevalence are combined, are discussed including the interdependence of test accuracy, prevalence and predictive values or the sequential application of a screening and a confirmatory test. In addition, real prevalences derived from prevalences determined by an imperfect test are presented. We conclude that information on prevalences of toxic health effects is required to allow a complete assessment of the relevance of toxicological test. In this process, lessons can be learned from evidence-based approaches in clinical diagnostics.

Diagnosis↗
PubMed2006

Toxicological safety evaluation of DNA plasmid vaccines against HIV-1, Ebola, Severe Acute Respiratory Syndrome, or West Nile virus is similar despite differing plasmid backbones or gene-inserts.

The Vaccine Research Center has developed a number of vaccine candidates for different diseases/infectious agents (HIV-1, Severe Acute Respiratory Syndrome virus, West Nile virus, and Ebola virus, plus a plasmid cytokine adjuvant-IL-2/Ig) based on a DNA plasmid vaccine platform. To support the clinical development of each of these vaccine candidates, preclinical studies were performed to screen for potential toxicities (intrinsic and immunotoxicities). All treatment-related toxicities identified in these repeated-dose toxicology studies have been confined primarily to the sites of injection and seem to be the result of both the delivery method (as they are seen in both control and treated animals) and the intended immune response to the vaccine (as they occur with greater frequency and severity in treated animals). Reactogenicity at the site of injection is generally seen to be reversible as the frequency and severity diminished between doses and between the immediate and recovery termination time points. This observation also correlated with the biodistribution data reported in the companion article (Sheets et al., 2006), in which DNA plasmid vaccine was shown to remain at the site of injection, rather than biodistributing widely, and to clear over time. The results of these safety studies have been submitted to the Food and Drug Administration to support the safety of initiating clinical studies with these and related DNA plasmid vaccines. Thus far, standard repeated-dose toxicology studies have not identified any target organs for toxicity (other than the injection site) for our DNA plasmid vaccines at doses up to 8 mg per immunization, regardless of disease indication (i.e., expressed gene-insert) and despite differences (strengths) in the promoters used to drive this expression. As clinical data accumulate with these products, it will be possible to retrospectively compare the safety profiles of the products in the clinic to the results of the repeated-dose toxicology studies, in order to determine the utility of such toxicology studies for signaling potential immunotoxicities or intrinsic toxicities from DNA vaccines. These data build on the biodistribution studies performed (see companion article, Sheets et al., 2006) to demonstrate the safety and suitability for investigational human use of DNA plasmid vaccine candidates for a variety of infectious disease prevention indications.

Acquired Immunodeficiency Syndrome↗
PubMed2006

Toxicologic findings in suicide: a 10-year retrospective review of Kentucky medical examiner cases.

Toxicologic analysis is an integral component in the investigation of suicide and requires correlation with a detailed scene inspection, with an extensive exploration into the decedent's medical and social background to uncover suicidal ideation or intent and a postmortem examination of the body. In this review, the authors analyzed 2864 cases classified as suicide upon autopsy and toxicologic examinations between 1993 and 2002 in the Kentucky Division of Medical Examiner's Services. Blood and urine were collected in 95.0% and 72.3% of cases, respectively. A total of 32.5% of the victims had negative blood toxicologic results, and 52.7% of urine toxicology screens yielded no drugs. Analysis of the data indicated that 3 times as many women had taken antidepressants and more than twice as many had consumed opioids. Drug toxicity ("overdose") ranked as the third (9.9%) leading cause of suicide after firearm injury (67.5%) and hanging (13.7%). Women succumbed to drug toxicity more than men (27.5% versus 5.9%). Of the overdose deaths, 66.5% had a negative blood alcohol concentration (BAC), while antidepressants, opioids, and benzodiazepines were detected in blood in 54.4%, 37.4%, and 29.2% of the subjects, respectively. The collection of these data serves the goals of public health and clinicians in devising strategies for suicide prevention.

Adolescent↗
PubMed2003

Application of toxicological risk assessment principles to the chemical constituents of cigarette smoke.

OBJECTIVE: To provide a hazard prioritisation for reported chemical constituents of cigarette smoke using toxicological risk assessment principles and assumptions. The purpose is to inform prevention efforts using harm reduction. DATA SOURCES: International Agency for Research on Cancer Monographs; California and US Environmental Protection Agency cancer potency factors (CPFs) and reference exposure levels; scientific journals and government reports from the USA, Canada, and New Zealand. STUDY SELECTION: This was an inclusive review of studies reporting yields of cigarette smoke constituents using standard ISO methods. DATA EXTRACTION: Where possible, the midpoint of reported ranges of yields was used. DATA SYNTHESIS: Data on 158 compounds in cigarette smoke were found. Of these, 45 were known or suspected human carcinogens. Cancer potency factors were available for 40 of these compounds and reference exposure levels (RELs) for non-cancer effects were found for 17. A cancer risk index (CRI) was calculated by multiplying yield levels with CPFs. A non-cancer risk index (NCRI) was calculated by dividing yield levels with RELs. Gas phase constituents dominate both CRI and NCRI for cigarette smoke. The contribution of 1,3-butadiene (BDE) to CRI was more than twice that of the next highest contributing carcinogen (acrylonitrile) using potencies from the State of California EPA. Using those potencies from the USEPA, BDE ranked third behind arsenic and acetaldehyde. A comparison of CRI estimates with estimates of smoking related cancer deaths in the USA showed that the CRI underestimates the observed cancer rates by about fivefold using ISO yields in the exposure estimate. CONCLUSIONS: The application of toxicological risk assessment methods to cigarette smoke provides a plausible and objective framework for the prioritisation of carcinogens and other toxicant hazards in cigarette smoke. However, this framework does not enable the prediction of actual cancer risk for a number of reasons that are discussed. Further, the lack of toxicology data on cardiovascular end points for specific chemicals makes the use of this framework less useful for cardiovascular toxicity. The bases for these priorities need to be constantly re-evaluated as new toxicology information emerges.

Dioxins↗
PubMedDate not supplied

Concomitant toxicokinetics: techniques for and interpretation of exposure data obtained during the conduct of toxicology studies.

Toxicokinetic analyses have become a routine component of preclinical toxicology studies with pharmaceutical candidates. Evaluation of plasma and/or tissue samples from animals used in toxicology studies (or concurrent satellite groups) provides information on dose proportionality, the potential for dose accumulation, and the sex and species differences in distribution and elimination. Toxicokinetic information is used by toxicologists, toxicology management, clinicians, institutional review boards, regulatory agencies to ensure that exposure has occurred in animal species to a sufficient extent to minimize the potential risk of toxicities in humans. The requirements for descriptive toxicokinetics change depending on the stage of development of new drug candidates. Early in development, documentation of exposure in 1 species and sex of laboratory animal might be enough to justify preliminary development costs and initiation of product development. Later in development, it becomes necessary to know how new drug candidates are distributed and eliminated following subchronic and chronic administration in multiple species and both sexes. Finally, knowledge of toxicokinetics is used to help establish doses in long-term oncogenicity studies. Scientific, public, and regulatory pressures have recently dictated that the number of animals used in toxicology studies be closely monitored and minimized. Toxicokinetic evaluation of new drug candidates by a staggered sampling design is now routinely performed in our laboratories to maximize information obtained while reducing animal use.

Animals↗
PubMed2006

Hyperprolactinaemia as an adverse effect in regulatory and clinical toxicology: role in breast and prostate cancer.

Historically, hyperprolactinaemia has been considered of low toxicological relevance when detected in toxicity studies, and even mammary carcinogenesis induced in the rat by prolactin excess has been considered of no relevance to humans. However, recent findings from human epidemiology and molecular biology suggests that prolactin is a risk factor for human breast cancer, and probably prostate cancer. Therefore, this new evidence should be considered in the various decisions to develop and license a new drug or chemical if the compound causes hyperprolactinaemia. This emerging evidence suggests that prolactin can also be produced locally from human breast cancer cells, and that, regardless of source (ie, pituitary or autocrine/paracrine production from cancer cells), prolactin is mitogenic, stimulates proliferation and suppresses apoptosis in breast and prostate cancer cells. This review outlines the evidence that hyperprolactinaemia should be considered a toxicological adverse effect and concludes that prolactin-induced rodent mammary carcinogenesis is relevant to humans and is not species-specific. The effects of prolactin on the prostate gland are also discussed; hyperprolactinaemia may be an additional risk factor for prostate cancer and this also requires consideration in toxicological risk assessments. The implications of increased prolactin secretion as an adverse effect for regulatory toxicology of drugs and chemicals, and in high risk patients receiving therapeutic drugs with hyperprolactinaemic side effects, is discussed. Alteration of prolactin level is also a novel mechanism that requires consideration in endocrine disruption research, since both endogenous oestrogens and also xenoestrogens stimulate prolactin secretion or affect prolactin receptors.

Animals↗
PubMed2001

The selection of marmoset monkeys (Callithrix jacchus) in pharmaceutical toxicology.

Prior to controlled clinical trials in human volunteers or patients it is required that novel pharmaceuticals are evaluated for pre-clinical safety in a rodent and a non-rodent ('second') species. In most cases the rodent species used has been the rat and the second species has been the dog or macaque (usually cynomolgus or rhesus) monkey. However, there is an increasing trend within the United Kingdom (UK) pharmaceutical industry to use the common marmoset (Callithrix jacchus) for pre-clinical toxicology programmes. This paper examines the practicality of using the common marmoset (henceforth referred to as 'the marmoset') in toxicological testing and reviews metabolic and pharmacodynamic similarities between this species and humans. It then discusses some of the advantages and disadvantages of the use of this species when compared with two other alternatives to the dog and macaque, namely the ferret and minipig. In particular, the marmoset has clear advantages over the macaque in terms of animal welfare and practicality. There is regulatory acceptance of this species for Investigational New Drug (IND), Clinical Trial Exemption (CTX), New Drug Application (NDA) and Marketing Authorization Application (MAA) registrations. Whilst the dog is likely to be maintained as the primary non-rodent species in toxicology, the marmoset has been, and will likely continue to be, adopted as an additional non-rodent species in pre-clinical toxicology programmes where appropriate.

Animal Welfare↗
PubMed2005

Ushering in the new toxicology: toxicogenomics and the public interest.

New scientific tools spawned by the genomics revolution promise to improve our ability to identify causative factors in human diseases. But as these new tools elucidate the complex interactions between chemical toxins and biologic systems, the strain on traditional ways of understanding toxic effects grows. Despite major advances in the science and technology of these new toxicogenomics tools, scientific and political complexities threaten to delay the use of toxicogenomics to further the public interest or--worse--to advance its use initially to weaken the regulation and safety of widely used chemicals. To gain further insight into the scientific and political landscape of the new toxicology, we interviewed 27 experts from a variety of disciplines and sectors. Interviewees expressed widespread agreement that the new toxicology promises a significant increase in the amount of information available on toxic effects of chemicals. But the interviews show that the promise of the new toxicology will be realized only if technical and political obstacles can be overcome. Although scientific rigor is necessary for the new toxicology to move forward, the scientific and public-interest communities must ensure that inappropriate definitions of rigor, as well as proprietary interests, do not create unnecessary barriers to more effective public health protection.

Gene Expression↗
PubMed1996

The NIEHS Predictive-Toxicology Evaluation Project.

The Predictive-Toxicology Evaluation (PTE) project conducts collaborative experiments that subject the performance of predictive-toxicology (PT) methods to rigorous, objective evaluation in a uniquely informative manner. Sponsored by the National Institute of Environmental Health Sciences, it takes advantage of the ongoing testing conducted by the U.S. National Toxicology Program (NTP) to estimate the true error of models that have been applied to make prospective predictions on previously untested, noncongeneric-chemical substances. The PTE project first identifies a group of standardized NTP chemical bioassays either scheduled to be conducted or are ongoing, but not yet complete. The project then announces and advertises the evaluation experiment, disseminates information about the chemical bioassays, and encourages researchers from a wide variety of disciplines to publish their predictions in peer-reviewed journals, using whatever approaches and methods they feel are best. A collection of such papers is published in this Environmental Health Perspectives Supplement, providing readers the opportunity to compare and contrast PT approaches and models, within the context of their prospective application to an actual-use situation. This introduction to this collection of papers on predictive toxicology summarizes the predictions made and the final results obtained for the 44 chemical carcinogenesis bioassays of the first PTE experiment (PTE-1) and presents information that identifies the 30 chemical carcinogenesis bioassays of PTE-2, along with a table of prediction sets that have been published to date. It also provides background about the origin and goals of the PTE project, outlines the special challenge associated with estimating the true error of models that aspire to predict open-system behavior, and summarizes what has been learned to date.

Animals↗
PubMed1998

Current approaches toward chemical mixture studies at the National Institute of Environmental Health Sciences and the U.S. National Toxicology Program.

The National Institute of Environmental Health Sciences (NIEHS) has several new initiatives involving chemical mixtures and has recognized the need to develop new experimental approaches to enhance our efforts in this area. Responding to recent increases in nominations of complex occupational exposures for toxicologic assessment by the U.S. National Toxicology Program, the NIEHS and the National Institute for Occupational Safety and Health have begun a program to characterize exposures through field studies, identify biomarkers of exposure in workers, and recreate relevant mixed exposures in a laboratory setting. A second initiative with the National Center for Environmental Health/Centers for Disease Control and Prevention will examine blood samples from the U.S. National Health and Nutrition Examination Survey population surveys for selected endocrine-disrupting agents and for common patterns of persistent xenobiotics, providing critical information for the design of animal studies to assess risks of relevant chemical mixtures to humans. New toxicology testing methods (lower cost, faster) will enhance our ability to study chemical mixtures (e.g., dioxin and dioxinlike chemicals, combination AIDS therapies). Ongoing method development efforts involve in vitro functional toxicology assays, screens for estrogenic activity, and carcinogenesis studies in transgenic mice. A major scientific initiative with mixtures involves studies of individual and mixtures of dioxin and dioxinlike chemicals to determine if toxic equivalence factors predict carcinogenic potency in traditional and transgenic bioassays. Complementing these studies is an increased emphasis on physiologically based pharmacokinetic modeling, an activity central to the proper interpretation of chemical mixture studies.

Animals↗
PubMed1998

Approaches to developing alternative and predictive toxicology based on PBPK/PD and QSAR modeling.

Systematic toxicity testing, using conventional toxicology methodologies, of single chemicals and chemical mixtures is highly impractical because of the immense numbers of chemicals and chemical mixtures involved and the limited scientific resources. Therefore, the development of unconventional, efficient, and predictive toxicology methods is imperative. Using carcinogenicity as an end point, we present approaches for developing predictive tools for toxicologic evaluation of chemicals and chemical mixtures relevant to environmental contamination. Central to the approaches presented is the integration of physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) and quantitative structure--activity relationship (QSAR) modeling with focused mechanistically based experimental toxicology. In this development, molecular and cellular biomarkers critical to the carcinogenesis process are evaluated quantitatively between different chemicals and/or chemical mixtures. Examples presented include the integration of PBPK/PD and QSAR modeling with a time-course medium-term liver foci assay, molecular biology and cell proliferation studies. Fourier transform infrared spectroscopic analyses of DNA changes, and cancer modeling to assess and attempt to predict the carcinogenicity of the series of 12 chlorobenzene isomers. Also presented is an ongoing effort to develop and apply a similar approach to chemical mixtures using in vitro cell culture (Syrian hamster embryo cell transformation assay and human keratinocytes) methodologies and in vivo studies. The promise and pitfalls of these developments are elaborated. When successfully applied, these approaches may greatly reduce animal usage, personnel, resources, and time required to evaluate the carcinogenicity of chemicals and chemical mixtures.

Algorithms↗
PubMed1987

Amphetamine detection during toxicology screening of a university medical center patient population.

The frequency of detection of "amphetamines" (amphetamine and/or methamphetamine) in the toxicology tests of a university medical center patient population was evaluated by retrospective review of the results of 2,900 toxicology test profiles performed on urine during the year 1986-87. Ten percent of these (291 cases) were positive for either amphetamine alone or amphetamine in conjunction with methamphetamine--a substantial increase from the 3% noted in 1978 at this medical center. Amphetamines were detected predominantly in males (164 cases). The most common age range for the entire series was 21 to 30 years (61% of cases). The typical user was a 27 year old Caucasian man who used amphetamines alone or in combination with at least one other drug with about equal frequency. The sympathomimetic amines (ephedrine, phenylpropanolamine, and pseudoephedrine) were the most frequently associated category of other drugs, perhaps reflecting either adulteration of the amphetamines with these compounds or concurrent ingestion of over-the-counter preparations containing these agents. Requests for those toxicology tests which subsequently revealed amphetamines mostly originated in the emergency room (30% of cases) although 25% originated on the trauma service and 17% on the obstetrics service. Twelve percent of cases occurred in neonates, presumably reflecting transplacental transmission of amphetamines detected in mothers that were studied simultaneously. Amphetamine and methamphetamine were detected together 84% of the time. Analysis of amphetamines should be an integral part of toxicology testing performed on a university medical center patient population.

Adolescent↗
PubMed1976

Results of a nine-laboratory survey of forensic toxicology proficiency.

Toxicological determinations are crucial to coroners' or medical examiners' judgments that drugs are significantly involved in a death. However, differences in laboratory procedures, thoroughness of screening, and limits of detection may result in artifactual differences in the toxicological results and the subsequent interpretations of them. To test this possibility, we conducted a toxicology proficiency-testing survey of nine collaborating laboratories. The results for the proficiency samples point out starting interlaboratory differences in accuracy and precision of detection of drugs. These observed variations in toxicological proficiency may introduce a significant source of error in drug-death statistics and in epidemiological deductions based on these statistics.

Ethanol↗
PubMedDate not supplied

[Biomarkers for toxicity and metabolic abnormalities of the main severe poisonings. Clinical and toxicologic symptoms. Conservative determination].

The members of the joint group "Toxicology and Clinical Biology" of the French Society of Clinical Biology (SFBC), the French Society of Analytical Toxicology (SFTA), and the Society of Clinical Toxicology (STC), suggest guidelines to meet the requirements of clinical biologists who are not specialized in toxicology. Based on good laboratory practice they propose a number of guidelines. Three synthetic tables have been established. They are not only toxicity biomarkers and metabolic disorders associated with the main severe intoxications, but also clinical signs that are observed during these intoxications, finally biological sampling as a precautionary measure. The table also takes into account approximately fifty xenobiotics: main clinical signs emergency, identification or quantification of the suspected product, useful biological markers, therapeutic, quantitations necessary to take into consideration patient care, and poison antidotes, are described. Recommendations regarding medical and forensic techniques are also proposed by the group. It is also necessary to collect and store biological samples when the individual patients are in charge. These samples will be analyzed or not depending on the individual case history.

Biomarkers↗
PubMed1992

Perinatal toxicology screening.

Accurate identification of substance abusing mothers and their infants is critical for appropriate medical management as well as the collection of accurate information on the effects of illicit drug use on perinatal morbidity, mortality, and long-term neurobehavioral outcome in the infants. This study examines the differences found using two methods for urine toxicology screening at the time of obstetrical admission to the hospital. The institution of universal screening identified significantly more women than were previously identified through the use of a risk-directed protocol (P less than .0001). Women identified using either protocol were significantly more likely than toxicology-negative women to have had poor prenatal care and to have smoked and used alcohol during pregnancy (P less than .001). In the population studied, the multiple criteria needed to accurately identify mothers with positive-toxicology screens would also include screening over one half of the toxicology-negative mothers.

Female↗
PubMed2004

Two years' activity of the Veterinary Toxicology Attention Service of Lugo, Spain.

The Veterinary Toxicology Attention Service was created at the beginning of 2001 as the first on-line toxicology service for veterinarians and animal owners in Spain. In the present study, data about the general functioning of the Service and the toxicological analysis and consultations performed are summarized. Canine-related cases constituted the main call group and veterinary practitioners represented half of the consultations. Coordination between all veterinary toxicology services in Spain and the rest of the European Union should improve this service.

Animals↗
PubMed1991

Application of forensic toxicology to the problem of domestic violence.

The role of the forensic toxicologist in helping to determine causes of death or in aiding in the resolution of "driving under the influence" or similar cases is well known and clearly understood. Less clearly defined is the position of the forensic toxicologist vis-à-vis other socially significant problems. However, as the 21st century approaches, it is worth considering how forensic toxicology can help in unraveling some of these problems. The problem of violence between intimates--that is, domestic violence--is a social problem in which it has been long felt that alcohol has played a part. Until now, though, no carefully controlled toxicological studies have been conducted to substantiate this or to determine whether other drug use is associated with domestic violence. At the San Francisco Medical Examiner's Office, toxicological data from both the victim and the suspect in 20 cases of domestic violence that ended in homicide have been gathered. It was found that alcohol or other drugs or a combination of these factors was invariably present in the suspect, the victim, or both. The implications of these results and how they can be used to develop a toxicological strategy to help reduce the most serious consequences of domestic violence are presented.

Cocaine↗
PubMed2006

[Practice of toxicology screening in an emergency department].

UNLABELLED: The present study examines standards of toxicology screening in the Emergency Department. METHODS: A retrospective analysis was performed on 583 patients for whom 713 different toxicology assays were conducted. RESULTS: The most commonly used test was the urine toxicology assay which was found positive in 10% of the subjects. Most of the patients in this group were treated with respective antidotes before the results of the tests became available. One out of 13 subjects who denied acetaminophen ingestion showed toxic blood levels. High carboxyhemoglobin saturation was found only in subjects with symptoms of intoxication. CONCLUSIONS: The medical utility of urine toxicology assay is not clear, as patients reviewed were treated according to their clinical conditions. Acetaminophen blood levels should be examined more frequently, as symptoms are vague and appropriate treatment is very effective. Carboxyhemoglobin saturation should be examined whenever exposure is suspected and symptoms and or signs are compatible with intoxication.

Acetaminophen↗