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PubMed1997

Integrated approaches for the analysis of toxicologic interactions of chemical mixtures.

Although an overwhelmingly large portion of the resources in toxicologic research is devoted to single chemical studies, the toxicology of chemical mixtures, not single chemicals, is the real issue regarding health effects of environmental and/or occupational exposure to chemicals. The relative lack of activities in the area of toxicology of chemical mixtures does not suggest ignorance of the importance of the issue by the toxicology community. Instead, it is a reflection of the difficulty, complexity, and controversy surrounding this area of research. Until recently, much of the literature on the toxicology of chemical mixtures has been either very focused on certain specific interaction studies or slanted toward broad-based, relatively vague theoretical deliberation. The typical interaction study involved binary mixtures at relatively high dose levels with acute toxicities as endpoints. Although the theoretical papers have been valuable contributions, little is available on actual, practical experimental approaches toward a systematic solution of this immensely complex area of research. We present here a broad discussion on the important issues of the toxicology of chemical mixtures. First, we provide some background information with respect to the problem and significance of toxicology of chemical mixtures in relation to some of the real life issues. Second, we review and compare the existing experimental approaches relevant to toxicologic interactions of chemical mixtures. Third, we propose three integrated approaches that involve the combination of physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling with: (1) Monte Carlo simulation, (2) median effect principle (MEP), and (3) response surface methodology (RSM). These modeling approaches, coupled with very focused mechanistically based toxicology studies, could be the basis for solving the problems of toxicology and risk assessment of chemical mixtures.

Analysis of Variance↗

PubMedDate not supplied

Toxicology: past, present, and future.

Toxicology is the study of poisons and poisoning and has an ancient and venerable history. Although there have been numerous notorious poisonings throughout the ages and rather astute descriptions of toxic agents, the scientific study of toxicology did not commence until the 19th century. There was rapid development of analytical methods in the late 19th century and then an acceleration of both method and scientific development in the latter half of the 20th century. Toxicology today can be subdivided into clinical toxicology, forensic toxicology, industrial or occupational toxicology, environmental toxicology, pharmaceutical toxicology, experimental toxicology, and workplace drug testing. The historical development of these overlapping areas of toxicology will be discussed, culminating in a prediction as to what the future may bring.

Environmental Medicine↗

PubMed2005

The role of laboratory examinations in medical toxicology.

Medical toxicology is a medical subspecialty focusing on the diagnosis, management and prevention of poisoning and other adverse health effects due to medications, occupational and environmental toxins, and biological agents. The medical toxicology laboratories operates an analytical facility for clinical toxicology (intentional or unintentional drug overdose), environmental medicine (occupational and environmental toxicology, workplace drug monitoring), drug of abuse management, therapeutic drug monitoring (TDM) and in some cases forensic toxicology. This article is focus on clinical toxicology, monitoring of drug abused patients and TDM. Still the most popular in medical toxicology is determination of xenobiotics in classic biological materials (blood/plasma, urine) however alternative materials (saliva, hairs) cause increasing attention. Alternative materials has special value in drug of abuse management (evaluation of drug abstinence), when collecting the blood create some problems and urine samples can be adulterated. For screening usually immunology based assays are applied and for some xenobiotics thin-layer chromatography (TLC) method. Conformation and quantitative analysis are carrying on using chromatographic method. In clinical toxicology chemical analysis are performed for diagnostic, therapeutic and some time for legal purposes. If results of toxicological analysis have direct influence on diagnosis or treatment they should be available during 2 hours other determination ought to be performed during 24 or 48 hours. Integral part of toxicological analysis is interpretation of results carried over by well-trained analyst with close co-operation with clinical toxicologist (physician).

Biomarkers↗

PubMed1992

Toxicology training in US and Canadian medical schools.

The objective was to determine the extent of toxicology training in US and Canadian Medical Schools. The authors took a phone survey of the medical schools in the United States and Canada. Questions asked included whether school had a required toxicology course, in what context toxicology was taught, whether basic poison management was taught, and whether a doctoral toxicologist was on staff. Quantitation of hours of toxicology instruction and toxicology-related questions was also sought. Of the 142 medical schools in the United States and Canada, 123 schools were contacted (85.4%); 107 of these schools were US schools while 16 were Canadian medical schools. One hundred two schools (82.8%) stated that toxicology was taught in pharmacology or pathology courses, while only six schools (4.9%) had separate formal toxicology courses. An average of 5.04 hours (+/- 4.6 hours) of toxicology was taught in US courses, while the Canadian average was 6.04 hours (+/- 5.2 hours). Basic poison management was taught in 75 of the schools (61%), while a toxicologist (holding either an MD or PhD degree) was on staff in 56 of the 110 schools responding to this question (51%). While no relationship existed between having a toxicologist on staff and whether poison management was taught in US schools, a significant relationship was noted in Canadian schools (P less than .05). The authors conclude that toxicology as a separate discipline (and poison management in particular) is not routinely taught in medical school.

Canada↗

PubMed2000

Threshold values in toxicology - useful or not?

In many fields of toxicology, numbers are used as threshold values, e.g. as "acceptable daily intake values" resulting in maximum permissible concentrations in food or in animal feed by using "safety factors"; maximal admissible concentrations of toxic substances in the air at the workplace; cut-off values in analytical toxicology; limit values for biological specimens in the case of driving under the influence of drugs, guidance values for environmental specimens, etc. The philosophy behind these values must be well understood and they should only be applied to real cases by persons with enough toxicological background. The bad use of these numbers in toxicology can have dramatic consequences. Especially in regulatory toxicology their use should be made with great care. Moreover, tremendous improvements in analytical methodology, e.g. the decreasing of the limits of detection for many potentially toxic substances in recent years, should not end up in an overestimation of risks to humans. To avoid these abuses careful interpretations of analytical findings by qualified toxicologists are of paramount importance. The use and abuse of some of these threshold values will be outlined in several applications from analytical toxicology, risk assessment issues, forensic toxicology in post-mortem cases, as well as from the drugs and driving cases. Generally, if threshold values are considered as guidance values and not as the "absolute truth" in toxicology, they may be very useful in the interpretation of toxicology data.

Food Inspection↗

PubMed1980

Historic development of forensic toxicology in America up to 1978.

The development of forensic toxicology in the United States is reviewed from colonial times. Medical education started expanding after Independence, but no program in medical jurisprudence existed until 1804, when Dr. James S. Stringham initiated such a teaching program at Columbia University in New York City. Since then, instruction in medical jurisprudence has become more or less a part of the medical school's curriculum. Little has been written in the field of toxicology in contrast to overall European development. With the availability of contributions from European and British authors, the development of chemical toxicology in this country started to take shape, with significant progress occurring after the Civil War. The original contributions in toxicology were done by Drs. Wormley, Reese, and Witthaus. The faults of the coroner system led its replacement in Massachusetts with the office of medical examiner in 1877. The Chief Medical Examiner's Office of New York started functioning in 1918 and a toxicology laboratory was founded under the direction of Dr. Alexander Gettler, whose students spread the ideas of toxicology throughout the country. This institution is regarded as the birthplace of American forensic toxicology. Other significant events include the formation of the American Academy of Forensic Sciences after World War II and the establishment of the American Board of Forensic Toxicology in 1975; both have contributed greatly to the development of forensic toxicology in the United States.

Adult↗

PubMed2005

Distance learning in toxicology: resident and remote; Scotland, IPCS, IUPAC, and the world.

Globally, very few college or university chemistry courses incorporate toxicology although public perception of chemicals and the chemical industry as threats to health and the environment has had an adverse effect on chemistry and on the use of its products. The International Union for Pure and Applied Chemistry (IUPAC) through its Commission on Toxicology recognized this and, with the support of the Committee on the Teaching of Chemistry has used the IUPAC web site to promote distance learning in toxicology for chemists. After preparation of a thoroughly refereed consensus Glossary of Terms for Chemists of Terms Used in Toxicology, a textbook Fundamental Toxicology for Chemists and a set of educational modules entitled Essential Toxicology were compiled and put through the normal thorough review procedure of IUPAC before being approved by the organization. There is now an additional Glossary of Terms Used in Toxicokinetics. The modules are freely downloadable in Adobe PDF format and are designed to be used both by educators and by students. Educators are asked to select whatever is appropriate to their students and to use the material as they wish, adding content specifically relevant to their circumstances. For self-study, the web modules have self-assessment questions and model answers. Currently the original Glossary for Chemists of Terms Used in Toxicology is being revised and it is expected that this will lead to further developments. The currently available components of the IUPAC programme may be accessed through the IUPAC website at the Subcommittee on Toxicology and Risk Assessment page: http://www.iupac.org/divisions/VII/VII.C.2/index.html.

Education, Distance↗

PubMed1998

Developmental toxicology: adequacy of current methods.

Toxicology embraces several disciplines such as carcinogenicity, mutagenicity and reproductive toxicity. Reproductive toxicology is concerned with possible effects of substances on the reproductive process, i.e. on sexual organs and their functions, endocrine regulation, fertilization, transport of the fertilized ovum, implantation, and embryonic, fetal and postnatal development, until the end-differentiation of the organs is achieved. Reproductive toxicology is divided into areas related to male and female fertility, and developmental toxicology. Developmental toxicology can be further broken down into prenatal and postnatal toxicology. Today, much new information is available about the origins of developmental disorders resulting from chemical exposure. While these findings seem to promise important new developments in methodology and research, there is a danger of losing sight of the precepts and principles established in the light of existing knowledge. There is also a danger that we may fail to correct shortcomings in our existing procedures and practice. The aim of this presentation is to emphasize the importance of testing substances for their impact in advance of their use and to underline that we must use the best existing tools for carrying out risk assessments. Moreover, it needs to be stressed that there are many substances that are never assessed with respect to reproductive and developmental toxicity. Similarly, our programmes for post-marketing surveillance with respect to developmental toxicology are grossly inadequate. Our ability to identify risks to normal development and reproduction would be much improved, first if a number of straightforward precepts were always followed and second, if we had a clearer understanding of what we mean by risk and acceptable levels of risk in the context of development. Other aims of this paper are: to stress the complexity of the different stages of normal prenatal development; to note the principles that are applicable in developmental and especially prenatal toxicology; to describe the different agents that might act as developmental toxicants or teratogens; to show the broad scope of different effects caused by developmental toxic agents; and to indicate methods to detect and to recognise causes of developmental defects with the primary objective of preventing these disorders.

Abnormalities, Drug-Induced↗

PubMed2005

Toxicology screening in orthopedic trauma patients predicting duration of prescription opioid use.

Following hospitalization for orthopedic trauma, some patients continue to use opioids following fracture healing. This retrospective cohort study of 50 patients with high-energy fractures was conducted to determine if toxicology screening tests upon admission can predict subsequent opioid use. Data were collected from clinical records and a statewide electronic database of prescription records. Six months following hospital discharge, those with positive toxicology used more Following hospitalization for orthopedic trauma, some patients continue to use opioids following fracture healing. This retrospective cohort study of 50 patients with high-energy fractures was conducted to determine if toxicology screening tests upon admission can predict subsequent opioid use. Data were collected from clinical records and a statewide electronic database of prescription records. Six months following hospital discharge, those with positive toxicology used more. Following hospitalization for orthopedic trauma, some patients continue to use opioids following fracture healing. This retrospective cohort study of 50 patients with high-energy fractures was conducted to determine if toxicology screening tests upon admission can predict subsequent opioid use. Data were collected from clinical records and a statewide electronic database of prescription records. Six months following hospital discharge, those with positive toxicology used more opioids (730 mg vs. 364 mg; P = .04) expressed as morphine equivalents than those with negative toxicology and were more likely to continue using opiates at the end of the 3rd, 4th, 5th, and 6th month after discharge. Patients hospitalized for high-energy fractures with positive admission toxicology are at risk for prolonged opiate use during the initial six months following discharge.

Adult↗

PubMed1996

An overview of the development, validation, and application of neurobehavioral and neuromolecular toxicity assessment batteries: potential applications to combustion toxicology.

Currently, there are few alternatives to the use of animals in toxicology for human risk assessment. Neurobehavioral toxicology is an emerging area in which complex performance capacity is evaluated during or following toxicological exposure. While a number of single tests and a few more complex neurobehavioral batteries exist, no fully validated and comprehensive neurobehavioral toxicity assessment battery has yet been developed. The Neurobehavioral Toxicity Assessment Battery (NTAB) is a multi-test battery being developed by the Naval Medical Research Institute Detachment (Toxicology) (NMRI/TD) to categorize the potential neurobehavioral toxicity of compounds of Navy interest, especially those found in combustion atmospheres. The NTAB is intended to identify specific areas of deficit (e.g. motivational, sensory, motor, and cognitive) from complex changes in performance induced by toxic exposures, as well as to provide a mechanism to evaluate recovery of neurobehavioral integrity. Portions of the NTAB have been successfully used to assess the risk of brief exposure to low concentrations of combustion gases, including smoke from electrical aircraft fires, ozone-depleting substances and their replacements, and the novel neuroconvulsant trimethylolpropane phosphate. The goal of the NMRI/TD Neurobehavioral Toxicology Group and the Tri-Service Toxicology Consortium's neurobehavioral toxicology program is the incorporation of more molecular techniques involving neurophysiology, neuropharmacology, in vivo electrochemistry, and real-time microdialysis for correlative use with the neurobehavioral battery in human risk assessment. This overview discusses the application of neurobehavioral and neuromolecular endpoint test batteries to combustion toxicology.

Animals↗

PubMed2004

Particle and Fibre Toxicology, a new journal to meet a real need.

This Editorial is to announce Particle and Fibre Toxicology, a new Open Access, peer-reviewed, online journal published by BioMed Central. The field of particle and fibre toxicology has a long and famous history stretching from Agricola and Paracelsus in the 15th and 16th century to the challenges of the 21st century-nanoparticles, nanotubes and particulate matter (PM10) to name just three. Throughout this time there has been no single journal dedicated to the toxicology of particles and fibres and this is finally corrected by the launch of Particle and Fibre Toxicology. The rationale for Particle and Fibre Toxicology rests on this need for a single multi-disciplinary journal that can cover all research relevant to particle and fibre toxicology, from Hygiene studies, through particle generation and characterisation, to animal, cell and human toxicology studies, dosimetry and modelling. The editorial also deals with the philosophy and practicalities of Open Access publishing, the journal's peer-review policy and conflict-of-interest. Particle and Fibre Toxicology is aimed at bringing together multi-disciplinary research findings towards a better understanding of how particles and fibres adversely affect the lungs and the body generally. We hope that the launch of the new journal will aid in the advance of this important discipline to the greater benefit of occupational and public health and invite scientists working in this key discipline to submit their research.

Journal Article↗

PubMed1982

Toxicology in business decision making.

More than ever before, toxicology and its sister health sciences and technologies are needed as members of the business team to ensure sound business decision making for both new and existing businesses. Yet the marriage of toxicology and business is an uneasy one since toxicology is both the bringer of bad news and a major resource for the solution of problems. Both business and toxicology have much to learn about each other to make the marriage work and to make full use of toxicology's scientific advice in reaching sound decisions on the safe production, distribution, and handling of a company's products. Toxicology also has a central and difficult role in helping business navigate the turbulent waters of regulation or of potential or actual litigation. From his own experience in organizing a corporate health, safety, and environmental department, the author describes the concepts that must be understood and the marshaling of resources needed to ensure that toxicology can play its full role in business decision making.

Commerce↗

PubMed1991

Predictive value of animal studies in toxicology.

The three main purposes of experimental toxicology are (1) determination of the toxicological spectrum in selected laboratory animal species; (2) extrapolation to other species and prediction of adverse effects in man; and (3) determination of safe levels of exposure. Toxicology has reached a satisfactory level of performance in identifying toxicity in animals, and experimental techniques are now available to characterize the toxicological potential of chemical substances in great detail. In many instances, extrapolation of toxicological findings in animals to man is possible. It must also be admitted that toxicological studies have, at times, failed to predict human toxicity. In many cases, this can be explained by biological differences between animals and man. A particularly difficult problem is the "low incidence responses" that occur only in especially sensitive individuals. They represent a challenge that can be met only be a determined research effort. Failure to predict toxic responses in man is sometimes also brought about by the toxicologists' own faults. It is essential, therefore, that we analyze the errors committed in the past and continuously evaluate and improve our performance. Society's demand for specific safe levels of exposure is difficult to meet. After a long period of confusion and confrontation, toxicology appears to be on the road to a truly science-based methodology for risk assessment.

Animals↗

PubMed2005

Non-precautionary aspects of toxicology.

Empirical studies in toxicology aim at deciphering complex causal relationships, especially in regard to human disease etiologies. Several scientific traditions limit the usefulness of documentation from current toxicological research, in regard to decision-making based on the precautionary principle. Among non-precautionary aspects of toxicology are the focus on simplified model systems and the effects of single hazards, one by one. Thus, less attention is paid to sources of variability and uncertainty, including individual susceptibility, impacts of mixed and variable exposures, susceptible life-stages, and vulnerable communities. In emphasizing the need for confirmatory evidence, toxicology tends to penalize false positives more than false negatives. An important source of uncertainty is measurement error that results in misclassification, especially in regard to exposure assessment. Standard statistical analysis assumes that the exposure is measured without error, and imprecisions will usually result in an underestimation of the dose-effect relationship. In testing whether an effect could be considered a possible result of natural variability, a 5% limit for "statistical significance" is usually applied, even though it may rule out many findings of causal associations, simply because the study was too small (and thus lacked statistical power) or because some imprecision or limited sensitivity of the parameters precluded a more definitive observation. These limitations may be aggravated when toxicology is influenced by vested interests. Because current toxicology overlooks the important goal of achieving a better characterization of uncertainties and their implications, research approaches should be revised and strengthened to counteract the innate ideological biases, thereby supporting our confidence in using toxicology as a main source of documentation and in using the precautionary principle as a decision procedure in the public policy arena.

Dose-Response Relationship, Drug↗

PubMed2005

Latin America's present and future challenges in toxicology education.

Industrialization that Latin America has experienced during the past 50 years, the increase of population and the growth of chemical-related industries has generated a variety of environmental problems that must be addressed. After assessing these profound changes, greater emphasis should be placed on the study of environmental health and toxicology. Latin American countries face many problems that are common to other developing nations. Therefore, there is a demand for safety assessment and regulatory control of chemicals that create a need for increasing numbers of toxicologists. To meet this demand, educational programs in toxicology have to be designed. This paper utilizes a consultation questionnaire that includes toxicology-network members, scientists and educational institutions where toxicology is taught. An analysis of the information collected is made, with an emphasis on what we currently lack and on future challenges for toxicology professionals. Although the response from the study institutions was 65% (13 countries out of 20), the paper aims to assess the present situation of toxicology. The convenience for a certification/recognition for toxicologists is also evaluated. Action needs to be taken to promote scientific development based on regional specific needs that require increasing at the number of toxicology programs, and promoting of cooperation between academics and researchers. Among the limitations we have are the variability of curricula, objectives and priorities. The increasing globalization of markets and regulations requires the harmonization of graduate/postgraduate programs to ensure that risk assessment and management are dealt with uniformly. Cooperation among our countries and international assistance should play a more prominent role in the promotion of regional integration and the more efficient utilization of international experience in defining educational policies.

Latin America↗

PubMed2005

Africa's present and future needs in toxicology education: Southern African perspective.

Degrees and diplomas as well as certificates that are granted by universities and technikons in South Africa in scientific disciplines, such as forensic medicine, pharmacology, marine and veterinary sciences, environmental health, and occupational hygiene, include toxicology as one of the subjects in their overall syllabus. However, aspects of toxicology included in each of these courses are biased towards that particular subdiscipline and basic level of toxicology may be taught. Educational needs in toxicology in South Africa can be summarized as follows: (a) recognition of toxicology as a discipline in its own right at these tertiary education institutions and (b) creation of opportunities to study and obtain higher degrees in one or more of the many subdisciplines of toxicology. The results from a survey conducted on the toxicology syllabi offered at these tertiary education institutions are used to substantiate these needs.

Education↗

PubMed2004

The U.S. National Library of Medicine's Toxicology and Environmental Health Information Program.

For nearly 40 years, the National Library of Medicine's (NLM) Toxicology and Environmental Health Information Program (TEHIP) has been a significant leader in organizing and providing public access to an extensive storehouse of toxicological information through its online databases. With the advent of the Internet, TEHIP has expanded its role to also serve as a pre-eminent portal to toxicological information worldwide. Its primary databases reside within the web-based TOXNET system, and include the scientifically peer-reviewed Hazardous Substances Data Bank (HSDB), the U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS) and Toxics Release Inventory, the National Cancer Institute's Chemical Carcinogenesis Research Information System (CCRIS) and the TOXLINE file of over 3 million bibliographic references. TEHIP's ChemIDplus is an extensive chemical dictionary that extends beyond simple nomenclature to offer displays of molecular structures and links from particular chemicals to other databases containing more information. Specialty files in occupational safety and health, and household products have recently been added to TEHIP's suite of resources. Additional databases in risk assessment, drugs, toxicology education, and global resources, are under development. "Special Topics" pages lead users to structured summaries and links in areas such as arsenic, chemical warfare agents, biological warfare, and West Nile Virus. A database on alternatives to the use of live animals, a three-module toxicology tutor, and a glossary of terms in toxicology are among TEHIP's other information aids, as well an increasing commitment to serving consumers, as witnessed by the animated ToxTown program. Outside the sphere of TEHIP, NLM offers additional databases, such as PubMed, of significant value to toxicology researchers.

Animals↗

PubMedDate not supplied

Some current approaches for studying combination toxicology in chemical mixtures.

Using conventional toxicology methodologies and at the mode and rate of studying chemicals in the last 25 yr, it is doubtful that society will ever have adequate toxicology information on the majority of the chemicals we used now on in the future. Considering further the issue of health effects of chemical mixture exposure (i.e. real-world issues), the problem of not being able to obtain adequate toxicology information is amplified. From a different perspective, concerns over animal rights have raised the consciousness of many biomedical researchers regarding animal experimentation. As many as 17-100 million animals are estimated to be killed for biomedical research in the US alone each year; therefore, minimizing animal usage judiciously in toxicological research should be in the mind of every responsible toxicologist. From these considerations, it is apparent that new, alternative, less animal-intensive, shorter-term and less expensive toxicology methods must be developed if there is to be a reasonable chance to deal with the hundreds of thousand of chemicals, as well as the near-infinite number of chemical mixtures, in the environment. Some of the recent advances indeed are heading towards that direction. In this article, a number of approaches for research work on combination toxicology of chemical mixtures are given; the examples are selected based on one or more of the following criteria: (1) minimizing animal usage; (2) shortening experimental durations; (3) studying environmentally realistic concentrations; (4) utilizing statistical/mathematical modelling; (5) advancing efficient experimental designs and (6) developing predictive toxicology.

Animal Rights↗