US National Toxicology Program Research Articles

Chronic inhalation/carcinogenicity studies and their applications to prevent the occupational cancers: A review of recent reports

There are many carcinogens in workplaces that could cause occupational cancers. Compared with acute toxicity, chronic toxicity is a property of a substance that has toxic effects on a living organism when that organism is exposed to the chemicals continuously or repeatedly. Due to the increasing awareness of the importance of chronic toxicity or carcinogenicity studies, this type of research is on the rise, as much information can be gained from investigating occupational cancers. This study involves a critical review of the recent literature relating to chronic-inhalation or carcinogenicity tests that have been reported regarding inhalation exposure in laboratory animals, including rats and mice. Many of the chronic-inhalation/carcinogenicity studies are performed by governmental and for-profit-organizations, such as the International Agency for Research on Cancer (IARC), the US National Toxicology Program (NTP), the Japan Bioassay Research Center (JBRC), and the Battelle Institute, etc. As research leads to the development of novel types of industrial chemicals, there is a growing need to understand and evaluate the health impacts of these new chemicals in terms of occupational cancers; thus it is essential that we undertake proper and informative research and decision-making. Future research is needed to better characterize the toxicity associated with the chronic inhalation of chemicals and to refine the development of toxicity values. The Occupational Safety and Health Research Institute (OSHRI) in Korea Occupational Safety and Health Agency (KOSHA) are attempting to develop a robust system for chronic-inhalation/carcinogenicity studies and our goal is to undertake multiple studies to prevent occupational cancers.

Determination of formaldehyde in hair creams by gas chromatography-mass spectrometry.

The perfume and cosmetics industry are one of outstanding industrial sectors in Brazil. With an average annual growth of 11% over the last ten years, Brazil has achieved third place in the world ranking for consumption of cosmetics. Hair products are amongst the most consumed cosmetics and the market is growing every day. The active ingredients in hair straightening creams vary according to the product and usually include glutaraldehyde, sodium hydroxide, calcium hydroxide, formaldehyde, pyrogallol, thioglycolic acid, and others. Currently, the most widely used chemical compound in hair products to alter the protein structure of hair to affect smoothing is formaldehyde. Four international research institutions have assessed the carcinogenic potential of formaldehyde: the International Agency for Research on Cancer (IARC), the Environmental Protection Agency (EPA), the US National Toxicology Program, and the Occupational Safety and Health Association (OSHA). These studies demonstrated that exposure to formaldehyde can cause cancer of the pharynx and nasopharynx, increase the chance of pneumonia, dermatitis and induce allergic reactions (irritation of eyes, nose and throat, insomnia, chest pains, rashes, asthma attacks, among others). In 2001, the National Health Surveillance Agency (ANVISA), which is a branch of the Brazilian Ministry of Health, issued a resolution to control the use of formaldehyde, restricting it to a concentration of up to 0.2 % in cosmetics. However, the maximum (and safe) amount of formaldehyde (0.2%) permitted in cosmetic formulations is insufficient to produce straightened hair and in addition, is a health violation. Hair products for children have been identified for the presence of formaldehyde thus highlighting the importance for regulatory control in the cosmetic industry. The literature discusses somemethodologies and techniques for the analysis of formaldehyde in various samples such as blood, food samples, air, and cosmetics amongst others. Techniques such as spectrophotometry, capillary electrophoresis, and electrochemistry were used to determine formaldehyde. However, most of these techniques involve a series of tedious and labour-intensive extraction steps and they also suffer from low limits of detection (LOD) and quantification (LOQ). High performance liquid chromatography (HPLC) is the most widely applied method for the determination of formaldehyde. Gas chromatography coupled to mass spectrometry (GC-MS) is a versatile analytical technique and attempts have been made to apply GC-MS to the determination of formaldehyde with limited success. Unfortunately, the thermal instability makes direct quantification of formaldehyde by

Cross matching observations on toxicological and clinical data for the assessment of tolerability and safety of Ginkgo biloba leaf extract.

Ginkgo biloba is one of the most widely used herbal remedies in Europe and the US. It may be purchased in different types of formulations, but most of the clinical studies have been performed with the controlled G. biloba extract EGb761(®). Indications include Alzheimers disease, cardiovascular disease, dementia, memory loss, and cerebral ischemia. The pharmacological modes of action cover antioxidant effects, radical scavenging, inhibition of platelet activating factor, alterations in membrane fluidity (signal transduction), and inhibition of glucocorticoid synthesis. Due to the widespread and long-term use of G. biloba - about a million doses of EGb761(®) are sold per day - tolerability and safety are a crucial issue. Based on broad and long-term clinical use of G. biloba extracts, it is regarded as well tolerated in man. Cross matching, a tool we introduced, combines different fields of knowledge and types of data to a consolidated result. In this article, we combine toxicological and clinical data and utilize other sources of information to assess tolerability and safety of G. biloba. It is well known that because of biological differences between animals and man or even between animal species, animal experiments do not necessarily mimic the effects in humans. Therefore, for adequate risk assessment, the relevance of non-clinical toxicological findings should be correlated with human data. The cross matching of toxicological data and results from clinical studies is possible because many toxicological and clinical studies are available on G. biloba. We give an in depth analysis of the modes of action in animals and describe toxicological studies with regard to metabolism, pharmacokinetics, genotoxicity, as well as carcinogenicity (e.g., the Technical Report TR 578 of the US National Toxicology Program). In addition, 75 clinical trials with high methodological quality are summarized. They included a total of 7115 patients treated with G. biloba. Based on this extensive amount of information, the broad variety of investigations, and their accordance we conclude that G. biloba extract is well tolerated and safe for humans.

Which level of evidence does the US National Toxicology Program provide? Statistical considerations using the Technical Report 578 on Ginkgo biloba as an example

The US National Toxicology Program (NTP) is assessed by a statistician. In the NTP-program groups of rodents are fed for a certain period of time with different doses of the substance that is being investigated. Then the animals are sacrificed and all organs are examined pathologically. Such an investigation facilitates many statistical tests. Technical Report TR 578 on Ginkgo biloba is used as an example. More than 4800 statistical tests are possible with the investigations performed. Due to a thought experiment we expect >240 false significant tests. In actuality, 209 significant pathological findings were reported. The readers of Toxicology Letters should carefully distinguish between confirmative and explorative statistics. A confirmative interpretation of a significant test rejects the null-hypothesis and delivers “statistical proof”. It is only allowed if (i) a precise hypothesis was established independently from the data used for the test and (ii) the computed p-values are adjusted for multiple testing if more than one test was performed. Otherwise an explorative interpretation generates a hypothesis. We conclude that NTP-reports – including TR 578 on Ginkgo biloba – deliver explorative statistics, i.e. they generate hypotheses, but do not prove them.

Biological Networks for Predicting Chemical Hepatocarcinogenicity Using Gene Expression Data from Treated Mice and Relevance across Human and Rat Species

BackgroundSeveral groups have employed genomic data from subchronic chemical toxicity studies in rodents (90 days) to derive gene-centric predictors of chronic toxicity and carcinogenicity. Genes are annotated to belong to biological processes or molecular pathways that are mechanistically well understood and are described in public databases.ObjectivesTo develop a molecular pathway-based prediction model of long term hepatocarcinogenicity using 90-day gene expression data and to evaluate the performance of this model with respect to both intra-species, dose-dependent and cross-species predictions.MethodsGenome-wide hepatic mRNA expression was retrospectively measured in B6C3F1 mice following subchronic exposure to twenty-six (26) chemicals (10 were positive, 2 equivocal and 14 negative for liver tumors) previously studied by the US National Toxicology Program. Using these data, a pathway-based predictor model for long-term liver cancer risk was derived using random forests. The prediction model was independently validated on test sets associated with liver cancer risk obtained from mice, rats and humans.ResultsUsing 5-fold cross validation, the developed prediction model had reasonable predictive performance with the area under receiver-operator curve (AUC) equal to 0.66. The developed prediction model was then used to extrapolate the results to data associated with rat and human liver cancer. The extrapolated model worked well for both extrapolated species (AUC value of 0.74 for rats and 0.91 for humans). The prediction models implied a balanced interplay between all pathway responses leading to carcinogenicity predictions.ConclusionsPathway-based prediction models estimated from sub-chronic data hold promise for predicting long-term carcinogenicity and also for its ability to extrapolate results across multiple species.

Statistical evaluation of toxicological assays: Dunnett or Williams test—take both

The US National Toxicology Program recommends the use of the parametric multiple comparison procedures of Dunnett and Williams for the evaluation of repeated toxicity studies. For endpoints where either increasing or decreasing effects are of toxicological relevance, we recommend the use of the two-sided Dunnett test exclusively. For the many other endpoints, where a priori only one direction is of toxicological relevance, however, we recommend the combination of Dunnett and Williams test. In particular, we recommend the so-called Umbrella-protected Williams test which offers insights for all interesting monotone and non-monotone alternatives while only suffering a marginal loss in power compared to the Dunnett test. We illustrate the power difference analytically and compare the approach for different endpoint types using three real data examples to alternative tests available. Nonparametric tests, which are suitable for the evaluation of skewed distributed or scores data, are also considered. Particular attention is given to the different interpretations of the findings revealed by the different test. R programs used for the analyses are provided.

Bisphenol A: Update on newly developed data and how they address NTP’s 2008 finding of “Some Concern”

Bisphenol A (BPA) is a component of polycarbonate plastics and epoxy resins used in many commercial products including coatings and liners of food containers. Low levels of BPA can be detected in over 90% of human urine samples in the US, indicating that exposure to BPA is widespread. In 2008, the US National Toxicology Program's Center for the Evaluation of Risks to Human Reproduction (NTP-CERHR) expressed concerns regarding BPA's potential health effects, and suggested improved study designs and methodologies that they believed would address those concerns. This paper discusses some of the controversial issues surrounding BPA, summarizes the current regulatory status of BPA, reviews recent pharmacokinetic studies, and describes ongoing and planned research on the effects of BPA. In addition, we evaluate two papers studying BPA neurobehavioral effects, identified by the European Food Safety Authority and the German Federal Institute for Risk Assessment as being valid for use in risk assessment, to determine whether they address the NTP-CERHR methodological concerns. The data from these studies would likely be sufficient for NTP to lower its concern level for neurobehavioral effects of BPA. At this time, many regulatory agencies from around the world support the use of BPA in food contact materials.

MicroRNA expression profiles distinguish the carcinogenic effects of riddelliine in rat liver

Pyrrolizidine alkaloids (PAs) are the most common plant constituents that poison livestock, wildlife and humans. Riddelliine is a prototype genotoxic PA and has been nominated to be classified as a reasonably anticipated human carcinogen by the US National Toxicology Program (NTP) in the 12th Report on Carcinogens. Riddelliine's nomination is due to the high incidence of liver tumours that were observed in both mice and rats in the NTP tumourigenicity bioassay study. In this current study, we explored whether riddelliine treatment could alter microRNA (miRNA) expression in rat liver and whether the possible deregulation of miRNA was related to mutagenicity and carcinogenicity of riddelliine. Groups of six rats were administered riddelliine at a mutagenic dose of 1 mg/kg body weight or with control vehicle 5 days a week for 12 weeks. A group of six rats treated with aristolochic acid, a renal carcinogen, was used as a tissue-specific negative control. The animals were sacrificed 1 day after the last treatment and the livers were isolated for miRNA expression analysis using miRNA microarrays. miRNA expression was significantly altered by riddelliine treatment. Principal component analysis and hierarchical clustering analysis showed that the miRNA expression profiles were clearly classified into two groups, riddelliine treatment versus other samples. Forty-seven miRNAs were significantly dysregulated by riddelliine treatment, among which 38 were up-regulated and 9 were down-regulated. Functional analysis of these differentially expressed miRNAs by riddelliine revealed that these miRNAs were involved in liver carcinogenicity and toxicity, such as liver proliferation, liver necrosis/cell death, hepatocellular carcinoma, liver hepatomegaly, liver inflammation and liver fibrosis. These results suggest that miRNAs actively respond to a mutagenic dose of riddelliine and the pattern of miRNA expression has the potential to be used as a biomarker of genotoxicity and carcinogenicity for riddelliine and possibly other PAs.

Dose-Dependent Neurologic Abnormalities in Workers Exposed to 1-Bromopropane

Objectives:To investigate the health effects of 1-bromopropane (1-BP) and its dose-dependency in 1-BP production factories in China.Methods:Data of 60 female and 26 male workers in three 1-BP factories and the same number of age-, sex-, and region-matched controls were interviewed and examined. The

Two-year toxicity and carcinogenicity studies of Panax ginseng in Fischer 344 rats and B6C3F1 mice.

Ginseng is one of the most popular herbal supplements on the US market. Numerous reports of adverse effects from products containing ginseng have been filed with the US Food and Drug Administration (FDA) and the literature documents a "ginseng abuse syndrome" among regular users. However, the chronic toxic effects of ginseng are not well characterized. Because of its significant human exposure and the fact that little information on its toxicity is available, Panax ginseng was nominated by the US National Institutes of Health (NIH) to the US National Toxicology Program (NTP) to assess its carcinogenic potential. In this paper, we reported the results of NTP chronic toxicity and tumorigenicity bioassay. It shows that, under these experimental conditions, Panax ginseng is not toxic or tumorigenic.

A review of mammalian carcinogenicity study design and potential effects of alternate test procedures on the safety evaluation of food ingredients

Extensive experience in conducting long term cancer bioassays has been gained over the past 50 years of animal testing on drugs, pesticides, industrial chemicals, food additives and consumer products. Testing protocols for the conduct of carcinogenicity studies in rodents have been developed in Guidelines promulgated by regulatory agencies, including the US EPA (Environmental Protection Agency), the US FDA (Food and Drug Administration), the OECD (Organization for Economic Co-operation and Development) for the EU member states and the MAFF (Ministries of Agriculture, Forestries and Fisheries) and MHW (Ministry of Health and Welfare) in Japan. The basis of critical elements of the study design that lead to an accepted identification of the carcinogenic hazard of substances in food and beverages is the focus of this review. The approaches used by entities well-known for carcinogenicity testing and/or guideline development are discussed. Particular focus is placed on comparison of testing programs used by the US National Toxicology Program (NTP) and advocated in OECD guidelines to the testing programs of the European Ramazzini Foundation (ERF), an organization with numerous published carcinogenicity studies. This focus allows for a good comparison of differences in approaches to carcinogenicity testing and allows for a critical consideration of elements important to appropriate carcinogenicity study designs and practices. OECD protocols serve as good standard models for carcinogenicity testing protocol design. Additionally, the detailed design of any protocol should include attention to the rationale for inclusion of particular elements, including the impact of those elements on study interpretations. Appropriate interpretation of study results is dependent on rigorous evaluation of the study design and conduct, including differences from standard practices. Important considerations are differences in the strain of animal used, diet and housing practices, rigorousness of test procedures, dose selection, histopathology procedures, application of historical control data, statistical evaluations and whether statistical extrapolations are supported by, or are beyond the limits of, the data generated. Without due consideration, there can be result conflicting data interpretations and uncertainty about the relevance of a study’s results to human risk. This paper discusses the critical elements of rodent (rat) carcinogenicity studies, particularly with respect to the study of food ingredients. It also highlights study practices and procedures that can detract from the appropriate evaluation of human relevance of results, indicating the importance of adherence to international consensus protocols, such as those detailed by OECD.

Benzene as a cause of lymphoproliferative disorders

There is a long standing issue concerning the strength of evidence relating benzene to lymphocytic neoplasms. Because benzene is a known cause of human acute myelogenous leukemia there has been little reason for organizations such as the International Agency for Research on Cancer (IARC) or the US National Toxicology Program (NTP) to perform standard hazard identification reviews of benzene as a possible cause of other cancers such as lymphomas. Increased understanding of underlying mechanisms of carcinogenesis, as is reflected in the greater scope given to mechanistic evidence in assigning overall sufficiency of evidence for carcinogenicity by both IARC and NTP, suggests that the evidence supporting benzene as a cause of lymphoma likely has passed the threshold required for being listed as a known causal relationship. A broad range of genotoxic effects in the lymphocytes of benzene-exposed workers has been well documented, as has the role of chromosomal effects in carcinogenesis. There is also increasing evidence of a close relationship between lymphoid tumors and the types of myeloid tumors known to be caused by benzene. This includes the not infrequent finding of biphenotypic lineage as well as the formation of lymphoid as well as myeloid leukemias following chemotherapy. Studies of the mechanism of benzene toxicity are consistent with a relatively non-specific mechanism capable of producing multiple chromosomal changes, and there is evidence that the early hematopoietic stem cell, which is believed to be targeted by benzene in causing myeloid cancers, is also the progenitor of lymphocytic cell types. Furthermore, the classification of lymphomas has evolved so that non-Hodgkin lymphoma now includes such formerly distinct disorders as chronic lymphocytic leukemia and multiple myeloma, and there is less of a distinction between leukemia and non-leukemia forms of lymphoma.

Aflatoxicosis in Chickens (Gallus gallus): An Example of Hormesis?

Poultry has commonly been considered highly susceptible to aflatoxins. However, among domestic fowl there is wide variability in specific species sensitivity to these mycotoxins. Comparative toxicological studies in avian species have shown that ducklings and turkey poults are the most sensitive species to aflatoxins, quails show intermediate sensitivity, whereas chickens are the most resistant. Hormesis is a dose-response phenomenon characterized by low-dose stimulation and high-dose inhibition. The low-dose stimulation is typically maximal at only about 30 to 60% greater than controls. Hormesis has been noted in regards to changes in body weight in numerous studies, including those performed for the US National Toxicology Program, with over 50 chemicals. The present paper assesses how relatively low levels of aflatoxin consumption in feed may affect the growth rate of chickens. In general, multiple independent investigations have shown that such aflatoxin consumption affects growth in a hormetic-like biphasic manner with a low dose stimulation and a high dose inhibition. Such observations were then generalized to other toxic agents and animal models, suggesting that low doses of stressor agents induce adaptive responses as reflected in accelerated growth rates. The implications of such hormetic dose responses are briefly discussed.

Carcinogenic Food Contaminants

A large number of scientific studies and reviews have addressed the potential for dietary components to influence the risk of developing cancer. One topic of particular interest has been the impact of food contaminants. Two complementary programs, among others, have reviewed and synthesized information on the carcinogenic potential of food contaminants and judged the degree of evidence linking different food contaminants to the risk of cancer in humans. These programs, the International Agency for Research on Cancer's IARC Monographs on the Evaluation of Carcinogenic Risks to Humans and the US National Toxicology Program's Report of Carcinogens have reviewed hundreds of chemicals, mixtures, and natural products and then graded the cancer risk posed to humans. Contaminants with the highest level of evidence include aflatoxin, alcoholic beverages, 2,3,7,8-tetracholordibenzo-p-dioxin. Agents with a moderate level of evidence include acetaldehyde, polycyclic aromatic hydrocarbons, some nitrosamines, and yerba mate. Agents with a low level of evidence include bracken fern, fumonsin B1, ochratoxin, and others. This review presents a summary of the evidence for the carcinogenicity of these and other agents and the ranks provided by two important assessment programs.

A Survival-Adjusted Quantal Response Test for Comparing Tumour Incidence Rates

Summary The paper presents a case-study of skin fibromas among male rats in the 2-year cancer bioassay of methyleugenol that was conducted by the US National Toxicology Program (NTP). In animal carcinogenicity experiments such as this one, tumour rates are often compared with the Cochran–Armitage (CA) trend test. The operating characteristics of the CA test, however, can be adversely affected by survival differences across groups and by the assumed dose metric. Survival-adjusted generalizations of the CA test have been proposed, but they are still sensitive to the choice of scores that are assigned to the dose groups. We present an alternative test, which outperforms the survival-adjusted CA test which is currently used by the NTP to compare incidence rates. Simulated data from a wide range of realistic situations show that the operating characteristics of the test proposed are superior to those of the NTP’s survival-adjusted CA test, especially for rare tumours and wide logarithmic spacings of the dose metric.

Medio ambiente y cáncer pediátrico

Cancer is the final result of the variable combination of two determinants: endogenous or constitutional factors and exogenous or environmental factors. Between 85 % and 96 % of pediatric cancers (PC) are probably associated with environmental risk factors (RF), most of which have not been identified. The spectacular progress made in survival in PC contrasts with the lack of knowledge of the RF implicated in its etiopathogenesis. 1) To analyze up-to-date knowledge of the interaction among environmental RF in the etiopathogenesis of PC, and 2) to inform pediatricians of the "Environment and Pediatric Cancer" research project directed by the Pediatric Environmental Health Specialty Unit of the Hospital Infantil Universitari La Fe in Valencia (Spain). Current medical records focus almost exclusively on the diagnosis and treatment of cancer. The Pediatric Environmental Medical Record will contain the validated items required to document and presence or absence of endogenous and exogenous RF associated with PC described in the literature, as well as the main human cancerogenic agents identified by the International Agency for Research on Cancer and the US National Toxicology Program. The project aims to determine the frequency of endogenous and exogenous RF associated with PC in Spain. This project will enable hypotheses to be formulated for future epidemiologic case-control and cohort studies in Spain and other European countries, thus stimulating the introduction of educational and preventive policies in the Spanish population. The project requires the aid of all hospital and non-hospital pediatricians involved in pediatric cancer in informing parents and offering them the possibility of voluntarily collaborating in the "Environment and Pediatric Cancer" project by contacting the Pediatric Health Specialty Unit (Unidad de Salud Medioambiental del Hospital Infantil La Fe de Valencia [www.pehsu.org]). The collaboration of our colleagues will be essential in gaining greater insight into the RF associated with PC and in achieving prevention in the medium and long term.

Evaluation of Some In Vitro Tests to Reduce and Replace the Sub-acute Animal Toxicity Studies

The toxicologic and carcinogenic potential of chemicals is usually determined through a sequence of acute, sub-acute (14-day), sub-chronic (90-day) and chronic (two-year) studies in rats and mice of both sexes. The US National Toxicology Program (NTP) does not conduct acute toxicity studies. Dose levels for 14-day toxicity studies are typically estimated from information in the literature, if available. The toxicology information obtained from 14-day studies is used in the selection of doses for 90-day studies. The protocol for 14-day studies consists of five doses and control groups and five animals per group of each sex and species, resulting in the use of 120 animals per study. At present, in addition to refining the current testing protocols, the NTP is evaluating the potential for in vitro test methods to partially or completely avoid the need for 14-day toxicity studies, especially for chemicals where the dermal route of exposure is used. The in vitro assays used were the EpiDerm bioassay to estimate dermal irritation, the neutral red uptake (NRU) bioassay to estimate systemic toxicity and the primary rat hepatocyte cytotoxicity (PRHC) assay to estimate hepatotoxicity. The purpose of using these assays was to assess their potential for predicting relative in vivo toxicity and to support dose selection decisions for 90-day studies. In general, based on these limited number of studies, the EpiDerm and NRU tests were predictive of the responses observed in in vivo studies. However, a larger comparative database is needed to derive definitive conclusions regarding the value of in vitro tests in the prediction of in vivo effects.

Naphthalene--an environmental and occupational toxicant.

For many years naphthalene had been considered as a non-carcinogenic polycyclic aromatic hydrocarbon (PAH). Airborne naphthalene concentrations have always been observed to be below the limit values of various national committees, such as the threshold limit value (TLV) of the American Conference of Governmental Industrial Hygienists (ACGIH) and the MAK of the Deutsche Forschungsgemeinschaft (DFG) (10 ppm). Since 2000, when the US National Toxicology Program revealed clear evidence of the carcinogenic activity of naphthalene in rats, international agencies [the International Agency for Research on Cancer (IARC), the US Environmental Protection Agency (US EPA), DFG] have reclassified naphthalene as a potential human carcinogen, and the European Union (EU) is currently preparing a new risk assessment report. It is presently unknown how to protect humans from health risks resulting from occupational and environmental naphthalene exposure. Knowledge about the external and internal exposure of humans serves as the key determinant in a comprehensive risk assessment. We review here ambient monitoring studies concerning the external naphthalene exposure that results from ubiquitous environmental sources (indoor and outdoor air, water, soil, food) and from a variety of critical workplaces (coking plants, creosote impregnation, distillation of coal tar and naphthalene, manufacture of refractories, graphite electrodes, aluminium and mothballs). Based on results of ambient monitoring studies published so far, a new hygiene-based exposure limit of 1.5 mg naphthalene per cubic metre of air (0.3 ppm) is proposed. Furthermore, results from biological monitoring studies are summarised in this article. The internal burden was almost exclusively determined by means of the urinary metabolites 1-naphthol and 2-naphthol, but it is currently not possible for one to evaluate a biological tolerance level (BAT) or a biological exposure index (BEI). Based on the toxicokinetics and metabolism of naphthalene, the central question on its carcinogenicity is briefly sketched. Naphthoquinones play an important role in this context. Their adducts with macromolecules may be the parameters of choice for the estimation of effects to human health.

A survey of the Predictive Toxicology Challenge 2000-2001.

The Predictive Toxicology Challenge (PTC) was initiated to stimulate the development of advanced techniques for predictive toxicology models. The goal of this challenge was to compare different approaches for the prediction of rodent carcinogenicity, based on the experimental results of the US National Toxicology Program (NTP). 111 sets of predictions for 185 compounds have been evaluated on quantitative and qualitative scales to select the most predictive models and those with the highest toxicological relevance. The accuracy of the submitted predictions was between 25 and 79 %. An evaluation of the most accurate models by toxicological experts showed, that it is still hard for domain experts to interpret the submitted models and to put them into relation with toxicological knowledge. PTC details and data can be found at: http://www.predictive-toxicology.org/ptc/.

Toxicity characterization of environmental chemicals by the US National Toxicology Program: an overview

The US National Toxicology Program (NTP) is an interagency program whose mission is to evaluate agents of public health concern by developing and applying the tools of modern toxicology and molecular biology. Chemicals substances or physical agents selected for toxicology and carcinogenesis evaluations by the NTP are usually studied in a series of subacute (14-day exposure), subchronic (90-day exposure) and chronic (2-year exposure) studies in rodents. The NTP has published more than 500 reports of the findings and conclusions from its toxicology and carcinogenesis studies. In more specialized studies, the NTP also evaluates adverse effects on the structure and function of the immune, reproductive, nervous, and respiratory systems. The program attempts to evaluate and appropriately incorporate new technologies to improve the way we study the toxicity of chemicals. For example, the program has extensively evaluated several transgenic mouse models for their potential use as short-term cancer screens and has been a full participant in an international effort to examine their usefulness in pharmaceutical registration. Toxicogenomics, an emerging scientific field that examines the expression of thousands of genes simultaneously in response to chemical exposure, holds promise for future application to better understand the underlying mechanisms of chemical toxicity. A number of public health issues being addressed by the NTP are not only of national importance but also have global impact, such as the potential for endocrine disruptors to influence development and carcinogenesis and the safety of herbal medicines and dietary supplements. The program participates in the preparation of national and international toxicity testing guidelines and the findings from NTP studies are widely used for risk assessments by international organizations and federal agencies. The NTP maintains databases that contain toxicity, and health and safety information on a large number of chemicals. These databases are available from the NTP web site (http://ntp-server.niehs.nih.gov) and are accessed over 100 000 times a month from around the world.