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Toxicology studies suggest that exposure to certain types of engineered nanomaterials (ENMs) may cause adverse health effects, but little is known about the workforce in the United States that produces or uses these materials. In addition, occupational exposure control strategies in this industry are not well characterized. This study identified U.S. ENM manufacturers and users (other than carbon nanotubes and nanofibers, which have been characterized elsewhere), determined workforce size, characterized types and quantities of materials used, occupational exposure control strategies, and the feasibility of occupational ENM exposure studies.Eligible companies were identified and information was collected through phone surveys on nanomaterials produced or used, workforce size, location, work practices, and exposure control strategies. The companies were classified into groups for additional examinations.Forty-nine companies producing or using ENMs in the U.S. were identified. These companies employed at least 1,500 workers. Most companies produced or used some form of nanoscale metal. More than half of the eligible companies were suppliers for the coatings, composite materials, or general industries. Each company provided information about worker exposure reduction strategies through engineering controls, administrative controls, or personal protective equipment. Production-scale companies reported greater use of specific exposure control strategies for ENMs than laboratory-scale companies.Workplaces producing or using ENMs report using engineering and administrative controls as well as personal protective equipment to control worker exposure. Industrywide exposure assessment studies appear feasible due to workforce size. However, more effort must be taken to target industries using specific ENMs based on known toxicological effects and health risks.

The US Environmental Protection Agency Endocrine Disruptor Screening Program (EDSP) is a tiered screening approach to determine the potential for a chemical to interact with estrogen, androgen, or thyroid hormone systems and/or perturb steroidogenesis. Use of high-throughput screening (HTS) to predict hazard and exposure is shifting the EDSP approach to (1) prioritization of chemicals for further screening; and (2) targeted use of EDSP Tier 1 assays to inform specific data needs. In this work, toxicology data for three triazole fungicides (triadimefon, propiconazole, and myclobutanil) were evaluated, including HTS results, EDSP Tier 1 screening (and other scientifically relevant information), and EPA guideline mammalian toxicology study data. The endocrine-related bioactivity predictions from HTS and information that satisfied the EDSP Tier 1 requirements were qualitatively concordant. Current limitations in the available HTS battery for thyroid and steroidogenesis pathways were mitigated by inclusion of guideline toxicology studies in this analysis. Similar margins (3–5 orders of magnitude) were observed between HTS-predicted human bioactivity and exposure values and between in vivo mammalian bioactivity and EPA chronic human exposure estimates for these products’ registered uses. Combined HTS hazard and human exposure predictions suggest low priority for higher-tiered endocrine testing of these triazoles. Comparison with the mammalian toxicology database indicated that this HTS-based prioritization would have been protective for any potential in vivo effects that form the basis of current risk assessment for these chemicals. This example demonstrates an effective, human health protective roadmap for EDSP evaluation of pesticide active ingredients via prioritization using HTS and guideline toxicology information.

Sulfoxaflor, a novel active substance that targets sap-feeding insects, induced rodent hepatotoxicity when administered at high dietary doses. Specifically, hepatocellular adenomas and carcinomas increased after 18 months in male and female CD-1 mice at 750 and 1250 ppm, respectively, and hepatocellular adenomas increased after 2 years in male F344 rats at 500 ppm. Studies to determine the mode of action (MoA) for these liver tumors were performed in an integrated and prospective manner as part of the standard battery of toxicology studies such that the MoA data were available prior to, or by the time of, the completion of the carcinogenicity studies. Sulfoxaflor is not genotoxic and the MoA data support the following key events in the etiology of the rodent liver tumors: (1) CAR nuclear receptor activation and (2) hepatocellular proliferation. The MoA data were evaluated in a weight of evidence approach using the Bradford Hill criteria for causation and were found to align with dose and temporal concordance, biological plausibility, coherence, strength, consistency, and specificity for a CAR-mediated MoA while excluding other alternate MoAs. The available data include: activation of CAR, Cyp2b induction, hepatocellular hypertrophy and hyperplasia, absence of liver effects in KO mice, absence of proliferation in humanized mice, and exclusion of other possible mechanisms (e.g., genotoxicity, cytotoxicity, AhR, or PPAR activation), and indicate that the identified rodent liver tumor MoA for sulfoxaflor would not occur in humans. In this case, sulfoxaflor is considered not to be a potential human liver carcinogen.

Fiber dimension (especially length) and biopersistence are thought to be important variables in determining the pathogenicity of asbestos and other elongate mineral particles. In order to prepare samples of fibers for toxicology studies, it is necessary to develop and evaluate methods for separating fibers by length in the micrometer size range. In this study, we have filtered an aerosol of fibers through nylon screens to investigate whether such screens can efficiently remove the long fibers (L >20 μm, a typical macrophage size) from the aerosol stream. Such a sample, deficient in long fibers, could then be used as the control in a toxicology study to investigate the role of length. A well-dispersed aerosol of glass fibers (a surrogate for asbestos) was generated by vortex shaking a Japan Fibrous Material Research Association (JFMRA) glass fiber powder. Fibers were collected on a mixed cellulose ester (MCE) filter, imaged with phase contrast microscopy (PCM) and lengths were measured. Length distributions of the fibers that penetrated through various screens (10, 20 and 60 μm mesh sizes) were analyzed; additional study was made of fibers that penetrated through double screen and centrally blocked screen configurations. Single screens were not particularly efficient in removing the long fibers; however, the alternative configurations, especially the centrally blocked screen configuration, yielded samples substantially free of the long fibers.

ADX71943 is a potent and selective GABA(b) receptor positive allosteric modulator (PAM) which exhibits poor aqueous solubility at all physiologically relevant pHs. The aim of this study was to identify an adequate formulation to improve the solubility of ADX71943 to achieve a sufficiently high plasma exposure after oral administration to support the toxicology program. Considering the overall physicochemical properties and the low solubility of ADX71943 in a variety of solvents, solid dispersion, and particle size reduction have been successfully chosen as potential strategies to improve its oral bioavailability. Both technologies have proven useful in improving the in vitro dissolution profile and as a result of the solubility enhancement, higher bioavailability was obtained in vivo. As the solid dispersion gave better bioavailability (30-fold compared with the neat active pharmaceutical ingredient (API)), this formulation was selected for the toxicology study. Changing the crystalline form of ADX71943 into amorphous state by preparing a solid dispersion has greatly improved its oral bioavailability and has allowed achieving the required plasma concentration needed in toxicology studies.

For several years, the FDA has requested that sponsors submit clinical trial data in CDISC SDTM format. Recently, the FDA has begun requiring submissions of other forms of data to be in standardized CDISC formats, for example, CDISC ADaM for analysis data, and CDISC SEND for animal toxicology studies. While commercial tools have been available to validate CDISC SDTM data since the beginning of this standardsadoption process, they have not been freely available to everybody. OpenCDISC. org was initiated in 2008 as an open source community dedicated to the creation of extensible tools for the implementation of CDISC standards, with an initial focus on data validation. The OpenCDISC Validator is built using Java and is configurable so that it can check not only various versions of CDISC data, but can also be tailored to meet the specific needs of a particular submission or a particular setting within a pharmaceutical company. The tool is configured using XML files, which can be modified or created us...

A Right-First-Time approach is described for developing bona fide formulations for First-In-Human (FIH) to Proof-Of-Concept (POC) studies to meet an overarching goal of reduced project cycle time from IND to NDA (as short as four years). Bona fide formulations are tailor-made according to the drug's biopharmaceutical properties including solubility, permeability and stability. Solubilization techniques are used extensively to reduce oral absorption variability for most compounds. Bona fide formulations contain all necessary functional excipients such as diluent, solubilizer, stabilizer, pH adjuster, disintegrant and lubricant so formulation changes are minimized to avoid significant PK bridging studies. Cycle time of FIH formulation development is aligned with IND-enabling toxicology studies, generally 4-6 months. Resources range from 0.5 full time equivalents (FTE) for a BCS-1 compound to 3 FTE for a BCS-4 compound with high drug delivery hurdles. We have achieved our goal by taking the same formulation from FIH to POC 90% of the time and maintaining the same formulation platform from POC to commercial manufacturing 80% of the time in the past eight years. This strategy enables cycle time reduction from 7 to 4 years for IND to NDA by overlapping clinical study phases and eliminating clinical downtime due to PK bridging studies.

There are many ways in which the dose can be expressed in inhalation toxicology studies. This can lead to confusion when comparing results from studies performed in different laboratories. A working party of the Association of Inhalation Toxicologists has reviewed this subject in detail and has collected data from 10 inhalation laboratories and used these data to determine a new algorithm for the calculation of Respiratory Minute Volume (RMV), one of the most important factors in the calculation of delivered dose. The recommendations of the working party for regulatory inhalation toxicology studies with pharmaceuticals are as follows: 1. The dose should be reported as the delivered dose calculated according to the formula: DD = C x RMV x D(xIF)/BW, where DD = delivered dose (mg/Kg); C = concentration of substance in air (mg/L); RMV =respiratory minute volume or the volume of air inhaled in one minute (L/min); D = duration of exposure (min); IF = proportion by weight of particles that are inhalable by the test species, the inhalable fraction (inclusion of this parameter is not essential provided that the aerosol has reasonable respirability for the intended species. If it is included, the way in which it is determined should be clearly stated); BW = bodyweight (Kg). 2. The RMV for mice, rats, dogs and cynomolgus monkeys should be calculated according to the formula:RMV(L/min) = 0.608 x BW(Kg)(0.852). 3. If deposited dose or the amount of material actually retained inthe respiratory tract is presented as supplementary information,the way in which it is calculated should be clearly stated.4. Dose should always be presented in mg/Kg but may also bepresented in other ways, such as mg/unit body surface area, as supplementary information.

The assessment of the quality levels of pharmaceutical formulations is done through various validation parameters. Validation of these analytical test procedures is the process by which it is established that the test methods meet the requirements for the intended analytical application. The validation criterion also applies to bioanalytical methods used for non‐human pharmacology/toxicology studies and preclinical studies. Bioanalytical method validation includes all the procedures, which demonstrate that a particular method used for quantitative measurement of analytes in a given biological matrix, such as blood, plasma, serum, or urine, is reliable and reproducible for the intended use.

Nanomaterials are now being manufactured and used in many products. However, our knowledge of the human health effects and environmental concentrations of engineered nanomaterials or nanoparticles is incomplete. This article gives a toxicologists perspective, outlining possible routes of uptake by humans, environmental concentrations, known or suspected toxic effects, and the practical implication for human health risk assessments and public perception. Humans are already exposed to a range of natural and man-made nanoparticles in the air, and exposure via the food chain, water supply, and medical applications is likely. Toxicology studies on animals, and cells in vitro, raise the possibility of adverse effects on the immune system, oxidative stress related disorders, lung disease and inflammation. However, the doses needed to produce these effects are generally high and it remains to be seen if such exposure is possible via the environment or the work place. Data on exposure is also needed for r...

Due to the potential for long-term, low-level exposure of environmental species to pharmaceuticals in the environment, concerns over chronic ecotoxicity have been raised. Pharmaceuticals typically have specific enzyme and receptor-based modes of action, which are extensively studied in mammals during drug development. A survey of the literature demonstrated that there is conservation of many enzyme/receptor systems between mammalian and teleost systems. Based on this conservation of enzyme/receptor systems across teleost species, a model has been developed to utilize the information from mammalian pharmacology and toxicology studies to evaluate the potential for chronic receptor mediated responses in fish. In this model, a measured human therapeutic plasma concentration (HTPC) is compared to a predicted steady state plasma concentration (FSSPC) in fish, and an effect ratio (ER = HTPC/FSSPC) is computed. The lower the ER, the greater the potential for a pharmacological response in fish. Data collection and...

Sufficient information is available to show that pesticides can be properly applied and used safely in forest management. However, much of the information on the effects of pesticides on soil organisms is often based on methodologies involving soil processes (i.e., toxicology studies) rather than on individual groups of organisms. Because more than one group of soil organisms may carry out the same function, the effects of pesticides on a particular group can be missed. On the other hand, while laboratory test may show pesticide effects on one group under an array of controlled conditions, the same organism may respond differently in a field setting. Not much information is available on soil organisms resulting from combining various silvicultural herbicides or pesticides. Information is presented to show that with few exceptions, pesticides can affect soil organism populations, but the effects may be short-term with little noticeable long-term affect on soil health and quality.

The skin as a route of entry for toxic chemicals has caused increasing concern over the last decade. The assessment of systemic hazards from dermal exposures has evolved over time, often limited by the amount of experimental data available. The result is that there are many methods being used to assess safety of chemicals in the workplace. The process of assessing hazards of skin contact includes estimating the amount of substance that may end up on the skin and estimating the amount that might reach internal organs. Most times, toxicology studies by the dermal route are not available and extrapolations from other exposure routes are necessary. The hazards of particular chemicals can be expressed as "skin notations", actual exposure levels, or safe exposure times. Characterizing the risk of a specific procedure in the workplace involves determining the ratio of exposure standards to an expected exposure. The purpose of this review is to address each of the steps in the process and describe the assumptions that are part of the process. Methods are compared by describing their strengths and weaknesses. Recommendations for research in this area are also included.

The Annapolis Center, in partnership with the Society of Toxicology and the American College of Clinical Pharmacology, convened a workshop to draft a series of accords (or principles) to help guide the interpretation and use of data from toxicology studies in human health-risk assessment and risk management. Workshop participants included 12 toxicologists from the fields of environmental health assessment, food safety, and pharmaceutical development. The participants hope that the accords set forth here will serve as guideposts for the purposes of evaluating the strengths and weaknesses of past risk analyses, and of improving the quality of future analyses. The accords are the product of the workshop participants' consensus and do not necessarily represent the opinions of the participants' employers.

Assessment of the endocrine function in toxicology studies implies hormone determination in a number of animal species. Radioimmunoassay (RIA) constitutes the most widely used methodology for this purpose. RIA, however, presents important disadvantages inherent in the use of radiosotopes. In an attempt to look for nonisotopic alternatives to animal hormone dosage, two commercial, nonisotopic assays for the direct measurement of total human thyroxine concentration were compared with an RIA used routinely in our laboratory. Total thyroxine (T 4) in the miniature pig was the parameter chosen for this comparison study. Several protocols, using identical miniature-pig samples, were used to compare stability, precision, sensitivity, accuracy, and bias. Precision and sensitivity studies determined the useful detection range for RIA, enzyme immunoassay (EIA), and luminescent immunoassay (LIA), which were 0.95-9.50 mug/dL, 2.70-13.00 mug/dL, and 0.45-20 mug/dL, respectively. Matrix-effect studies showed that only ...

The Compass Plot, a new graphical methodthat combines the advantages of the star plot andthe analysis of means (ANOM), has beenintroducedfordisplaying the results of experiments. Incontrast to the star plot, this plot allows statistical inferences to be made for treatment and for factor effects. In contrast to ANOM, this plot is good for comparison in multiresponse experiments, a scenario becoming more commonplace in toxicology with the advent of increasing numbers of chemical mixture studies. An example of a 2 3 factorial chemical exposure experiment is considered here.

A quality-management program (QMP) has been launched at the Naval Medical Research Institute Toxicology Detachment to support the planning, assessment, interpreting, and reporting of toxicology study data. The QMP conforms to the intent of the Good Laboratory Practice established by the Food and Drug Administration and the Environmental Protection Agency for regulatory compliance. The biomedical data necessary to characterize the toxicity of materials of interest to the Navy are used to formulate occupational and environmental health-hazard evaluations and risk assessments, including appropriate exposure limits for personnel for Navy-specific circumstances of exposure. The goal of the QMP is to help management and investigators ensure the quality and integrity of the data collected in laboratory animal toxicology studies. These data are used to reduce or eliminate potential health risks from exposure to toxicants during Navy operations. The primary purpose of the risk-reduction program is to help ensure readiness to accomplish the military mission. This article briefly reviews the need for the QMP and the military relevance of the quality-assurance requirements. The pros and cons of establishing the QMP are discussed, and examples of specific research projects and programs that support the need for a quality management program are presented. Aspects of integrating the QMP program to ensure compliance with Good Laboratory Practice are reviewed, and the value of the improvements in the quality of data from the Naval Medical Research Institute/Toxicology Detachment is summarized.

The mouse has been used almost exclusively as the experimental animal for host resistance studies in the United States. Host resistance models in mice have been validated and these types of studies are an integral part of the National Toxicology Program's (NTP) immunotoxicology testing program. Given that the Fischer 344 rat is the animal of choice for the NTP's toxicology studies, it was desirable to develop host resistance assays in this rat strain, eliminating the need to extrapolate doses between mouse and rat models. These studies were aimed at the development and the validation of a host resistance model to Listeria monocytogenes, a gram-positive, facultative intracellular bacterium, in the Fischer 344 rat. The results demonstrated that L. monocytogenes infection in the Fischer 344 rat produces a very similar disease with respect to onset and duration as in the mouse. Animals inoculated with up to 3 105 viable colony forming units (CFU) of L. monocytogenes were capable of resisting overt disease whe...

In this program, as in all public health research, defining and quantifying “dose”; of an agent is a critical step. The primary foci of the dosimetry risk evaluation research program are (1) improved definition and quantification of dosage in humans; (2) development of exposure systems for in vivo toxicology studies which are capable of adequately reproducing in experimental animals the level and distribution of energy absorption sustained by humans using wireless communication instruments; and (3) development of exposure systems for in vitro toxicology studies which produce as uniform an exposure as possible, while maintaining cell temperature as close to 37°C as possible, at the frequencies, modulations, and power levels similar to those employed in cellular technology.

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.

Results of in vivo toxicology studies over the last decade have led to increased interest in the potential carcinogenicity of crystalline silica. Most significantly, the International Agency for Research on Cancer in 1987 declared crystalline silica a 2A carcinogen (sufficient evidence in animals, insufficient evidence in humans). A review of published animal studies suggests that this classification is based on results in a single species of rodent (rat) in which no adequate dose—response data exist and where comparability of methods is difficult. Investigations using at least three other common rodent species have been uniformly negative even in strains with acknowledged sensitivities to a broad range of pulmonary carcinogens. Several investigators have observed that lung tumors develop in the rat as a response to a number of inert dusts when other species respond with only minor changes in pulmonary tissues and cells. In the rat, changes in clearance mechanics may be related to increased cellu...

Jugular vein cannulation of rats is a method widely used in biochemical toxicology studies to allow intravenous administration of toxicants and/or temporal collection of blood samples. Methods typi...

A chronically instrumented dog model has been developed to conduct preclinical studies of the cardiovascular pharmacology and toxicology of pharmaceuticals. Eight conscious, unrestrained dogs can be simultaneously studied while cardiovascular signals are acquired through the use of flexible tethers, sealed mercury rotary connectors, and digital data acquisition and analysis systems. Test articles can be administered by either oral or intravenous routes. Intravenous infusions are performed via indwelling cannulae and remote controlled infusion pumps. The principle of operation is explained for implantable micromanometers, and sonomicrometers as well as electromagnetic, transit time, and Doppler blood flowmeters. Historical references are provided for the development of several of these devices. Techniques are described to perform aseptic thoracotomy surgery and to implant devices to measure cardiac left ventricular and aortic blood pressure, left ventricular wall thickness or segment length, and blood flow...

To improve the clinical utility of amphotericin B, we have developed a novel formulation of amphotericin B, Amphocil® (also known as Amphotericin B Colloidal Dispersion, or ABCD). Amphocil is a uniform disc-shaped complex of amphotericin B and sodium cholesteryl sulfate in a molar ratio of 1:1. The complex has a mean hydrodynamic diameter of approximately 115 nm and is thermodynamically stable. In an extensive series of pharmacodynamic, pharmacokinetic and toxicology studies, Amphocil was found to be less toxic than conventional amphotericin B (Fungizone®), providing a four- to five-fold improvement in safety, while remaining effective in treating a variety of fungal infections. Plasma pharmacokinetics and tissue disposition of amphotericin B differ in several respects after administration of Amphocil and conventional amphotericin B, due to a rapid uptake of Amphocil by liver. Animals receiving Amphocil demonstrated reduced peak levels in plasma, prolonged residence time and lowered levels of amph...

Utibapril is a novel thiadiazoline that is currently under investigation as an antihypertensive agent. The major degradation product, a diacid FPL 63674XX, is biologically active. An HPLC method has been developed to simultaneously determine both utibapril and its diacid in rodent laboratory diet used to dose animals in long term toxicology studies. The method is based on liquid-solid extraction of the compounds followed by direct injection of the extract. Gradient elution chromatography is utilized to better separate the diacid from interferences. Recovery of utibapril and the diacid from the lab diet was found to be 97.6 ± 0.44% and 99.7 ± 2.8%, respectively (n=3) at 0.43% w/w levels. The separation is achieved on a octadecylsilane column using a flow rate of 0.75 ml/min and a column temperature of 70°C. The UV detector was set at 260 nm. A linear and step gradient program was established using mobile phases consisting of 0.05 M

Results obtained in animal toxicology studies are extrapolated to humans to set standards in the workplace and to evaluate the levels of contaminants found in the environment. Predictions are made about potential adverse effects in humans based on the toxicity observed in laboratory animals if human data are limited or nonexistent. This approach is an important first step. However, humans do not always respond to chemical exposures in the same way animals do, nor is it always true that proximity to a chemical substance necessarily means that the chemical is actually taken up and absorbed or that absorption is complete. Most common chronic diseases of the general population are multifactorial in origin. Important factors that modulate chronic diseases are genetic make-up, chronic virus infections, improper nutrition, smoking, and drug and alcohol abuse. Exposure to trace amounts of synthetic chemicals found in the environment has, in most instances, little or no impact. However, certain occupation...

The use of a molecular encapsulator, α-cyclodextrin (α-CD), as a novel gavage dosing vehicle in toxicology studies was investigated. p-Chloro-α,α,α-trifluorotoluence (CTFT) was chosen as the test chemical. CTFT can be easily encapsulated at the molecular level using α-CD molecular encapsulator in aqueous solution. The resulting molecular-encapsulated CTFT precipitates can be suspended homogeneously in water and can be used as a gavage formulation. The stability and syringeability of this gavage formulation were evaluated prior to being used in a toxicology study. Comparative studies showed that the molecular encapsulator released CTFT more rapidly than conventional corn oil vehicle after gavage dosing to male F344 rats. The results of this study indicate that the molecular encapsulator can be used as an alternative gavage vehicle in toxicology studies of water-insoluble or volatile chemicals to avoid the potential side effects of corn oil vehicle. Procedures for the analysis of the molecular-encapsulated ...

The indications of immunologic dysfunction following low level exposure of rodents or even man to certain chemicals and drugs have raised concern regarding methodology and approaches for routine assessment of immunobiological effects. The immunogiological effect observed may either indicate impaired immunopotentiation or hypersensitization. The assays selected for testing should be relevant to the human experience and adaptable to certain practical considerations such as cost, reproducibility of data, ease of performance and application to routine toxicology studies. Using these considerations, a tier approach was proposed consisting of assays for screening for immunologic effects (Tier I) and assays to help define the mechanisms responsible for the immunobiological effects observed (Tier II). A tier of assays was also proposed for measuring the sensitization potential of certain compounds. Certain assays from the screening tier were assembled into a hypothetical and practical test battery to screen for immunological effects of a chemical with potential immunosuppressive properties. Information provided by this test battery should provide a reasonable and sensitive data base from which a standard of evaluation could be made regarding the safety of the test (1) compound.

Xylene isomers and mixed xylenes were administered to male and female Sprague-Dawley rats to evaluate their effects on standard toxicological parameters which included body and organ weights, hematology, serum chemistries, urinalysis and histopathological examination. In the initial study, m, o- or p-xylene were administered in corn oil by gavage for 10 consecutive days at dose levels of 250, 1000 and 2000 mg/kg/day. The most noteworthy changes were increased liver weight in both sexes for all three isomers while decreases in spleen and thymus weights were seen less frequently. Rats were subsequently exposed to mixed xylenes by gavage in corn oil for 90 consecutive days at dose levels of 150, 750 and 1500 mg/kg/day. The most significant findings of the subchronic study were enlarged livers and kidneys. Histopathological evaluation of liver and kidney tissues revealed an increased incidence of minimal chronic renal disease in only female rats, while treatment related hepatic histopathological changes were not detected in either sex.

The Fischer 344 rat is being used increasingly in toxicology studies. There have been few reports in which rats of this strain were used in teratology and reproduction studies, but comparison of teratologic data with other toxic and points and kinetic information would be greatly facilitated by using the same strain. Therefore, the embryotoxic effects of two positive teratogens, aspirin and hydroxyurea, were compared in Fischer rats and in the commonly used Wistar rats. Aspirin was administered in single oral doses of 500 and 625 mg/kg on d 10; hydroxyurea was injected ip at 500 mg/kg on d 11. Dams were sacrificed on d 20 and fetuses examined for skeletal and visceral defects. Male and female fetal weights and lengths were significantly reduced in treated groups in both strains. Both teratogens caused a significant increase in resorptions in Wistar and Fischer rats. A wide variety of skeletal alterations were induced by both teratogens in both strains. These included extra ribs, fused or missing ribs, extra thoracic and lumbar vertebrae, split vertebral centra, and missing vertebrae. Only a small number of Fischer fetuses exhibited visceral malformations such as hydrocephaly and cleft palate. The frequency of soft-tissue malformations, including cleft palate and severe cardiac anomalies, was much higher in Wistar fetuses.

Published data on the toxicity of nitrogen dioxide (as a model compound) from five laboratory animal species were utilized to scale the relationship of dose and toxic effect to the human species. A minute volume of inspired air was used as a metabolic scaling factor, predicting a median lethality during the time of exposure of 174 ppm NO 2 for a 1‐h exposure for people. This work demonstrates a method of predicting effects in people when only data for laboratory animals exist. It also shows the value of planning toxicology studies that utilize several animal species, so that their data may be applied to forecasting the human condition.

A number of toxicological studies in animals have been performed in order to evaluate the safety of omeprazole. This paper presents the most important findings in these studies, which were performed in accordance with internationally approved guidelines.