bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative Hepatotoxicity of Inhaled Cadmium Chloride and Cadmium Oxide
Authors: Grose E. C. , Richards J. H. , Jaskot R. H. , Ménache M. G. , Graham J. A. , Dauterman W. C.
Published: November 2007

The toxicity of inhaled aerosols of cadmium chloride (CdCl2) and cadmium oxide (CdO) on hepatic biochemical function was compared. Male rats were exposed for 2 hours to concentrations of 0.45 and 4.5 mg Cd/m3. Serum and liver enzymes and histological changes were studied immediately and 72 hours after exposure. Exposure to 4.5 mg/m3 CdCl2 and CdO resulted in an increase in liver Cd content. This deposition was not observed at the lower concentrations. Following exposure to 4.5 mg/m3 CdCl2, decreases in body and liver weight, as well as decreased activities of glutathione (GSH)-reductase, GSH-peroxidase, and glucose-6-phosphate dehydrogenase (G-6-PDH) were observed. Increases in serum bilirubin and activities of creatine kinase, lactate dehydrogenase, and aspartate aminotransferase were evident 72 hours after exposure. Exposure to 4.5 mg/m3 CdO caused decreased activities of GSH-reductase and peroxidase, G-6-PDH, and an increased activity of serum alkaline phosphatase and lactate dehydrogenase. Exposure to 0.45 mg/m3 CdCl2, produced more hepatic effects than did a similar exposure to CdO. This differential response between inhalation of CdCl2 and CdO was probably due to a rapid clearance of CdCl2 or Cd2+ ions from the lung and transport to the liver via the systemic blood circulation.
Behavioral Toxicology of Volatile Organic Solvents. IV. Comparisons of the Rate-Decreasing Effects of Acetone, Ethyl Acetate, Methyl Ethyl Ketone, Toluene, and Carbon Disulfide on Schedule-Controlled Behavior of Mice
Authors: Glowa J. R. , Dews P. B.
Published: November 2007

The effects of acetone (ACE), ethyl acetate (EAC), methyl ethyl ketone (MEK), toluene (TOL), and carbon disulfide (CS2) were compared on schedule-controlled responding of mice. Responding (the interruption of a photocell beam located behind a nose-poke hole) was maintained under a fixed interval (FI) 60-second schedule of milk presentation in a sealed inhalation chamber. Cumulative concentration-effect functions were obtained by increasing the concentration of each solvent within the chamber, at 30-minute intervals until responding was abolished. Responding was assessed again 30 minutes after the termination of exposures to levels that abolished responding, to assess the extent of recovery. TOL, CS2, and ACE slightly increased rates of responding at lower concentrations. Each solvent decreased responding in a concentration-related manner at higher concentrations, with responding being decreased 50% by 10,694 ppm ACE, 594 ppm EAC, 2891 ppm MEK, 1784 ppm TOL, and 2242 ppm CS2. Responding recovered 30 minutes after exposures completely for ACE, EAC, and MEK, approximately 75% for TOL, but not at all for CS2. These data suggest that the acute behavioral toxicity of EAC, relative to that found for the other solvents, may be greater than that reflected in current threshold limit values (TLV).
Carcinogenicity of Acylating Agents: Chronic Bioassays in Mice and Structure-Activity Relationships (SARC)
Authors: Van Duuren B. L. , Melchionne S. , Seidman I.
Published: November 2007

A small number of acylating agents are known to be carcinogenic. The structure-activity relationships and carcinogenicity (SARC) of these compounds are reviewed in this report. In addition, the results of chronic bioassays of three previously untested compounds are described. Female ICR/Ha Swiss mice, 30–50 per group, were used in all tests. The test duration was 18–22 months. Diethylcarbamyl chloride (DECC), ethyl chloroformate (ECF), and dichloroacetyl chloride (DCAC) were tested by repeated skin application, in two-stage carcinogenesis with phorbol myristate acetate (PMA) as promoter, and by repeated subcutaneous injection. Dimethylcarbamyl chloride was used as a positive control together with control groups. All three compounds showed marginally significant incidences of papillomas and carcinomas when tested as initiators. ECF and DCAC did not show skin tumorigenicity in the repeated skin application tests. DECC showed weak carcinogenicity compared to DMCC. Subcutaneous injection resulted in the same pattern of tumorigenicity. Thus, the four acylating agents showed the following decreasing order of carcinogenicity: DMCC > DECC > ECF ≅ DCAC. All four compounds hydrolyze rapidly in water, with the following decreasing order of rate of hydrolysis: DCAC > DMCC ECF ≅ DECC. Their mechanisms of hydrolysis are: DMCC, DECC, and DCAC, SN1; ECF, SN2. There is no clear correlation between rate or mechanism of hydrolysis and carcinogenicity of these acylating agents.
Comparative Studies on Lipid Peroxidation in the Kidney of Rats, Mice, and Hamsters and on the Effect of Cysteine, Glutathione, and Diethyl Maleate Treatment on Mortality and Nephrotoxicity After Administration of Potassium Bromate
Authors: Kurokawa Y. , Takamura N. , Matsuoka C. , Imazawa T. , Matsushima Y. , Onodera H. , Hayashi Y.
Published: November 2007

As an index of lipid peroxidation (LPO), levels of thiobarbituric acid (TBA)-reactive substances were examined in the kidneys of male F344 rats, BDF1, CDF1, and B6C3F1 mice, and Syrian golden hamsters after a single intravenous (IV) administration of potassium bromate (KBrO3) at various doses. In the rats, LPO levels were significantly increased in both a dose-dependent and time-dependent manner. However, when the rats were given intraperitoneal (IP) injection of cysteine, the levels of LPO were not significantly different between KBrO3-treated animals and controls. In CDF1 mice, the slight increases in LPO levels observed were much weaker and not statistically significant. On the other hand, treatment of BDF1 and B6C3F1 mice or hamsters with KBrO3 resulted in decreased values as compared to controls. The effect of treatment with cysteine, glutathione (GSH), or diethyl maleate (DEM) on mortality was tested in male F344 rats given IV injection of KBrO3 at various doses. Significant reduction and elevation in the mortality were observed in rats treated with cysteine or GSH and DEM, respectively. Significant dose-dependent and time-dependent increases were observed in the levels of serum non-protein nitrogen (NPN), blood urea nitrogen (BUN), and creatinine, and absolute and relative weight of the kidneys in male F344 rats administered KBrO3 IV. Microscopically, the appearance of numerous eosinophilic droplets in the cytoplasm of proximal tubular epithelium of KBrO3-treated rats was noteworthy. All these changes were reduced and exacerbated by treatment with cysteine or GSH and DEM, respectively. The possibility of LPO formation in the kidney by active oxygen radicals generated by KBrO3 is suggested. A possible relationship between LPO levels in the kidney and species differences in the renal toxicity and carcinogenicity of KBrO3 is implicated.
The Rat Adrenal Medulla. I. The Normal Adrenal
Authors: Tischler A. S. , Delellis R. A.
Published: November 2007

The morphology and physiology of the adrenal medulla are described, emphasizing the rat medulla as an experimental model. Current concepts are reviewed relating to the development of medullary cell lineages and to factors that affect synthesis, storage, and secretion of hormones in the adrenal medulla. The pathophysiological implications of adrenal medullary cells as a multimessenger system are discussed.
The Rat Adrenal Medulla. II. Proliferative Lesions
Authors: Tischler A. S. , DeLellis R. A.
Published: November 2007

Many strains of rats develop spontaneous or drug-induced adrenal medullary proliferative lesions. However, there is often ambiguity about whether the changes observed are hyperplastic or neoplastic and if the term “pheochromocytoma” is appropriate for the lesion in rodents. Various considerations are presented, and the evolution and morphology of the changes are discussed. The lesions are of practical interest because they have at times impeded drug licensing applications.
Adrenal Gland Toxicity: Chemically Induced Dysfunction
Authors: Colby H. D.
Published: November 2007

Among the endocrine organs, the adrenal cortex appears to be the most vulnerable to chemically induced injury. A wide variety of chemicals has been found to cause morphological or functional lesions in the gland. Some of the lesions are highly localized to specific anatomical zones of the adrenal cortex, and the resulting functional deficits depend on the physiological role(s) of the zone affected. In addition, metabolic activation is an important factor contributing to the gland's vulnerability to chemical injury. For example, carbon tetrachloride (CCl4) causes adrenocortical necrosis, but only of the innermost zone of the gland, the zona reticularis. The apparent reason for the localized effect of CCl4 in the adrenal cortex is that only the cells of the zona reticularis have the enzymatic capacity to activate CCl4, resulting in lipid peroxidation and covalent binding to cellular macromolecules. By contrast, the mineralocorticoid antagonist, spironolactone, causes functional lesions in the adrenal cortex that are limited to the middle zone of the gland, the zona fasciculata. The explanation again involves metabolic activation; only the zona fasciculata converts spironolactone to a highly reactive metabolite that effects the destruction of several enzymes that are required for steroid hormone synthesis. These findings indicate that bioactivation plays a critical role in the mechanism(s) of action of various toxic agents on the adrenal cortex and also may be responsible for the anatomically localized effects of many chemicals.
Sugars and Adrenomedullary Proliferative Lesions: The Effects of Lactose and Various Polyalcohols
Authors: Baer Albert
Published: November 2007

Various substances have been found that destabilize the adrenomedullary system and cause a shift from normal to abnormal function and from controlled to uncontrolled growth. Some of these substances belong to the category of the sugar alcohols and slowly digested carbohydrates. An effect on the adrenal medulla of rats has been documented for sorbitol, xylitol, lactitol, and lactose. In rats, the polyol-induced formation of adrenal tumors involves at least three factors: a high genetic susceptibility that predisposes to adrenomedullary proliferation, an intestinal hyperabsorption of calcium followed by a disturbance of the calcium homeostatic hormonal system, and a functional and proliferative responsiveness of the adrenal gland to such changes in calcium homeostasis. In humans, none of these conditions is fulfilled. The genetic susceptibility is apparently very low, as shown by the rare occurrence of pheochromocytomas. Polyols do not measurably affect calcium uptake and calcium homeostasis, and there is no known association between hypercalciuria or hypercalcemia and a higher risk for pheochromocytomas in humans.
Proliferative Lesions of the Adrenal Medulla in Rats Treated with Zomepirac Sodium
Authors: Mosher A. H. , Kircher C. H.
Published: November 2007

Two 24-month oral (gavage) carcinogenicity studies with zomepirac sodium were conducted in Wistar rats. Adrenal medullary proliferative lesions (focal hyperplasia and benign medullary tumors) were increased in male rats. The morphological character and biological behavior of the adrenal medullary proliferative lesions were benign and had no apparent affect on mortality. Zomepirac sodium can be added to a list of chemically and pharmacologically diverse group of substances that have been associated with increased incidences of adrenal medullary proliferative lesions in the aged rat.
Differences in International Regulatory Needs and Approaches
Authors: Christian Mildred S.
Published: November 2007

The purpose of this symposium is to educate the scientists working in the various areas of research and regulation in developmental and reproductive toxicology regarding differences and commonalities in regulatory needs and concerns. Multiple agencies and professional societies are attempting to develop guidelines for performing safety evaluations that will allow single tests to meet the requirements of more than one agency in order to reduce animal usage and decrease testing costs. This presentation, and the two that follow, describe some of the problems addressed, the approaches used, and the current regulatory requirements of Japan and the U.S. EPA.
Japanese Perspectives on the Reproductive and Developmental Toxicity Evaluation of Pharmaceuticals
Authors: Tanimura Takashi
Published: November 2007

The current Japanese guidelines for reproductive and developmental toxicity studies of drugs stress the need for examination of the effects of drugs on the behavior and fertility of the offspring. In 1986, the Ministry of Health and Welfare initiated a review of all current toxicity test guidelines, one of the objectives of the review being to increase the international harmonization of such guidelines. The final report of the Reproduction Study Subgroup was officially released on September 11, 1989. A summary of the conclusions of the study subgroup follows: To attain international conformity of guidelines requires scientific discussion among international organizations, but an early solution will be difficult. A more practical way is to accept studies performed in conformity with other guidelines if the applicant submits a document demonstrating that the same degree of safety for human reproduction and development required by the Japanese guidelines can be judged from the characteristics and clinical indications of the drug., Positive discussion is also necessary with other countries to agree on conditions under which studies performed according to the Japanese guidelines will be acceptable to such countries. In addition, the current status of behavioral teratology tests in Japan surveyed by the Behavioral Teratology Meeting, Japanese Teratology Society is presented.
An Overview of the U.S. EPA Proposed Amendments to the Guidelines for the Health Assessment of Suspect Developmental Toxicants
Authors: Kimmel Carole A. , Kimmel Gary L. , Francis Elaine Z. , Chitlik Laurence D.
Published: November 2007

The U.S. Environmental Protection Agency has recently proposed amendments to the Guidelines for the Health Assessment of Suspect Developmental Toxicants. These amendments expand and clarify points made in the original guidelines, and add new information based on advances in the field. For example, the original risk assessment guidance was developed around several basic assumptions that were implicit in the earlier document, but that are clearly stated in the proposed amendments. Also, several consensus workshops were held following the completion of the 1986 guidelines, and the conclusions of these workshops have been incorporated. These include workshops dealing with the relationship of maternal and developmental toxicity, and with the development of an approach for a weight-of-evidence classification. In addition, a reference dose for developmental toxicity (RfDT) is proposed, based on short-term exposure, to distinguish it from the Rf D for chronic exposure. Other proposed changes include the expansion of the functional developmental toxicity section to reflect the Agency's testing guidelines for developmental neurotoxicity, and the human studies section which now gives more guidance on the use of human data in risk assessment. A number of other minor proposed changes are discussed. The final amended guidelines are currently undergoing Agency review and should be completed within the next year.
A Statistical Basis for Using Fewer Rabbits in Dermal Irritation Testing
Authors: Hatoum Nabil S. , Leach Chester L. , Talsma Daniel M. , Gibbons Robert D. , Garvin Paul J.
Published: November 2007

An acceptable and validated in vitro method to evaluate the potential of a chemical to cause dermal irritation does not exist; therefore, in vivo studies remain the only alternative. Currently most laboratories utilize 6 rabbits per test, but this group size may not be necessary to derive the desired information. Data generated from 6-rabbit skin irritation tests of 105 materials were used to determine the ability of irritation scores from all possible combinations of 5-, 4-, 3-, or 2-rabbit subsets to predict the Draize score derived from 6 rabbits. There are 630, 1575, 2108, and 1575 possible combinations of 105 studies for the 5-, 4-, 3-, and 2-rabbit subseta, respectively. We classify materials using a four-level adjectival rating system based on (among other factors) the Draize score, Comparisons indicated that the 5-, 4-, 3-, and 2-rabbit scores were in 96, 94, 91, and 88% agreement, respectively, with the classification assigned on the basis of the 6-rabbit score. The correlation coefficients for randomly selected subsets of 5-, 4-, 3-, and 2-rabbit scores versus the 6-rabbit Draize score were 0.996, 0.994, 0.986, and 0.977, respectively. This study indicated that 3 rabbits per test group allow for adequate assessment of the dermal irritation potential of a chemical. These results also conformed closely to those obtainetd from a previous statistical study using eye irritancy data from 155 chemicals, where 3-rabbit subsets were 94% predictive of the 6-rabbit tests.
Subchronic Studies of Thenyldiamine in Fischer 344 Rats
Authors: Jackson Carlton D. , Cronin Gerald M. , Stone Theodore W.
Published: November 2007

Thenyldiamine, an antihistamine used extensively as a sleep aid, has not been adequately studied for subchronic or chronic toxicity. This report presents the results of subchronic studies of thenyldiamine in the rat. Fischer 344 rats were administered thenyldiamine hydrochloride in their feed at dose levels of 0, 250, 500, 1000, 2000, and 4000 ppm (calculated as free amine) for 14 days or at dose levels of 0, 125, 250, 500, 1000, and 2000 ppm for 90 days. There were no mortalities in either study. Except for decreased weight gain, no significant treatment-related toxicity was observed in the 14-day study. In the 90-day study, 500 ppm and 1000 ppm were the lowest doses responsible for causing a significant decrease in weight gain in females and males, respectively. Clinical signs, gross observations at necropsy, and organ weights in the 90-day study were not remarkable. Histologically, a treatment-related mild fatty change was found in the livers of male rats, but the effect was so mild as to make the significance questionable. Treatment-related changes were also observed in the parotid salivary glands, but the significance of these changes was also questionable in view of the variability of this gland and its recognized physiological responses to antihistamines.
Multi-Organ Carcinogenicity of 3,3′-Dimethoxybenzidine Dihydrochloride Given in Drinking Water to F344/N Rats
Authors: Morgan D. L. , Bucher J. R. , Huff J. E. , Haseman J. K. , Eustis S. L. , Lemen J. K. , Ulland B. M. , Mennear J. H.
Published: November 2007

3,3′-Dimethoxybenzidine dihydrochloride (DMOB) was evaluated for chronic toxicity and carcinogenicity because benzidine, a structurally related chemical, is a known human carcinogen, and because of potential human exposure during production of bisazobiphenyl dyes. Previous carcinogenicity studies of DMOB were considered to be inadequate. Toxicology and carcinogenesis studies were conducted by administering 0,80,170, or 330 ppm DMOB (>97.5% purity) in drinking water to groups of F344/N rats for 21 months. Seventy rats of each sex were used in the control group, 45 in the low-dose, 75 in the mid-dose, and 70 in the high-dose group. Ten rats of each sex in the control and 330 ppm dose groups were evaluated after 9 months. After exposure for 9 months, chemical-related neoplastic effects included liver foci, carcinoma of the preputial gland in one male, carcinoma of the clitoral gland in one female, and carcinoma of the Zymbal gland in two male rats. Although designed for 24 months, these studies were terminated at 21 months because significant numbers of exposed rats died with tumors or were sacrificed in moribund condition. Chemical-related nonneoplastic effects were hematopoietic cell proliferation in the spleen, and cystic and centrilobular degeneration and necrosis of the liver. 3,3′-Dimethoxybenzidine was clearly carcinogenic for male and female F344/N rats. After exposure for up to 21 months, significantly increased incidences of neoplasms were observed in multiple sites: skin, Zymbal gland, preputial and clitoral glands, oral cavity, small and large intestines, liver, brain, mesothelium, mammary gland, and uterus of treated rats.
Examples of Alternative Use in Toxicology for Common Species
Authors: Chengelis Christopher P.
Published: November 2007

The principle of refinement of animal usage in toxicology dictates that the appropriateness of a particular animal species for a particular protocol or experiment be thoroughly explored. Species are selected all too often on the basis of convenience or tradition. Rats are traditionally used for acute lethality testing and carcinogenicity testing. Dogs are traditionally used as a “nonrodent” species for general toxicity assessments. This review seeks to make the case that, for both scientific and economic reasons, other species can be appropriately substituted for rats or dogs for general toxicity assessment studies. These alternative species need not be totally exotic, but can, in fact, be species used in other areas of toxicology. Earthworms and fish are nonvertebrate animals used in environmental assessment studies. Earthworms could be used for lethality assessment in place of rodents, particularly for “QC batch” release or toxicity rating purposes. Fish could be used to further define hepatic carcinogenicity. Guinea pigs are frequently used for dermatologic studies, but rarely for other purposes. While a rodent, the guinea pig possesses many physiologic and metabolic characteristics that may make it more appropriate than rats for the chronic testing of certain classes of chemicals (NSAIDs, peroxisomal proliferators). Ferrets have been well studied in teratologic assessments, but have not gained wide acceptance as a “nonrodent” model. This review discusses in detail the available technology and published data that justifies the expanded and appropriate use of these “alternative” species. Special emphasis is given to xenobiotic metabolism, which is a major determinant in speciesrelated differences in toxicity.
Consideration of Variables in Evaluation of Toxicity to Skin
Authors: Singer Edward J.
Published: November 2007

Certain systems for estimation of toxicity to skin are discussed, in which fuller consideration of variables led to improved study design and better prediction of human hazard. Three areas are considered: skin irritation; dermal carcinogenesis; prediction of carcinogenic potential (in vitro). (1) Variation in the guidelines of various U.S. and foreign agencies for evaluation of skin irritation and corrosiveness of chemicals was addressed by use of multiple-site patching in the rabbit. Data obtained from this “composite assay,” as well as from other published studies, indicated that no single set of guidelines was adequate for proper human hazard assessment. (2) Practical questions are raised about latency time and incidence of skin tumors from limited exposure to chemical carcinogens. In benzo[a]pyrene (BaP) carcinogenesis in mice, the duration of treatment is a key factor in tumor onset and frequency, with a “saturation level” resulting from interplay of duration and dose level. Age at inception of treatment can also be a factor in susceptibility to BaP-induced skin cancer, depending on conditions of exposure. (3) The question of carcinogenic potential of oil industry raw materials requires short-term answers, such as might be provided by an in vitro mutagenicity test. However, such tests are not appropriate for these water-immiscible mixtures. Studies on bioavailability of oil-related materials enabled modification of the Ames bacterial test, vastly improving sensitivity. With this modified Ames test, high correlation is seen among mutagenicity, content of polycyclic aromatics, and dermal carcinogenicity.
Validation of In Vitro Models
Authors: Frazier John M.
Published: November 2007

The 1980s have seen major research efforts focused on the development of alternative toxicity testing methodologies for the safety evaluation of chemicals. A difficult problem which has slowed the implementation of these methodologies has been validation. Validation means different things to different toxicologists; however, successful validation can take place only within the context of how the methodology is to be used: as a screen, an adjunct, or a replacement. The strategy for performing a validation study as well as the criteria for evaluation of the test methodologies will vary for each of these use categories. Correlative tests are adequate for screening purposes but mechanistic tests are required for adjuncts and replacements. The time has come to define the scientific basis of validation so that new methodologies can be efficiently processed through validation programs and incorporated into the safety evaluation process.
Basic Principles of Inhalation Exposure
Authors: Drew Robert T.
Published: November 2007

The focus of this symposium is the technology of nose exposure to rodents and the various kinds of measurements one can make before, during, and after exposure to obtain information about the dose and effects relative to the exposure. However, certain principles of inhalation exposure are common to all inhalation techniques. This introduction provides some historical perspectives in the development of both inhalation chambers and nose exposure techniques. It discusses the major advances in chamber design and nose exposure technology. The accumulation in and removal of test agents from the system is described. Two critical issues in inhalation studies, aerosol and vapor generation and techniques to measure the concentration of the test agents, are beyond the scope of this symposium and are not covered.
An Exhaled Breath Chamber System for Assessing Rates of Metabolism and Rates of Gastrointestinal Absorption with Volatile Compounds
Authors: Gargas Michael L.
Published: November 2007

The in vivo kinetic constants for chemical metabolism and the rate constant for uptake of chemical from the gastrointestinal (GI) tract following oral dosing are critical parameters for assessing the internal dosimetry of volatile compounds in rodents. An in vivo technique is presented that relies on determining chamber time courses under conditions where the only input to the chamber is from the exhaled breath of animals in the chamber. This is referred to as an exhaled breath chamber system and is used with animals previously exposed by constant concentration inhalation or by gavage dosing. The exhaled breath chamber profiles were analyzed using a physiologically based pharmacokinetic (PB-PK) model in which either metabolic constants or oral absorption rate constants were varied until agreement was achieved between simulated and experimental results. The exhaled breath system and approaches for data analysis are described. Previous studies are reviewed that estimate metabolic constants for 1, 1, 2-trichloroethane in the rat. Oral absorption kinetics for 1, 1, 1-trichloralethane in the mouse are also presented. This technique proved a successful alternative to in vivo gas uptake studies for determining metabolic rates for chemicals not suited to gas uptake and offers a noninvasive approach for assessing GI absorption of chemicals.
Large-Scale Assessment of Motor Activity in Rodents: Procedures for Routine Use in Toxicology Studies
Authors: Schulze Gene E.
Published: November 2007

An automated system for the routine large-scale assessment of motor activity in rats has been established in this laboratory for use in toxicity testing. This study was designed to evaluate the validity and sensitivity of motor activity measurements for routine use in toxicology studies. The effects of two known neurotoxins, acrylamide (ACR) and 3'3'-iminodipropionitrile (IDPN), were measured in rats using an automated photocell device in the context of a routine toxicology study. One hundred Sprague-Dawley rats (10/sex/group) were dosed with vehicle, ACR (10 and 30 mg/kg/day) or IDPN (50 or 125 mg/kg/day), by oral gavage 7 days per week for 5 weeks (except where otherwise indicated). Motor activity was measured in 5-min test sessions prior to initiating treatment, 6 and 24 h after the first dose, and weekly thereafter. Significant mortality occurred in high-dose ACR animals during Week 3. A 10-or 7-day recovery period was initiated after 20 or 22 daily doses for high-dose ACR and IDPN animals, respectively; after which, the high dose ACR and IDPN animals, respectively; after which, the high dose of ACE: was lowered to 20 mg/kg/day. Rapid habituation to the test environment occurred over the 5-imin testing sessions. Significant depressions in activity were observed in high-dose ACR males during Weeks 3 and 5 and in high-dose ACR females during Weeks 2-5. High-dose IDPN females showed no significant changes in activity. However, significant activity depressions were noted in males during weeks 1, 3, and 5. When depressions in activity occurred, they were apparent over the entire test session. The sensitivity of activity measures was sufficient to detect a 15% change in activity levels as compared with controls, with sufficient statistical power to meet regulatory requirements. Inclusion of motor activity assessments complements the additional parameters routinely measured in toxicology studies, augmenting hazard identification.
Subacute and Subchronic Oral Toxicity of p-Chlorotoluene in the Rat
Authors: Terrill James B. , Robinson Merrel , Wolfe Gary W. , Billups Leonard H.
Published: November 2007

p-Chlorotoluene was administered by corn oil gavage for 14 and 90 days to male and female Sprague-Dawley-derived rats at dosages of 200, 600, and 1800 mg/kg per day and 50, 200, and 800 mg/kg per day, respectively. In the 14-day study, 8 of 10 animals of each sex in the high-dose group died due to treatment. Other treatment-related signs for these animals included an adverse effect upon body weight and clinical signs of salivation, tremors, and prostration. In the 200 and 600 mg/kg per day groups there were no apparent treatment-related effects. In the 90-day study, 4 of 10 males and 2 of 10 females in the high-dose group died due to treatment. Other signs for this treatment group included an adverse effect upon body weight and clinical signs of languid behavior, prostration, tremors, sensitivity to touch, epistaxis, and respiratory distress. Increases in alkaline phosphatase and creatinine (males only), and increases in adrenal (absolute and relative, females), kidney (relative, both sexes), and liver (relative, both sexes) weights were also noted. Histopathologic findings of centrilobular hepatocellular hypertrophy, adrenal cortical hyperplasia, and exacerbation of chronic progressive nephropathy confirmed the clinical laboratory and organ weight results as being treatment related for the animals receiving 800 mg/kg per day for 90 days. Animals receiving 50 or 200 mg/kg per day (90 days) did not exhibit treatment-related findings.
Subchronic Toxicity Studies of 2,4,6-Trichlorophenol in Sprague-Dawley Rats
Authors: Bercz J. Peter , Robinson Merrel , Jones Lillian , Page Norbert P. , Parnell Michael J. , Wolfe Gary W.
Published: November 2007

2,4,6-Trichlorophenol (TCP) has been found in drinking water as a result of its use as a fungicide and due to its inadvertent production in the water purification process. This study was conducted since information on the toxicity from repeated ingestion was inadequate. Male and female Sprague-Dawley rats were gavaged with TCP administered in corn oil (2 ml/kg body weight) for 90 consecutive days at dose levels of 0, 80, 240, and 720 mg/kg per day. Treatment-related effects were observed at the highest dose (720 mg/kg/day) and consisted of salivation, urine stains on the fur, increase in absolute and relative weights of the kidneys, liver, adrenal glands, and testes. At this dose, increases were seen in serum protein, albumin, and alanine aminotransferase (ALT), with a decrease in urinary pH. Some effects observed at 240 mg/kg per day were an increase in the absolute and relative weights of the liver and adrenal glands in females, relative liver weights in males, and an increase in serum albumin in males. No treatment-related effects were observed at 80 mg/kg per day. No mortality or significant effects were observed at any dose level for body weight, food consumption, ophthalmic lesions, hematology, gross pathology, or histopathology. Based on clinical chemistry and organ weight changes, it appears that the liver, kidney, and adrenal glands were target organs for systemic toxicity to TCP in this study, although this was not correlated with histopathology lesions. It was concluded that 240 mg/kg/day represents a lowest observed adverse effect level (LOAEL), although the toxic effects were minimal. The no observed adverse effect level (NOAEL) for subchronic exposure to TCP by the oral route was 80 mg/kg per day.
The Effects of Four Types of Restraint on Serum Alanine Aminotransferase and Aspartate Aminotransferase in the Macaca fascicularis
Authors: Landi M.S. , Kissinger J.T. , Campbell S.A. , Kenney C.A. , Jenkins E.L.
Published: November 2007

To determine the effect of restraint on selected clinical laboratory parameters, cynomolgus monkeys were continuously restrained for 60 and 120 minutes in a restraining box, a restraint chair, and on a restraining board. Animals were also hand caught for manual restraint. Blood samples were collected at 11 time points over 168 hours and evaluated with a standard clinical chemistry profile. Only aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were statistically evaluated; no overt changes were noted in any other parameter. Significant differences between the enzyme levels of different restraint methods were not seen during the 60-min restraint studies, but were present during the 120-min restraint duration. For AST, chair and board restraint resulted in lower and higher enzyme levels, respectively, than the other methods. Levels of ALT for board restraint were significantly higher when compared with other methods. For both the 60-and 120-min restraint periods, AST values that were significantly elevated when compared with baseline were common at 4, 6, and 24 h. Significant ALT increases, when compared with baseline, occurred primarily at 6, 24, and 48 h. The results indicate that over time, restraint methods alone can affect AST and ALT levels in cynomolgus monkeys.
Mechanisms of Asbestos Carcinogenicity
Authors: Voytek Peter , Anver Miriam , Thorslund Todd , Conley Jill , Anderson Elizabeth
Published: November 2007

We present a brief review of different potential mechanisms at the molecular and cellular levels that may be involved in asbestos-induced carcinogenicity. The usefulness of considering such mechanisms in developing appropriate biologically based models to estimate carcinogenic risk at environmental levels of asbestos fibers is discussed.
The Effects of Ribavirin on Development and Reproduction: A Critical Review of Published and Unpublished Studies in Experimental Animals
Authors: Johnson E. Marshall
Published: November 2007

The effects of the antiviral agent ribavirin on reproduction and development have been examined by several experimental means in multiple animal species. In studies designed primarily to explore its mechanism of action on in utero development, the incidence, nature, and patterns of effect were directly correlated to embryonic gestational age at the time of maternal treatment. In a detailed evaluation of the pattern of embryonic cell death, there was a clear relationship between tissue necrosis and the types of congenital defects produced at effective doses. At subthreshold treatment levels there were no abnormalities in the young or necrotic areas in the embryonic/fetal tissues examined. When the developmental toxicity of ribavirin was examined, few if any, developmental malformations were present that could be related with confidence to the test agent. Several malformed fetuses were present in the highest dose level tested in rats (10 mg/kg/day) treated by gavage from Days 6-15 of pregnancy, but none were reported in rabbits similarly treated with as much as 1.0 mg/kg per day (highest dose tested) from Days 6-18 of pregnancy. The treatment level in rats may have been associated with maternal toxicity, but this important point is not established clearly for either species. When evaluated for effects on reproduction and postnatal survival in rats, ribavirin at levels of 60 and 90 mg/kg/day produced statistically significantly and/or clearly dose-related increased incidences of fetal resorptions, abnormalities, and reduced postnatal survival. Pregnant baboons given ribavirin orally at submaternally toxic levels of 60 or 120 mg/kg per day during critical periods of differentiation and organogenesis were reported to have produced no adverse effects on in utero development.
A Physiologically Based Pharmacokinetic Model of Parathion Based on Chemical-Specific Parameters Determined In Vitro
Authors: Sultatos Lester G.
Published: November 2007

Physiologically based pharmacokinetic (PBPK) modeling is an approach that has been used to predict successfully the pharmacokinetic disposition of numerous foreign chemicals. The accuracy of a PBPK model is dependent on the reliability of estimates of tissue/blood distribution coefficients (Kp) and appropriate kinetic constants descriptive of the elimination of the chemical under consideration. The present study evaluates the validity of the use of Kp values and kinetic constants determined in vitro for use in a PBPK model for the organothiophosphorus insecticide parathion. Kps were determined by equilibrium dialysis, whereas Vmaxs and Kms descriptive of the biotransformation of parathion were calculated from values determined previously in this laboratory. Using these kinetic constants to calculate a hepatic extraction ratio of parathion in the mouse yielded a value identical to that observed with mouse liver perfusions in situ performed previously in this laboratory. Use of Kp values and kinetic constants determined in vitro in a PBPK model accurately simulated levels of parathion in brain, lungs, blood, and liver up to 3 h after intravenous administration of this insecticide. This study demonstrates that chemical-specific parameters determined entirely in vitro can be used to construct accurate PBPK models.
Quantitative Structure—Activity Relationships (QSARs): An Integrated Multivariate Approach for Risk Assessment Studies
Authors: Tosato Maria Livia , Chiorboli Claudio , Eriksson Lennart , Jonsson Jorgen , Marchini Silvia , Passerini Laura , Pino Anna , Viganó Luigi
Published: November 2007

The conditions and methods for constructing reliable QSARs are revised in relation to each component of a QSAR study: the selection of a training set out of a QSAR compatible series, the collection of data pertinent to the descriptors matrix (X) and to the effects matrix (Y), the analysis of data to connect X to Y by a regression model, and the validation of the model. In discussing these conditions, attention is given to the constraints that arise from the theoretical foundation of QSARs as analogy models of local validity and to the complexity and limited knowledge about the mechanisms of action. Hence, emphasis is placed on the need and importance to adopt multivariate methods for dealing with (1) the characterization of the structures, (2) the selection of a representative set of training compounds, and (3) analysis of the data. It is finally shown that the same integrated multivariate approach applies to the modeling of biological activities and other properties—chemical and biological—as well as to the modeling of correlations between batteries of data. The role of QSAR in risk assessment is addressed in the second part of the article. The framework of a strategy for an efficient screening assessment of toxic substances through the modeling of their exposure and toxicity-related properties is outlined. Applications of the strategy are reported that deal with two series of compounds. Examples of toxicity and persistency models are illustrated.
Efficacy Comparison of Two Cholinolytics, Scopolamine and Azaprophen, When Used in Conjunction with Physostigmine and Pyridostigmine for Protection Against Organophosphate Exposure
Authors: Solana Richard P. , Gennings Chris , Carter Walter H. , Anderson Dana , Lennox Willard J. , Carchman Richard A. , Harris Larrel W.
Published: November 2007

Pretreatment with either pyridostigmine (PYR) or physostigmine (PHY) followed by atropineoxime therapy is very effective in reducing the lethality of organophosphorus nerve agents. The therapeutic efficacy of scopolamine (SCP) versus azaprophen (AZA), when used in conjunction with PHY and PYR (PHY/PYR) combination pretreatment, was evaluated in guinea pigs challenged with 2 half-lethal doses of soman. Maximum postsoman decrement of rotarod performance was measured. Response surface methodology was employed to describe the relationship between the decrement and the PHY/PYR dosages. Results show that AZA is a more effective pretreatment adjunct at the behavioral deficit-free doses tested, AZA or SCP is as effective with PHY alone as with a PHY/PYR combination. Thus, PYR adds essentially nothing to the carbamate combination against soman-induced behavioral deficit.
Distribution of Vanadate in the Rat Following Subcutaneous and Oral Routes of Administration
Authors: Al-Bayati Mohammed A. , Raabe Otto G. , Giri Shri N. , Knaak James B.
Published: November 2007

The distribution of radiolabeled vanadate (48V) was studied in rats following subcutaneous or oral route of administration (1.8 mg V/kg). Measurements included: (1) tissue uptake and retention; (2) gastrointestinal (GI) absorption efficiency; and (3) the fraction of the dose eliminated via the urinary and the GI tracts during the study period. The vanadium content of tissues and excreta was determined by gamma spectroscopy. All tissues analyzed were found to have a measurable level of vanadium after 2 hours of its administration by subcutaneous route. Soft tissues and blood showed the maximal measured concentration of vanadium at 2 hours, while in the bone, the maximal concentration was recorded at 1 day posttreatment. The distribution of vanadium in each tissue could be described by a two-compartment model. Vanadium was cleared rapidly from the soft tissues and slowly from the bone. The elimination half-lives of vanadium ranged between 11 and 132 hours for soft tissues and 376 hours for the bone. During the first day, 48.6% of the dosage was eliminated in the urine and 8.0% in the feces. The GI uptake following gavage was approximately 4.2% of the dosage at 24 hours posttreatment. Vanadium absorbed from the GI tract was distributed among the major tissues and about 66% of the absorbed fraction was excreted in the urine after two weeks posttreatment.
Subchronic Studies of Thenyldiamine in B6C3F1 Mice
Authors: Jackson Carlton D. , Cronin Gerald M. , Stone Theodore W.
Published: November 2007

Thenyldiamine was administered as an admixture in the feed to male and female B6C3F, mice for 14 days or for 90 days. Dose levels of 0, 250, 500, 1000, 2000, and 4000 ppm thenyldiamine were administered in both studies. There was little toxicity observed in the 14-day study. Male and female mice in the 4000 ppm dose groups gained less weight in the first week but appeared to recover and weighed essentially the same as controls at the end of the second week. No significant abnormal clinical observations were made during the study and no treatment-related lesions were observed at necropsy. Microscopic lesions were confined to focal necrosis of the liver with associated inflammatory cell infiltration. In the 90-day study, a more pronounced reduction of weight gain was seen in both males and females of the 4000 ppm dose group. Clinical observations were unremarkable. No abnormal lesions were observed at necropsy. Treatment-related microscopic lesions were confined to the liver of males and parotid salivary gland of both sexes. The parotid gland exhibited necrosis of individual acinar cells randomly distributed throughout the gland. Due to the physiological nature of the parotid gland, the toxicological significance of this lesion is questionable. The liver changes were very subtle, although the zone of affected cells was often extensive. The changes consisted of cytomegaly and karyomegaly of the hepatocytes which was centrilobular and diffuse. Whether the subtle changes represent a possible carcinogenic and/or promoting effect will require further studies to resolve. The results indicate an appropriate maximum tolerated dose for a lifetime chronic study would be between 2000 and 4000 ppm thenyldiamine.
Carcinogenicity of 3,3'-Dimethylbenzidine Dihydrochloride Given in Drinking Water to F344/N Rats
Authors: Morgan D. L. , Jokinen M. P. , Haseman J. K. , Ulland B. M. , Parker G. A. , Lemen J. K. , Mennear J. H.
Published: November 2007

3,3'-Dimethylbenzidine dihydrochloride (DMB) was evaluated for toxicity and carcinogenicity because of the potential for human exposure during production and use of bis-azobiphenyl dyes and because benzidine, a structurally related chemical, is a known human carcinogen. Two studies (9 and 15 months) were conducted by administering 0, 30, 70, or 150 ppm DMB (approx. 99% pure) in drinking water to F344/N rats. In the 15-month studies, 60 rats of each gender were used in the control group, 45 in the low-dose, 75 in the mid-dose, and 60 in the high-dose group. After exposure for 9 months, chemical-related neoplastic lesions were observed in the skin, Zymbal's gland, preputial gland, clitoral gland, liver, oral cavity, large and small intestines, and lung. Although designed for 24 months these studies were terminated after 15 months because significant numbers of treated rats were dying with tumors or were killed in moribund condition. Chemical-related nonneoplastic lesions included cystic degeneration and foci of alteration in the liver; exacerbation of nephropathy; hyperplasia of Zymbal's gland, preputial and clitoral glands, and alveolar epithelium. After exposure for 15 months, significantly increased incidences of neoplasms were observed at many organ sites: skin, Zymbal's gland, preputial and clitoral gland, liver, oral cavity epithelium, small and large intestines, mammary gland, lung, and mesothelium of treated rats. It is concluded that DMB is clearly carcinogenic for male and female F344/N rats.