bluuebunny/crossref_metadata_2025 huggingface dataset:
Animal Tests for Carcinogenesis: Relevance for Man
Authors: Roe F. J.C.
Published: November 2007

The theory that all carcinogens are mutagens has been disproved. Numerous nongenotoxic mechanisms are implicated in carcinogenesis. It is inconceivable that a single simple short-term test can be developed to predict nongenotoxic carcinogenicity. Pro longed disturbance of physiological and/or hormonal status may predispose to increased cancer risk. Overnutrition leads to a variety of physiological and hormonal disturbances in rats. It also predisposes to the early onset of ageing-related diseases and the development of a wide variety of benign and malignant neoplasms. It is suggested that overnutrition is associated with increased endogenous generation of electrophiles, which, on the one hand, age cells and tissues, and on the other, overwhelm the normally efficient DNA repair mechanisms. It is further suggested that hormones predispose to cancer by stimulating cellular proliferation and metabolic rate in target tissues. Thus, nongenotoxic mechanisms of carcinogenesis do involve DNA damage, but do so as a late stage rather than as a first event. The two-stage theory of carcinogenesis is misleading in this respect. Careful studies of the relationships between ageing and cancer risks are long overdue.
Newer Developments in Arsenic Toxicity
Authors: Aposhian H. Vasken , Aposhian Mary M.
Published: November 2007

There have been a number of new and exciting advances in the understanding of arsenic toxicity. Organic trivalent arsenicals have been the drug of choice in the treatment of African trypanosomes, the cause of sleeping sickness. In the past, various mechanisms have been proposed for their mode of action in the treatment of this parasitic disease. It now appears that these arsenicals form an adduct with N1,-N8(glutathionyl)spermidine which inhibits trypanothione disulfide reductase. This enzyme in conjunction with a nonenzymatic reaction is responsible for the maintenance of the required intracellular levels of GSH and perhaps other thiols in African trypanosomes. The primary targets of As3+ in mammalian systems are pyruvate dehydrogenase, thiolase, and glutathione reductase. Even though it appears that pyruvate dehydrogenase is the most sensitive target, the net result of these inhibitions is a decreased gluconeogenesis that should be taken into account when treating arsenic poisoning. Although these advances have been made in the understanding of arsenic toxicity, virtually no progress has been made in understanding the biochemical mechanism of action of arsine, probably the deadliest of all arsenic compounds. This lack of progress is disappointing as well as worrisome since arsine is one of the important starting materials in the newer high tech industries. There have been, however, advances made in the treatment of arsenic toxicity. Meso-2,3-dimercaptosuccinic acid (DMSA) and 2,3-dimercaptopropane-l-sulfonic acid are orally effective, dithiol chelating agents useful for treating arsenic poisoning. DMSA is an orphan drug for which a New Drug Application has been filed.
Beryllium: Toxicological Research of the Last Decade
Authors: Reeves Andrew L.
Published: November 2007

Review of the scientific advances in beryllium toxicology during the 1980s in the categories of toxicokinetics, toxicodynamics, experimental pathology, clinical diagnosis, and cancer epidemiology.
Induction of Metallothionein
Authors: Klaassen Curtis D. , Lehman-Mckeeman Lois D.
Published: November 2007

Metallothioneins (MTs) are cysteine-rich metal-binding proteins. These proteins play a pivotal role in heavy metal homeostasis and have been widely studied by biochemists, toxicologists, nutritional scientists, and molecular biologists. It is well established that MTs are inducible proteins. They are normally synthesized at low basal levels, but exposure to a wide variety of heavy metals and many organic compounds will dramatically increase synthesis of MTs. This paper summarizes MT induction by reviewing the chemicals that induce these proteins, the molecular mechanism involved in this induction, and the relationship between MT induction and biological function.
Structure and Function of the Normal Testis and Epididymis
Authors: Amann Rupert P.
Published: November 2007

The structure and function of the testis and epididymis are described, emphasizing the general similarities and specific differences between various species and humans. Current concepts of spermatogenesis are reviewed and the developmental stages of the germinal epithelium are discussed, as well as the complex hormonal interactions that take place. It is crucial to recognize that the efficiency of sperm production and the epididymal reserves in the human are considerably lower than those of conventional animal models. Therefore, the human male is more susceptible to a decline in fertility caused by a specific decrement in spermatogenesis than is an animal model.
The Trophic Effect of Luteinizing Hormone on the Rat Leydig Cell
Authors: Ewing Larry L.
Published: November 2007

Little is known about the factors controlling Leydig cell growth and differentiation. However, unique correlations exist between specific testicular compartments and the testosterone-secreting capacity of the testes. Selected experimental findings from three common laboratory animals—the rat, the hamster, and the guinea pig—are discussed.
SDZ 200–110 Induces Leydig Cell Tumors By Increasing Gonadotropins in Rats
Authors: Roberts Stanley A. , Nett Terry M. , Hartman Howard A. , Adams Thomas E. , Stoll Raymond E.
Published: November 2007

The administration of 62.5 mg/kg/day of SDZ 200–110, a calcium channel blocker, for 2 years increased the incidence of Leydig cell tumors while decreasing pituitary tumors in Sprague-Dawley rats. Lower doses did not change the incidence of these tumors. No other endocrine tumors were seen in rats or mice of either sex. A single gavage dose of 62.5 mg/kg/day decreased serum testosterone levels by 90% 4 hr after dosing. In vitro testosterone production by Leydig cells from these animals was minimally decreased, which suggests that a direct inhibition of steroid synthesis was removed during cell isolation. Dietary administration of the drug for 10 weeks did not significantly alter levels of serum hormones or testicular luteinizing hormone (LH) and gonadotropin-releasing hormone (GnRH) receptors, although a significant elevation of testicular testosterone levels was seen. Increased serum levels of LH and follicle-stimulating hormone (FSH) were seen after 52 and 66 weeks, respectively, of dietary feeding of 62.5 mg/kg/day. The increase in serum LH was observed to week 104, while FSH levels returned to control levels by week 94. No effect on gonadotropin receptors was seen at the 6.25 mg/kg/day dosage. The age-related increase in serum prolactin was markedly reduced by 62.5 mg/kg/day of SDZ 200–110 in weeks 66 to 104 and to a lesser extent at the 6.25 mg/kg/day dosage. Testicular LH receptors were decreased by the high dose in animals sacrificed after 90–104 weeks. In conclusion, SDZ 200–110 increases the incidence of Leydig cell tumors by elevating levels of serum gonadotropins. The suggested mechanism for this increase in gonadotropins is a result of the effects of SDZ 200–110 on serum hormones and testicular LH receptors. The drug was judged not to pose a risk to humans since no change in gonadotropin levels was observed after chronic treatment.
The Rapid and Sensitive Detection of Perturbations in Spermatogenesis: Assessment by Quantitative Dual Parameter (DNA/RNA) Flow Cytometry
Authors: Selden Jules R. , Robertson Richard T. , Miller Judith E. , Vetter Chris , Minsker David H. , Huber A. C. , Nichols Warren W.
Published: November 2007

This presentation will concentrate on the emerging field of flow cytometry. The first portion will be a review of the state-of-the-art applications of flow cytometry in the field of biomedical research; the second portion will describe the results of a preliminary study using a published technique that is useful in detecting cellular perturbations in germ cells. The model used in this study was the testis from the Sprague-Dawley rat. Adult rats received a single bolus of busulfan, and their testes were examined up to 56 days postadministration.
Testicular Lesions in Rats Treated with a Sympatholytic Hypotensive Agent (Losulazine)
Authors: Mesfin G. M. , Morris D. F. , Seaman W. J. , Marks T. A.
Published: November 2007

Groups of 25 male Sprague-Dawley rats were treated orally with losulazine at 0 (vehicle control), 4, 8, 16, or 32 mg/kg/day for 1 year. Daily clinical signs, weekly food consumption and body weight changes, and terminal hematologic and blood chemistry values were evaluated. Terminal urinalysis in 10 randomly selected rats from all groups and levels of serum luetinizing hormone, prolactin, and testosterone from control, low-, and high-dose groups were also evaluated. Fertility was determined in eight randomly selected rats from each group at 35–49 weeks. Reversibility of breeding performance was evaluated in 10 rats treated for 30 weeks and allowed to recover for 17 weeks. Selected organs were weighed and the testes and epididymides were microscopically evaluated in all rats that survived through the 1 year treatment period.

Rats treated with losulazine showed dosage-dependent ptosis, somnolence, fecal softening, and decreased food consumption with a corresponding retarded body weight gain. There were no biologically significant changes in hematologic, blood chemistry, or urinalysis values between treated and control rats. Relative spleen, heart, adrenal, and brain weights were increased in treated rats. There was a reversible dosage and time-dependent decreased fertility in rats treated with losulazine for 6–12 months. The incidence of testicular tubular atrophy/degeneration, usually confined to the subcapsular areas of the testes, and concentration of degenerate ge.minal cells in the epididymides, were increased in treated compared to vehicle control rats. Testicular lesions were not dosage related, were minimal to mild after 1 year of treatment, and were not attended by a decrease in relative testicular weights. Decreased fertility was not correlated with the apparently treatment-related testicular lesions. It could not be determined whether the minor testicular lesions seen in rats treated with losulazine were related to stressful conditions the rats were apparently under or to the effects of the drug on the hypothalamus-pituitary-gonadal axis or the sympathetic nervous system.
Evaluation of Reproductive Toxicity by Testicular Sperm Head Counts
Authors: Meistrich M. L.
Published: November 2007

The advantages of testicular sperm head counts are many, and the procedure should be encouraged. It is simple, quantitative, objective, and has excellent sensitivity. Effects can be measured for all stages of spermatogenesis, and indirect hormonal effects on spermatogenesis also can be detected. A large range for a dose-response curve exists, and there is a direct relationship to fertility in the animal. It is the only parameter that is really suitable for interspecies extrapolation, and in humans it is the parameter that can be applied to the quantitative assessment of reproductive risk.
Mechanisms of Psoralen Action in the Skin
Authors: Laskin Jeffrey D.
Published: November 2007

The combination of psoralens and ultraviolet light (UVA, 320–400 nm), also referred to as PUVA, is a potent modulator of epidermal cell growth and differentiation. Although it has been postulated that PUVA exerts its actions by binding to DNA, our laboratory has obtained evidence that a specific, saturable, high-affinity receptor site independent of the DNA mediates the biologic actions of these drugs. This receptor is a 22,000 molecular weight protein present in membrane and cytoplasmic fractions of responsive cell types. Treatment of cells with psoralens followed by UV light causes activation of the receptor. This leads to specific cell surface membrane alterations, in particular, phosphorylation of the receptor for epidermal growth factor (EGF). The EGF receptor is a transmembrane glycoprotein possessing intrinsic tyrosine kinase activity. Modification of the EGF receptor leads to a loss in its ability to bind EGF, as well as an inhibition of its tyrosine kinase activity. These data indicate that the psoralens act at the level of the cell membrane and that their biologic effects in the skin may be mediated by the ability of these drugs to disrupt normal growth factor functions.
Skin Penetration Method Suggested for Environmental Protection Agency Requirements
Authors: Zendzian Robert P.
Published: November 2007

The Environmental Protection Agency has circulated a protocol for examining the dermal absorption of pesticides in rats. This protocol will be considered as a guideline for determining the dermal absorption of pesticides. Approximately 40 pesticides have been evaluated with this protocol. Male rats are dosed dermally with labeled pesticide. Doses, in mg/cm2, are applied to the shaven skin of the back as the use product, diluted with water if necessary. The application site is protected with a nonocclusive device. Four rats per dose are exposed for 0.5, 1, 2, 4, 10, or 24 hrs. Samples collected are soap and water wash, skin at the application site, blood, total urine and feces, carcass, and selected tissues. Mass balance calculations include determination of pesticide that can be removed with soap and water, pesticide bound on or in the skin, total pesticide absorbed with time, blood concentrations with time, pesticide accumulation in target tissues, and pesticide excreted.
Skin Penetration of Pesticides
Authors: Simoneaux B. J. , Murphy T. G.
Published: November 2007

In vivo dermal penetration studies on rats have been investigated at Ciba-Geigy since 1981. Eleven different pesticides have been evaluated for dermal absorption during this time. Selected compounds with varying degrees of dermal absorption are discussed. An overview of the test protocol and nonocclusive appliance is shown. Data are presented to help evaluate whether bound skin residues after washing are permanently sequestered in skin.
Human Skin Binding and Absorption of Contaminants from Ground and Surface Water During Swimming and Bathing
Authors: Wester Ronald C. , Maibach Howard I.
Published: November 2007

Contaminants exist in ground and surface water. Human skin has the capacity to bind and then absorb these contaminants into the body during swimming and bathing. Powdered human stratum corneum will bind both lipid-soluble (alachlor, polychlorinated biphenyls [PCBs], benzene) and water-soluble (nitroaniline) chemicals. In vitro (human skin) and in vivo (Rhesus monkey) studies show that these chemicals readily distribute into skin, and then some of the chemical is absorbed into the body. Linearity in binding and absorption exists for nitroaniline over a 10-fold concentration range. Multiple exposure to benzene is at least cumulative. Binding and absorption can be significant for exposures as short as 30 min, and will increase with time. Absorption with water dilution increased for alachlor, but not for dinoseb. Soap reversed the partitioning of alachlor between human stratum corneum and water. The PCBs could be removed from skin by soap and water (70% efficiency) for up to 3 h and then decontamination potential decreased, due to continuing skin absorption. The model in vitro and in vivo systems used should permit easy estimation of this area of extensive human exposure effect on risk assessment.
Markers of Exposure to Carcinogens: Methods for Human Biomonitoring
Authors: Wogan Gerald N.
Published: November 2007

Methods have been developed for the detection of exposure to carcinogens and other DNA-damaging agents in experimental animals and humans, through the detection of carcinogens or metabolic derivatives of them in body fluids or adducts bound covalently to DNA or hemoglobin. These methods are being applied in studies of exposure to environmental carcinogens, the results of which demonstrate their adequacy for detecting ambient exposures. The successful use of urinary markers of genotoxic exposures has been reported with respect to nitrosoproline as an indicator of exposure to N-nitroso compounds. The same approach has been used to detect aflatoxin B1 (AFB1) metabolites and AFB1-N7-Gua as markers of exposure to aflatoxin B1. Detection of adducts formed between genotoxic agents and hemoglobin has been reported in studies of populations occupationally exposed to ethylene oxide, in which 3-hydroxyhistidine and 3-hydroxyva-line have been measured, and in smokers, whose hemoglobin has been found to contain levels of 4-aminobiphenyl and 3-hydroxyvaline that were correlated with the frequency of cigarette smoking. Albumin adducts of AFB1 have been identified in exposed people and their levels correlated with ingested amounts of the carcinogen.

DNA adducts of genotoxic agents have also been detected in the cells and tissues of exposed individuals. Several studies to date have focused on exposure to the ubiquitous polycyclic aromatic hydrocarbon benzo(a)pyrene. Immunoassays and physicochemical methods have been used to detect adducts formed through the major intermediate in the activation pathway, the benzpyrene-7,8-diol-9,10-epoxide (BPDE). BPDE adducts have been found in the DNA of peripheral leukocytes of workers in foundries, aluminum manufacturing plants, and coke oven plants, and also in roofers and cigarette smokers with the use of synchronous scanning fluorescence as well as by enzyme-linked immunosorbent assays (ELISA) or ultrasensitive enzyme radioimmunoassays (USERIA). DNA adducts of O6-methyl guanine have also been detected by immunoassay in the blood of populations at high risk for esophageal cancer. The method of 32P postlabeling has been used for the detection of DNA adducts in placentas, peripheral leukocytes, and oral mucosal cells of tobacco smokers as well as coke oven and foundry workers, and increased total levels of adducts were in general indicative of elevated levels of exposure.
Detection of Aromatic DNA Adducts in Human Cells and Fish Liver
Authors: Dunn Bruce P.
Published: November 2007

Both nuclease PI treatment and reverse-phase high-performance liquid chromatography (HPLC) were used to enrich hydrophobic/bulky DNA adducts in DNA digests. 32P-postlabeling procedures and thin layer chromatography were then used to detect and quantitate aromatic/bulky DNA adducts. For both human and fish DNA from individuals exposed to environmental carcinogens, the nuclease PI and HPLC enrichment procedures generally gave similar results. The bottom sediments of the Buffalo and Detroit rivers are contaminated with polycyclic aromatic hydrocarbon carcinogens, and brown bullheads in these rivers show a high rate of liver cancer. Compared to DNA from control fish raised in aquariums, DNA of livers of brown bullheads from the polluted rivers exhibited elevated levels of DNA adducts. DNA from human oral mucosal cells and lymphocytes exhibited DNA adducts, but adducts levels did not differ significantly in smokers and nonsmokers. Adduct levels in DNA from human lung biopsy tissue, however, were elevated in smokers compared to nonsmokers. In former smokers, adducts levels were highest in those who had recently quit, and lowest in those who had not smoked for 10 years or more. Measurement of DNA adducts by 32P-postlabeling appears to be a useful and particularly direct procedure for assessing genetic damage from environmental carcinogens.
Detection of Carcinogen–Macromolecular Adducts in Humans
Authors: Weston A. , Manchester D. K. , Povey A. , Harris C. C.
Published: November 2007

A major concern of molecular epidemiology is the identification of individuals at increased risk of cancer by obtaining evidence of high exposure to carcinogens that may lead to pathobiological lesions in target cells. DNA is considered to be a target for modification by mutagens and carcinogens; therefore, damage to DNA can be used as an internal, molecular dosimeter of carcinogen exposure. The reactive species of these carcinogens may bind either directly to DNA to form adducts or indirectly to cause secondary DNA lesions through free radicals and aldehydes. Highly sensitive and specific methods have been developed to measure DNA lesions and DNA repair products that are found in biological specimens from humans exposed to carcinogens in the environment. For example, DNA adducts have been measured in cells and tissues from people exposed environmentally to carcinogenic polycyclic aromatic hydrocarbons or alkylating agents. Antibodies recognizing carcinogen-DNA adducts have also been detected in human sera. Carcinogen-protein adducts are also being used as molecular dosimeters of carcinogen exposure. The advantages and limitations of the various methods used to measure carcinogen-macromolecular adducts are discussed here. The use of two or more complementary assays to obtain confirmatory results is recommended.
Assessing Indoor Air Pollution Exposure and Lung Cancer Risk in Xuan Wei, China
Authors: Chapman Robert S. , Mumford Judy L. , He Xingzhou , Harris D. Bruce , Yang Rudao , Jiang Weizhang
Published: November 2007

This report presents the risk-assessment-related aspects of a multidisciplinary study of indoor coal smoke pollution and lung cancer in Xuan Wei County, Yunnan Province, China. Xuan Wei presents a unique natural experiment in environmental carcinogenesis because lung cancer mortality rates and indoor pollution exposures vary widely within the County. Current evidence links lung cancer with domestic burning of “smoky coal,” as opposed to “smokeless coal” and wood. Efforts to determine the most carcinogenic components of smoky coal pollution are in progress, as are efforts to develop a quantitative relationship of pollution dose with lung cancer response in Xuan Wei. Some available evidence suggests that the composition of indoor pollution does not vary greatly throughout Xuan Wei, and thus that lung cancer risk is a function of overall pollution exposure. Other evidence suggests that different Xuan Wei fuels exhibit different carcinogenic potencies. On-site and laboratory studies are being conducted to differentiate between these possibilities.
Policies and Procedures for Establishing the National Exposure Registry
Authors: Burg Je Anne R.
Published: November 2007

The Agency for Toxic Substances (ATSDR) was mandated by Superfund legislation to create two national registries: a registry of persons exposed to hazardous substances and a registry of persons with serious diseases or illness. The polices and procedures for creating the first of these (The National Exposure Registry) have been established and are discussed here. The decision logic for site selection, the criteria for population selection, the data collection and storage, and related activities are detailed.
Sexual Differentiation in the Neonate: Rodent vs. Primate Comparisons
Authors: Manson Jeanne M.
Published: November 2007

There are some similarities and differences in the process of sexual differentiation during development in rodents and primates. The most obvious difference is in the timing of the critical periods for morphogenesis of the reproductive tract and sexual differentiation of the central nervous system (CNS). In primates these events occur late in the first trimester while in rodents they occur in the perinatal period.

The gonadal hormones involved in morphogenesis of the male reproductive tract are identical for all mammalian species studied. Testosterone is the androgen that induces differentiation of the seminal vesicles, vas deferens, and epididymis, while dihydrotestosterone (DHT) promotes differentiation of the external genitalia, urethra, and prostate.

Estrogens, derived from aromatization of testosterone, are the proximal determinants of male sexual differentiation of the CNS in rodents. In nonhuman primates, however, a nonaromatizable androgen, DHT, produces the same effect as testosterone on sexually differentiated behaviors in female offspring. Studies of male patients with 5α-reductase deficiency have suggested that maturation of male gender identity and psychosexual behavior in humans is critically dependent on testosterone but not on normal levels of DHT in prenatal and prepubertal life. Gender identity does not appear to be unalterably fixed in humans until the time of puberty and even at this and later times environmental factors have a strong impact.
Perinatal Immunotoxicity of Benzene Toward Mouse B Cell Development
Authors: Wierda Daniel , King Andrew G. , Luebke Robert W. , Reasor Mark J. , Smialowicz Ralph J.
Published: November 2007

Benzene is widely used by chemical industries and exposure to benzene has been shown experimentally to be immunotoxic in adult animals. This study addressed whether exposure of fetuses in utero to benzene compromises the development of fetal B lymphopoiesis and whether B-lymphocyte development recovers postnatally. Pregnant BALB/C dams were given intraperitoneal injections of benzene (100 mg/kg, twice daily) from day 12.5 of gestation through day 19.5 of gestation. Phenotypic analysis revealed that fetal liver cell suspensions from embryos exposed in utero contained fewer pre-B cells and B cells than corresponding controls. Fetal liver cell cultures established from these embryos also produced fewer B cells. In contrast, levels of pre-B cells were elevated in the livers of 8-day-old neonates that had been exposed to benzene in utero. Moreover, responsiveness to the B-cell mitogen, LPS, was significantly decreased in spleen cell cultures derived from these neonates. These results indicate that in utero exposure to high concentrations of benzene alters fetal B lymphopoiesis and may compromise immune responsiveness postnatally.
Neonatal Animal Models: Experimental Anencephaly and Similarities to Spina Bifida
Authors: Smith Michael T. , Wood L. R.
Published: November 2007

Anencephaly and spina bifida are the two most common neural tube defects (NTDs) that occur in humans. They cause considerable fetal wastage and neonatal morbidity and mortality. Numerous animal models have been discovered and have been used to study these malformations. We used the scanning electron microscope (SEM) to compare the development of embryonic stages of spina bifida and anencephaly. Pregnant 180 g Sprague-Dawley rats were given either a 1 ml subcutaneous injection of 1% trypan blue on gestational days 7-8 or an intragastric administration of 75,000 units of vitamin A on gestational days 8-10 to produce embryos with spina bifida or anencephaly. Controls were given vehicle only. The SEM examination of day 9 and 10 embryos revealed no morphologic differences between controls and subjects. Subsequent gestational days showed closure of neural tubes in controls but progressive opening of neural tubes (in the rostral and caudal regions) in experimental subjects. Growth of the dysmorphic neural tube region with subsequent sponteneous necrosis late in gestation resulted in the mature malformations of anencephaly and spina bifida. This study emphasizes the similarities in the developmental stages of spina bifida and anencephaly. We also surveyed a large series of human anencephalic autopsy specimens and noted striking similarities to the animal model.
Information Sources and Support Networks in Toxicology
Authors: Sidhu K. S. , Stewart T. M. , Nelton E. W.
Published: November 2007

This paper compiles sources of information dealing with environmental toxicology. Special emphasis has been put on information available from various computer databases and support networks. The information compiled will be useful for professionals entering the regulatory agencies as toxicologists or environmental health scientists.
Toxicity Induced by Subchronic Dermal Exposure to Paratertiary Butyl Benzoic Acid (pt BBA) in Fischer 344 Rats
Authors: Cagen S. Z. , Patterson D. R. , Wimberly H. C. , Lu C. C. , Gardiner T. H.
Published: November 2007

The subchronic dermal toxicity of aqueous solutions containing the diethanolamine salt of para-tertiary butyl benzoic acid was determined in Fischer 344 rats. Para-tertiary butyl benzoic acid (pt BBA) has important applications in the manufacture of resins, polymers, and corrosion inhibitors. Male and female rats were exposed topically 5 days/week for up to 13 weeks with dosing solutions that resulted in daily exposures of 0.0, 17.5, 35.0, 70.0, or 140.0 mg/kg pt BBA. These concentrations did not produce overt clinical signs of toxicity and did not cause irritation to dermal exposure sites. However, exposure to the two highest concentrations resulted in decreased weight gain. Exposure at all concentrations resulted in dosage-related increases in relative hepatic and renal weights. Exposure of males to the two highest concentrations caused decreased testis weight. Exposure-related pathologic changes were confined to three organ systems: cytoplasmic vacuolation in the liver; tubular dilation and papillary necrosis of the kidneys; and tubular degeneration in the testes. Accompanying aberations in clinical chemistry values suggested altered hepatic and renal function. In males exposed daily to 70.0 and 140.0 mg/kg pt BBA, the testicular effects were marked, but no effects were detected in rats exposed to 17.5 or 35.0 mg/kg of pt BBA.
Mechanistic Insights Gained from an Analysis of Carcinogenic Polycyclic Aromatic Hydrocarbons with the Computer Automated Structure Evaluation System
Authors: Rosenkranz Herbert S. , Klopman Gilles
Published: November 2007

The Computer Automated Structure Evaluation System (CASE) was used to identify the structural components responsible for either the mutagenicity or the carcinogenicity of polycyclic aromatic hydrocarbons (PAHs). These were found not to overlap and some of the structural components were endowed with much more biological activity than others.

A study was then undertaken to determine whether these structural features could explain the mutagenicity and carcinogenicity of 7,12-dimethylbenz(a)anthracene (DMBA). It was found that the structures identified by CASE could explain the mutagenicity and carcinogenicity qualitatively as well as quantitatively. Moreover, the identified structures were entirely consistent with recent findings on the metabolism and DNA adduct formation of DMBA.

These results are taken to indicate that CASE can be used to identify the structures in a molecule (e.g., PAH) that are sites of metabolism. Laboratory studies can then focus on that portion of the molecule.
Overexposures to Lead at a Covered Outdoor Firing Range
Authors: Tripathi R. K. , Sherertz P. C. , Llewellyn G. C. , Armstrong C. W. , Ramsey L.
Published: November 2007

Significant overexposures to airborne lead were found in a covered, outdoor firing range among seven cadets during firing of conventional, nonjacketed, lead bullets. The mean lead concentrations in general area air samples and personal-breathing-zone air samples were 68.36 μg/m3 and 128.46 μg/m3, respectively, calculated as an 8h, time-weighted average (TWA). Eight (44%) of 18 area air samples, taken as far as 50 yards from the firing line, and 10 (67%) of 15 personal breathing zone air samples exceeded the current Occupational Safety and Health Administration (OSHA) standard for occupational exposure to airborne lead (50μg/m3). Blood lead levels (using a t-test) were found to increase significantly in all cadets after day 2 ( p < 0.0001) and day 5 ( p < 0.0007) of firing conventional, nonjacketed, lead bullets. None of the blood level values exceeded the OSHA standard of 40 μg/dl. A strong positive correlation ( r = 0.92; p < 0.000001) existed between personal-breathing-zone air lead levels and the number of rounds fired by the cadets. A positive correlation also existed between blood lead levels and cumulative personal breathing zone air lead levels ( r = 0.85; p < 0.02), as well as the total number of rounds fired ( r = 0.84; p < 0.02). Based on environmental and medical data, it was concluded that a potential health hazard may exist due to inorganic lead exposure to cadets at this covered outdoor range during firing exercises.
Oncogene Activation in Multistage Carcinogenesis
Authors: Garte Seymour J.
Published: November 2007

Oncogene activation in multistage carcinogenesis is discussed. Results from a number of in vitro studies are cited. An understanding of the mechanisms that suppress activated ras oncogene-induced transformation by protease inhibitors is expected to shed light on the process of multistage carcinogenesis.
Induction of Cytochrome P450b and Its Relationship to Liver Tumor Promotion
Authors: Lubet R. A. , Nims R. W. , Ward J. M. , Rice J. M. , Diwan B. A.
Published: November 2007

A wide variety of compounds was examined for the ability to induce a specific form of hepatic cytochrome P450 and to promote the development of DEN-initiated liver tumors (adenomas and carcinomas) in rats over a 72 week period. The induction of cytochrome P450b was determined indirectly by measuring the hepatic induction of pentoxy-or benzyloxyresorufin O-dealkylase activities, which are highly specific substrates for the major phenobarbital-inducible forms of cytochrome P450 in the rat.(10) Results in the rat showed: (1) potent inducers (> 40 ×) of P450b (i.e., phenobarbital, barbital, ethylphenyl-hydantoin, and DDT) are all potent liver tumor promoters; (2) structural analogs that are not inducers of P450b (i.e., hexobarbital, monoethylbarbituric acid, monophenyl-barbituric acid, and diethylhydantoin) all fail to display significant liver tumor promoting activity; and (3) the concomitant induction of liver hypertrophy, microsomal epoxide hydrolase, and cytochrome P450b appears to be proportional and argues for some coordinated “pleiotropic” response of liver parenchyma to these inducers. Additional studies showed that phenobarbital induced cytochrome P450b and was a liver tumor promoter not only in rats, but also in mice and patas monkeys, but was inactive as an enzyme inducer and was a nonpromoter in the hamster.
A Chronic Inhalation Toxicity Study of Diesel Engine Emissions and Coal Dust, Alone and Combined
Authors: Lewis T. R. , Green F. H.Y. , Moorman W. J. , Burg J. R. , Lynch D. W.
Published: November 2007

To evaluate the potential health hazards of diesel engine emissions in underground coal mines, inhalation studies were performed using three species of animals. A wide range of toxicological responses was measured. Exhaust was provided by a 425 in.3 displacement four-cycle, water-cooled, naturally aspirated diesel engine (Caterpillar Model 3304) equipped with a water scrubber. Exposures were 7 h/day, 5 days/week, for periods up to 24 months. Micronized coal dust was generated using a Wright dust feeder. Four exposures were evaluated: (1) filtered ambient air, (2) 2 mg/m3 diesel particulate, (3) 2 mg/m3 respirable coal dust, and (4) 1 mg/m3 each of 2 and 3. Gaseous and vapor concentrations were similar in both exposures employing diesel exhaust. Male cynomolgus monkeys, Fischer-344 male and female rats, and female CD-1 mice were the experimental subjects. Monkeys were sacrificed at 24 months, rats at 3, 6, 12, and 24 months, and mice at 1, 3, and 6 months.

Gross morphology and histopathology demonstrated that both diesel and coal dust particles are deposited in the lungs and retained in alveolar tissue. Alveolar type II cell hyperplasia and pulmonary lipidosis occurred in rats, being most evident in rats exposed to diesel exhaust alone. There was, however, no evidence of emphysema or chronic bronchitis, and only minimal fibrosis was seen in association with the retained particulate. Both particulates affected the defense mechanisms of the lung. Exposure to coal dust activated responses associated with phagocytosis, whereas exposure to diesel exhaust depressed them. Severity of influenza challenge increased concomitantly with decreased interferon production in diesel-exposed mice. Exposure to diesel emissions did not result in genotoxic effects as measured by increases in sister chromatid exchange, chromosomal aberrations, micronucleus testing, and urine genotoxic assays. Pulmonary function studies in monkeys showed mild obstructive airway disease in coal dust, diesel exhaust, and the combined exposed animals. This effect was most pronounced in monkeys exposed to diesel exhaust. Evidence of restrictive lung disease was not seen in any group. Clearance of F3O4 particles appeared to be stimulated by exposure to diesel exhaust in the first 3 months, but long-term clearance of diesel particulate appeared to be inhibited. No evidence was found for increases in tumorogenicity (rats) or induction of xenobiotic metabolizing enzymes in the lung or liver (rats). Humoral and cellular immunities were not significantly affected by exposure (rats). No adverse seminal effects were observed in monkeys exposed for 2 years. There was no frank evidence of chronic toxicity as demonstrated by changes in mortality, body weight gains, organ-body weight ratios, or clinical parameters in rats or monkeys. Synergistic effects between diesel exhaust and coal dust were not demonstrated.
Effective Quality Assurance
Authors: Schroeder Robert S.
Published: November 2007

An effective quality assurance program is an integral part of laboratory operations. Its primary goal is to assist in the planning and documentation of studies as well as helping to generate trustworthy reports. An effective program is based on a cooperative attitude, support by management, professional respect, known and communicated requirements, and a system to generate data with integrity.
Analysis of the FDA GLP Compliance Audit Findings from 1979 to 1985
Authors: Dewoskin Robert S. , Schroeder Robert S. , Barkalow Robert E.
Published: November 2007

An independent panel of quality assurance professionals evaluated the U.S. Food and Drug Administration's FD483 forms. FD483 forms are used during laboratory site visits to document adverse findings. Findings were ranked for severity and identified as specific deviations from the good laboratory practice regulations. No trends were observed in the number or severity of the FD483 findings over a 7 year period. There was, however, considerable year-to-year variability in the types of facilities inspected and in the kinds of GLP deviations observed. Only 4% of the FD483s were judged as having an overall severity that would likely result in a disqualified study. The few academic and government laboratories that were evaluated generally fared poorly. A total of 225 FD483s were issued to 137 different laboratories. Of the 225 FD483s issued, 65% were issued to only 58 facilities during the initial and subsequent site visits.

The general conclusion is that more detailed information and a longer time frame are needed to observe trends in GLP compliance for different types of facilities and subsections of the GLPs. To allow a fair appraisal of the GLP compliance effort, research is needed to develop new and more consistent auditing methods that measure successful remedial actions and that provide testing facilities with information on how FD483 findings translate into GLP deviations and how deviations are ranked for severity.
A Systemic Exposure-Based Alternative to the Maximum Tolerated Dose for Carcinogenicity Studies of Human Therapeutics
Authors: Contrera Joseph F. , Jacobs Abigail C. , Prasanna Hullahalli R. , Mehta Mehul , Schmidt Wendelyn J. , de George Joseph
Published: November 2007

A systemic exposure-based alternative to the maximum tolerated dose (MTD) for high-dose selection in carcinogenicity studies for human therapeutics was accepted at the Second International Conference on Harmonization (ICH-2). The systemic exposure-based alternative to the MTD is suitable for nongenotoxic compounds with low rodent toxicity that are metabolized similarly in rodents and humans. This is the first product of an evaluation of current standards for rodent carcinogenicity studies of therapeutics. The relative systemic exposure is the ratio of the rat plasma area under the plasma concentration-time curve (AUC) at the MTD/human plasma AUC at the maximum recommended daily dose. An appropriate systemic exposure ratio for high-dose selection in carcinogenicity studies was empirically derived from the distribution of systemic exposure ratios attained by 35 compounds from 11 therapeutic categories in a Food and Drug Administration (FDA) database. Approximately one-third achieved a relative systemic exposure ratio <1 and two-thirds attained an exposure ratio of 10 or less, at the MTD. A systemic exposure ratio of at least 25 was accepted for high-dose selection in carcinogenicity studies at ICH-2. This ratio is high enough to detect all compounds with positive studies in the FDA database and would detect IARC 1 and 2A carcinogenic drugs. A ratio of 25 exceeds the systemic exposure ratio attained by 75% of drugs tested at the MTD in the FDA database and represents an adequate margin of safety which can be attained by a significant proportion of drugs.
Organochlorine Residues and Risk of Breast Cancer
Authors: Houghton Donna L. , Ritter Leonard
Published: November 2007

Considerable attention has recently been focused on the possible role of estrogenic compounds as etiologic agents in the development of human breast cancer. This review summarizes data from relevant laboratory and epidemiological studies to assess the hypothesis that exposure to organochlo-rines, and specifically 2,2-bis(p-chlorophenyl)-1,1,1-trichloroethane (DDT), increases breast cancer risk. Organochlorine compounds, including pesticides such as DDT and industrial compounds such as the polychlorinated biphenyls (PCBs), have had a long history of use. In general, these compounds are characterized by their high lipophilicity and environmental persistence. DDT was widely used in agriculture and public health programs from 1943 to 1972, when it was removed from use in the Western world. DDT is still used, however, in many developing nations. The International Agency for Research on Cancer concluded that there was adequate evidence that DDT was carcinogenic in laboratory animals, yet epidemiological evidence has not been compelling. The estrogenic activity of o, p'-DDT has been well characterized; however, the affinity of estrogen receptors for this compound is very weak and reported to be 1/2,000–1/10,000 that of 17β-estradiol. Epidemiologically, some investigators have reported elevated levels of 1,1-dichloro-2,2-bis(p-chloro-phenyl)ethylene, a DDT metabolite, and PCBs in breast adipose tissue and blood serum taken from breast cancer patients when compared with controls, while others have reported the absence of such an association. While the etiology of breast cancer is not fully understood, it is generally recognized that estrogenic compounds may increase the risk of disease. Contemporary human exposure to DDT and other organochlorines is very limited and would likely play an insignificant role when compared with other sources of exposure, such as estrogen replacement therapy and phytoestrogens in food.
Developmental Toxicity of Sodium Chlorite in the Rabbit
Authors: Harrington Robert M. , Romano Robert R. , Irvine Lorraine
Published: November 2007

Chloride dioxide (ClO2) is currently used in many countries as a drinking water disinfectant. Chlorite ion (ClO2-) is the primary degradation product of ClO2 when it is used to treat drinking water. In this study, mated female New Zealand white rabbits received either 0, 200, 600, or 1,200 ppm NaClO2 in their drinking water from Day 7 to Day 19 of pregnancy, inclusive, and were necropsied on Day 28 of pregnancy. Weight of the gravid uterus, number of corpora lutea, implantation sites, and live fetuses were recorded. Live fetuses were weighed, sexed, and examined for external, visceral, and skeletal abnormalities. Maternal food and water consumption were decreased at 600 and 1,200 ppm, however, no treatment-related maternal abnormalities were observed at necropsy. As expected in the presence of maternal effects, mean fetal weights were slightly lower at 600 and 1,200 ppm, with a slightly higher incidence of incomplete ossification of some bones. There were no treatment-related fetal structural abnormalities. Pre- and postimplantation losses were within expected ranges and other reproductive parameters were similar in all groups. At 200 ppm, there were no maternal or fetal effects. NaClO2 was not considered to be teratogenic or a selective developmental toxicant.
Reproductive Toxicity Study of Clarified Slurry Oil in the Rat
Authors: Hoberman A. M. , Christian M. S. , Roth R. , Lovre S. , Koschier F.
Published: November 2007

Clarified slurry oil (CSO, CAS #64741–62-4; also termed carbon black oil), a residual product from the fluidized catalytic cracker in petroleum refining, has the potential to be absorbed through the skin. The reproductive toxicity of CSO in male and female rats was evaluated by the topical route of exposure. CSO was administered dermally to male rats at dosages of 0 (vehicle), 0.1, 1, 10, 50, and 250 mg/kg/day for 70 days before a cohabitation period with untreated female rats. CSO was administered also to female rats at the same dosages for 14 days prior to a 7-day cohabitation period and continuing until Day 0 of gestation (day spermatozoa was present in a smear of the vaginal contents or a copulatory plug was observed in situ). The dosage volume in both experiments was 1 ml/kg, adjusted on each day of dosage based on individual body weights recorded immediately before application of CSO. Under the conditions of these experiments, the paternal no-observable-adverse-effect-level (NOAEL) for CSO administered dermally was 1 mg/kg/day. The 10, 50, and 250 mg/kg/day dosages of CSO caused body weight losses and/or decreased body weight gains and reduced feed consumption. The 50- and 250-mg/kg/day dosages also caused adverse clinical effects. No mating, fertility, or testicular end points in male rats were affected by the highest dosages tested; therefore, the reproductive NOAEL for male rats is <250 mg/kg/day. The maternal NOAEL for CSO administered dermally was 10 mg/kg/day. The 50-and 250-mg/kg/day dosages of CSO reduced body weight gains; 250 mg/kg/day also reduced feed consumption. There were no adverse effects on gonadal function, estrous cycles, mating behavior, conception rates, or reproductive organ weights; therefore, the reproductive NOAEL for female rats administered CSO dermally is at least 250 mg/kg/day.
Subchronic Inhalation Toxicity and Neurotoxicity Assessment of Cumene in Fischer 344 Rats
Authors: Cushman Janette R. , Norris James C. , Dodd Darol E. , Darmer Kenneth I. , Morris Carl R.
Published: November 2007

Male and female Fischer 344 rats were exposed to cumene vapor at 0, 100, 500, and 1,200 ppm for 6 h per day, 5 days per week, for 13 weeks; a satellite group received a single 6-h exposure. A subsequent 13-week study with a 4-week recovery period was conducted at 0, 50, 100, 500, and 1,200 ppm. Following the single exposure, the functional observational battery was altered at 500 and 1,200 ppm through 6 h postexposure. In the subchronic studies, there were no exposure-related changes in the functional observational battery, auditory brain stem response, brain measurements, or nervous system histopathology. Motor activity decreases seen only in male rats exposed to 500 or 1,200 ppm in the first study were not replicated in the second study. The 500-and/or 1,200-ppm groups showed transient decreases in body weight gain and food consumption, an increase in water consumption, and changes in several hematologic and clinical chemistry parameters. There were no exposure-related ophthalmologic findings or effects on spermatogenesis. Weights of liver, kidneys, and adrenal glands were increased in the 500- and 1,200-ppm groups. Renal proximal tubular cell hypertrophy, hyperplasia, and hyaline drop formation were observed in the male rats at 500 and 1,200 ppm. In conclusion, exposure to cumene vapor resulted in mild toxicity at 1,200 ppm, minimal effects at 500 ppm, and no observable effects at 50 and 100 ppm. Cumene vapor exposure was neither neurotoxic nor ototoxic in these studies.