Abstract  Rats of various postnatal ages were utilized to investigate developmental changes in the short-term distribution of [3H]mannitol, [3H]inulin and [51Cr]-tagged erythrocytes in both the cerebellum (CER) and cerebral cortex (CC). As the CNS undergoes maturation the most precipitous decrease in the 1-h radiomannitol (and inulin) space in the CER takes place during the second postnatal week whereas the greatest reduction in the spaces for both radioisotopes in the CC occurs during the earlier period between 0.5 and 1 week. The volume of distribution in immature brain tissue (1 week) into which [3H]mannitol penetrates in 1 h is substantially less (by 75--90%) than that into which this tracer permeates in non-neural tissue such as heart and liver; thus, even prior to the proliferation of glial elements, there is a limited barrier effect. At 3 weeks the permeability of the blood--brain barrier in the CER to mannitol is comparable to that in the CC. The vascularity of the CER (as estimated by residual [51Cr]erythrocyte-volume) is greater than that of the CC at each postnatal age investigated. The uptake of radiomannitol by the choroid plexus (blood--CSF barrier) in immature animals is a reflection primarily of developmental changes in volume of extracellular fluid rather than in permeability of the basolateral face of the choroidal epithelium. Qualitative differences, neonates vs adults, in the distribution of [3H]mannitol between CSF and brain tissue are attributable to maturational changes in secretory and permeability phenomena associated with the blood--CSF and blood--brain barriers.

Abstract  Endometriosis is a disease which afflicts women of reproductive age. It is one of the most common causes of pelvic pain and infertility; an estimated 5 million women in the U.S. are affected.1 Despite its apparent widespread occurrence, there are no national or international surveillance systems to determine how many suffer from this disease. Since there is no noninvasive test that is highly selective and specific for endometriosis, studies of its prevalence and incidence have been limited to women undergoing gynecologic operations.

Abstract  Because many diseases of the Western Hemisphere are hormone-dependent cancers, we have postulated that the Western diet, compared to a vegetarian or semivegetarian diet, may alter hormone production, metabolism, or action at the cellular level by some biochemical mechanisms. Recently, our interest has been mainly focused on the cancer-protective role of some hormonelike diphenolic phytoestrogens of dietary origin, the lignans and the isoflavonoids. The precursors of the biologically active compounds originate in soybean products (mainly isoflavonoids), whole grain cereal food, seeds, and probably berries and nuts (mainly lignans). The plant lignan and isoflavonoid glycosides are converted by intestinal bacteria to hormonelike compounds with weak estrogenic but also antioxidative activity; they have now been shown to influence not only sex hormone metabolism and biological activity but also intracellular enzymes, protein synthesis, growth factor action, malignant cell proliferation, differentiation, and angiogenesis in a way that makes them strong candidates for a role as natural cancer-protective compounds. Epidemiologic investigations strongly support this hypothesis because the highest levels of these compounds in the diet are found in countries or regions with low cancer incidence. This report is a review on recent results suggesting that the diphenolic isoflavonoids and lignans are natural cancer-protective compounds.

Abstract  A six compartment physiologically based pharmacokinetic (PB-PK) model was developed to describe the disposition of diethylene-1,4-dioxide (dioxane) and its principal metabolite beta-hydroxyethoxyacetic acid in rats, mice, and humans. The model was developed from experimentally measured partition coefficients (reported here for the first time) as well as pharmacokinetic data previously reported. The completed PB-PK model adequately described data from gavage and intravenous studies in rats, as well as inhalation studies in rats and humans. Substantial nonlinearities were observed in the kinetic behavior of dioxane under high exposure conditions (water concentrations greater than 0.1% dioxane and atmospheric concentrations greater than 300 ppm dioxane). The PB-PK model was subsequently used to prepare quantitative estimates of the "plausible upper bounds" on carcinogenic risk for human populations exposed to dioxane in air or water. Based on these quantitative estimates, it appears that human populations continuously exposed to 740-3700 ppb dioxane in air or 20,000-120,000 ppb dioxane in water would be unlikely to experience increased frequencies of tumors.

Abstract  Female Sprague-Dawley rats were given 0, 168, 840, 2550 or 4200 mg/kg of 1,4-dioxane 21 and 4 h before sacrifice. Hepatic DNA damage (by the alkaline elution technique), ornithine decarboxylase activity (ODC), reduced glutathione content, cytochrome P-450 content and serum alanine aminotransferase activity (ALT) were determined. Treatment with 1,4-dioxane increased hepatic DNA damage and cytochrome P-450 content at doses of 2550 and 4200 mg/kg. Large increases in the activity of hepatic ODC were observed at 840, 2550 and 4200 mg/kg of 1,4-dioxane. Thus the data suggest that 1,4-dioxane is a weak genotoxic carcinogen in addition to being a strong promoter of carcinogenesis (a non-genotoxic carcinogen).

Abstract  Four groups of rats, 60/sex/level, were maintained on drinking water containing 0, 1.0, 0.1, or 0.01% 1,4-dioxane for up to 716 days. Male and female rats receiving 1% dioxane (equivalent to approximately 1015 and 1599 mg/kg/day, respectively) showed decreases in body weight gains, survival rates, and water consumption. Hepatocellular and renal tubular degenerative changes, accompanied by regenerative activity, were similar to those reported in previous studies following exposure to toxic levels of dioxane. Hepatocellular and nasal carcinomas, occurring at this dose level, were considered related to the lifetime exposure to these massive toxic dosages of dioxane. Male and female rats receiving 0.1% dioxane (equivalent to approximately 94 and 148 mg/kg/day, respectively) in the drinking water had variable degrees of renal and hepatic degenerative changes, but there was no indication of treatment-related tumor occurrence. Male and female rats receiving 0.01% dioxane in the drinking water (equivalent to approximately 9.6 and 19.0 mg/kg/day, respectively) showed no evidence of tumor formation or other toxic effects considered to be related to treatment. These data indicate a dose response for the toxicity of dioxane.

Abstract  Dioxane (1,4-dioxane) is a colorless liquid used as a specialty solvent since about 1930. The prinicipal toxic effects of dioxane have long been known to be centrilobular, hepatocellular and renal tubular epithelial degeneration and necrosis (DeNavasquex, 1935; Fairley et al., 1934; Schrenk and Yant, 1936; Kesten et al., 1939). More recent reports by Argus et al. (1965) and Hoch-Ligeti et al.(1970) described nasal and hepatic carcinomas in rats ingesting water containing massive doses (up to 1.8% in the drinking water) of dioxane for over 13 months. Due to the massive doses which the rats received in these more recent studies, it is difficult to use the information to assess the hazard which may be incurred by individuals exposed to lower, more realistic levels of dioxane. Thus, a series of experiments has been conducted in our laboratory. This series has included a study of rats ingesting various dose levels of dioxane in the drinking water for 2 years (kociba et al., 1974), a study of rat exposed to vapors of dioxane for 2 years (Torkelson et al., 1974), and a study of the pharmacokinetics and metabolism of various dose levels of dioxane (Young et al. 1975).

Abstract  A cancer bioassay conducted in 1974 (Kociba et al.) indicated that rats given drinking water containing dioxane at a dose of 1184 mg.kg-1.d-1 produced an increased incidence of liver tumors. Applying the linearized multistage extrapolation model to these data, the administered dose estimated to present a human cancer risk of 1 in 100,000 (10(-5)) was 0.01 mg.kg-1.d-1. As in customary regulatory policy, this estimate assumed that humans were about 5.5 times more sensitive than rats on a mg/kg basis. However, this approach did not consider that the metabolism of dioxane is saturable at high doses. Based on experience with similar chemicals, it is known that the conventional risk extrapolation method may overestimate the most likely human cancer risk. In order to determine more accurately the likely human response following lifetime exposure to dioxane, a physiologically-based pharmacokinetic (PB-PK) model was developed. The objective of this study was to establish a quantitative relationship between the administered dose of dioxane and the internal dose delivered to the target organ. Using this PB-PK model, and assuming that the best dose surrogate for estimating the liver tumor response was the time-weighted average lifetime liver dioxane concentration, the cancer risk for humans exposed to low doses of dioxane was estimated. The dose surrogate in humans most likely to be associated with a tumorigenic response of 1 in 100,000 is 280 mumol/l, equivalent to an administered dose of about 59 mg.kg-1.d-1. The 95% lower confidence limit on the dose surrogate at the same response level is 1.28 mumol/l, equivalent to an administered dose of 0.8 mg.kg-1.d-1. This PB-PK analysis indicated that conventional approaches based on the administered doses in the rodent bioassay, if uncorrected for metabolic and physiological differences between rats and humans, will overestimate the human cancer risk of dioxane by as much as 80-fold.

Abstract  Using 3H-dioxane, the distribution of dioxane among a number of tissues and various subcellular fractions of rat liver was studied. At various times after i.p. injection, dioxane was found to distribute more or less uniformly among various tissues (liver, kidney, spleen, lung, colon and skeletal muscle), consistent with its polar/nonpolar nature. Studies of the nature of dioxane binding, however, revealed that the extent of “covalent” binding (as measured by incorporation into lipid-free, acid-insoluble tissue residues) was significantly higher in the liver (the main carcinogenesis target tissue), spleen and colon than that in other tissues. Investigations of the subcellular distribution in liver indicated that most of the radioactivity was in the cytosol, followed by the microsomal, mitochondrial and nuclear fractions. The binding of dioxane to the macromolecules in the cytosol was mainly noncovalent. The percent covalent binding was highest in the nuclear fraction, followed by mitochondrial and microsomal fractions and the whole homogenate. Pretreatment of rats with inducers of microsomal mixed-function oxidases had no significant effect on the covalent binding of dioxane to the various subcellular fractions of the liver. There was no microsome-catalyzed in vitro binding of 3H- or 14C-dioxane to DNA under conditions which brought about substantial binding of 3H-benzo[a]pyrene.

Abstract  The mechanisms responsible for ethanol-mediated teratogenesis have not been resolved. However, possible etiologies include the local formation of the teratogen acetaldehyde or oxygen radicals by fetal ethanol-oxidizing enzymes. As alcohol dehydrogenases are expressed at very low concentrations in human embryonic tissues, the ethanol-inducible P450 enzyme, CYP2E1, could be the sole catalyst of fetal ethanol oxidation. With this in mind, we examined the expression of this P450 in liver samples from fetuses ranging in gestational age from 16 to 24 weeks. Immunoblot analysis of fetal liver microsomes revealed the presence of a protein immunoreactive with CYP2E1 antibodies that exhibited a slightly lower molecular weight than that found in adult liver samples. Embryonic CYP2E1 expression was further confirmed by the reverse transcriptase reaction with RNA from a 19-week gestational fetal liver used as template. Catalytic capabilities of human fetal microsomes were assessed by measurement of the rate of ethanol oxidation to acetaldehyde, which were 12-27% of those exhibited by adult liver microsomes. Immunoinhibition studies with CYP2E1 antibodies revealed that the corresponding antigen was the major catalyst of this reaction in both fetal and adult tissues. We then assessed whether embryonic CYP2E1 was, like the adult enzyme, inducible by xenobiotics. Treatment of primary fetal hepatocyte cultures with either ethanol or clofibrate demonstrated a 2-fold increase in CYP2E1 levels compared with untreated cells. Collectively, our results indicate that CYP2E1 is present in human fetal liver, that the enzyme is functionally similar to CYP2E1 from adults, and that fetal hepatocyte CYP2E1 is inducible in culture by xenobiotics, including ethanol. Because fetal CYP2E1 mediates ethanol metabolism, the enzyme may play a pivotal role in the local production of acetaldehyde and free radicals, both of which have potential deleterious effects on the developing fetus.

Abstract  The fact that the chlorinated dioxins are highly toxic, teratogenic, and acnegenic does not of necessity indicate they are carcinogens as well. However, in view of the widespread use of products that might contain dioxins as contaminants and their extreme stability under environmental conditions, examination of their possible long term effects is imperative. This program was initiated to determine the chronic toxicity and potential carcinogenicity of a series of chlorinated dibenzodioxins by oral administration and skin application. The unsubstituted, 2,7 dichloro- and octachlorodibenzodioxins are relatively innocuous with regard to toxicity. The 2,3,7 trichloro-, 2,3,7,8 tetrachloro- and hexachlorodibenzodioxins, however, are quite toxic and require the use of specialized facilities to minimize the possibility of human exposure. This report describes the authors' results to date with the nontoxic dioxins. Work is being initiated with the toxic dioxins as they become available. These preliminary results are by no means conclusive with regard to the carcinogenicity of the chlorinated dioxins. The oral studies indicate primarily hepatotoxicity, expecially in the case of octachlorodibenzodioxin. The skin carcinogenesis assay for the nontoxic compounds is nearing completion, and no skin tumors have been observed in the complete carcinogenesis studies. The nature of the internal growths must still be determined at necropsy.

Abstract  A physiologically based pharmacokinetic model which describes the behavior of inhaled styrene in rats accurately predicts the behavior of in baled styrene in humans. The model consists of a series of mass-balance differential equations which quantify the time course of styrene concentration within four tissue groups representing (1) highly perfused organs, (2) moderately perfused tissues such as muscle. (3) slowly perfused fat tissue, and (4) organs with high capacity to metabolize styrene (principally liver). The pulmonary compartment of the model incorporates uptake of styrene controlled by ventilation and perfusion rates and the blood:air partition coefficient The metabolizing tissue group incorporates saturable Michaelis-Menten metabolism controlled by the biochemical constants Vmax and Km. With a single set of physiological and biochemical constants, the model adequately simulates styrene concentrations in blood and fat of rats exposed to 80, 200, 600, or 1200 ppm styrene (data from previously published studies). The simulated behavior of styrene is particularly sensitive to changes in the constants describing the fat tissue group, and to the maximum metabolic rate described by Vmax, The constants used to simulate the fate of stvrene in rats were scaled up to represent humans. Simulated styrene concentrations in blood and exhaled air of humans are in good agreement with previously published data. Model simulations show that styrene metabolism is saturated at inhaled concentrations above approximately 200 ppm in mice, rats, and humans. At inhaled concentrations below 200 ppm, the ratio of styrene concentration in blood to inhaled air is controlled by perfusion limited metabolism. At inhaled concentrations above 200 ppm. This ratio is controlled by the blood:air partition coefficient and is not linearly related to the ratio attained at lower (nonsaturating) exposure concentrations. These results show that physiologically based pharmacokinetic models provide a rational basis with which (1) to explain the relationship between blood concentration and air concentration of an inhaled chemical, and (2) to extrapolate this relationship from experimental animals to humans.

Abstract  This report presents detailed information on age- and gender-related differences in the anatomical and physiological characteristics of reference individuals. These reference values provide needed input to prospective dosimetry calculations for radiation protection purposes for both workers and members of the general public. The purpose of this report is to consolidate and unify in one publication, important new information on reference anatomical and physiological values that has become available since Publication 23 was published by the ICRP in 1975. There are two aspects of this work. The first is to revise and extend the information in Publication 23 as appropriate. The second is to provide additional information on individual variation among grossly normal individuals resulting from differences in age, gender, race, or other factors. This publication collects, unifies, and expands the updated ICRP reference values for the purpose of providing a comprehensive and consistent set of age- and gender-specific reference values for anatomical and physiological features of the human body pertinent to radiation dosimetry. The reference values given in this report are based on: (a) anatomical and physiological information not published before by the ICRP; (b) recent ICRP publications containing reference value information; and (c) information in Publication 23 that is still considered valid and appropriate for radiation-protection purposes. Moving from the past emphasis on 'Reference Man', the new report presents a series of reference values for both male and female subjects of six different ages: newborn, 1 year, 5 years, 10 years, 15 years, and adult. In selecting reference values, the Commission has used data on Western Europeans and North Americans because these populations have been well studied with respect to antomy, body composition, and physiology. When appropriate, comparisons are made between the chosen reference values and data from several Asian populations. The first section of the report provides summary tables of all the anatomical and physiological parameters given as reference values in this publication. These results give a comprehensive view of reference values for an individual as influenced by age and gender. The second section describes characteristics of dosimetric importance for the embryo and fetus. Information is provided on the development of the total body and the timing of appearance and development of the various organ systems. Reference values are provided on the mass of the total body and selected organs and tissues, as well as a number of physiological parameters. The third section deals with reference values of important anatomical and physiological characteristics of reference individuals from birth to adulthood. This section begins with details on the growth and composition of the total body in males and females. It then describes and quantifies anatomical and physiological characteristics of various organ systems and changes in these characteristics during growth, maturity, and pregnancy. Reference values are specified for characteristics of dosimetric importance. The final section gives a brief summary of the elemental composition of individuals. Focusing on the elements of dosimetric importance, information is presented on the body content of 13 elements: calcium, carbon, chloride, hydrogen, iodine, iron, magnesium, nitrogen, oxygen, potassium, sodium, sulphur, and phosphorus.

Abstract  The public depends on competent risk assessment from the federal government and the scientific community to grapple with the threat of pollution. When risk reports turn out to be overblown--or when risks are overlooked--public skepticism abounds. This comprehensive and readable book explores how the U.S. Environmental Protection Agency (EPA) can improve its risk assessment practices, with a focus on implementation of the 1990 Clean Air Act Amendments. With a wealth of detailed information, pertinent examples, and revealing analysis, the volume explores the "default option" and other basic concepts. It offers two views of EPA operations: The first examines how EPA currently assesses exposure to hazardous air pollutants, evaluates the toxicity of a substance, and characterizes the risk to the public. The second, more holistic, view explores how EPA can improve in several critical areas of risk assessment by focusing on cross-cutting themes and incorporating more scientific judgment. This comprehensive volume will be important to the EPA and other agencies, risk managers, environmental advocates, scientists, faculty, students, and concerned individuals.

Abstract  The nasal mucociliazy apparatus is an important component of the airway defenses. Studies were undertaken to determine the nature and distribution of acute effects of inhaled formaldehyde on the nasal mucociliary apparatus of male F-344 rats using whole body exposures. Formaldehyde exposures ranged from a single 6-hr period up to multiple 6-hr exposures daily for 3 weeks, with exposure concentrations of 15, 6, 2, 0.5, and 0 ppm. Within I hr of the last exposure, the rats were kilied and the nasal passages examined for effects on nasal mucociliary function. Exposure to 15 ppm formaldehyde induced inhibition of mucociliary function in specific regions of the nose, and mucostasis was generally more extensive than ciliastasis. These effects, which were initially confined to the anterior regions of the nose, became progressively more extensive for up to 2 weeks of exposure with only very slight progression during the third week. Inhibition of mucociliary function was much less severe with 6 ppm, minimal at 2 ppm, and not detected in rats following exposure to 0.5 ppm. The distribution of epithelial lesions, identified by histopathology, correlated well with the distribution of defective mucociliary function, but mucociliaiy function was a more sensitive indicator of toxicity. Localized defects in mucociliary function represent a potentially important consequence of exposure to formaldehyde.

Abstract  The purpose of this Toxicological Review is to provide scientific support and rationale for the hazard and dose-response assessment in IRIS pertaining to chronic exposure to 1,4-dioxane. It is not intended to be a comprehensive treatise on the chemical or toxicological nature of 1,4-dioxane. The intent of Section 6, Major Conclusions in the Characterization of Hazard and Dose Response, is to present the major conclusions reached in the derivation of the reference dose, reference concentration, and cancer assessment, where applicable, and to characterize the overall confidence in the quantitative and qualitative aspects of hazard and dose response by addressing the quality of the data and related uncertainties. The discussion is intended to convey the limitations of the assessment and to aid and guide the risk assessor in the ensuing steps of the risk assessment process.

Abstract  A pulse radiolysis technique was used to measure the UV absorption spectra of c-C4H7O2 and (c-C4H7O2)O2 radicals over the range 220–320 nm, (c-C4H7O2)250 nm=(5.9±0.6)×10-18 and [(c-C4H7O2)O2 ]240nm=(4.8×0.8)×10-18 cm2 molecule-1. The observed self-reaction rate constants for the c-C4H7O2 and (c-C4H7O2)O2 radicals, defined as -d[c-C4H7O2]/dt= 2k4[c- C4H7O2]2 and -d[(c-C4H7O2)O2 ]/dt=2k5obs[(c-C4 H7O2)O2]2 were k4=(3.3±0.4)×10-11 and k5obs=(7.3±1.2)×10-1 2 cm3 molecule-1 s-1. The rate constants for reactions of (c-C4H7O2)O2 radicals with NO and NO2 were k6 (1.2±0.3)×10-11 and k7=(1.3±0.3)×10-11 cm3 molecule-1 s-1, respectively. The rate constants for the reaction of F atoms with 1,4-dioxane and the reaction of c-C4H7O2 radicals with O2, were k3=(2.4±0.7)×10-10 and k2=(8.8±0.9)×10-12 cm3 molecule-1 s-1, respectively. A relative rate technique was used to measure the rate constant for the reaction of Cl atoms with 1,4-dioxane, k17=(2.0±0.3)×10-10 cm3 molecule-1 s-1. A long-pathlength FTIR spectrometer coupled to a smog chamber system was used to show that the sole atmospheric fate of the alkoxy radical (c-C4H7O2)O is decomposition via C–C bond scission leading to the formation of H(O)COCH2CH2OC(O)H (ethylene glycol diformate).

Abstract  Karbe and Kerlin have questioned the classification of spongiosis hepatis as a preneoplastic lesion or even a benign neoplasm, designated as spongiotic pericytoma, and have proposed to use the term cystic degeneration for this lesion in rats and fish. However, the reclassification of spongiosis as cystic degeneration is unwarranted for several reasons. In the rat, spongiosis hepatis represents a specific pathomorphologic entity, originating from the perisinusoidal (Ito) cells; it may occur spontaneously in aged animals but its number and size increases significantly after exposure to various (hepato)carcinogens. Comparative morphological, immunohistochemical, and autoradiographic studies in rats exposed to N-nitrosomorpholine revealed that spongiosis hepatis is an integral part of larger proliferative Ito-cell aggregates showing an autonomous, progressive growth. The classification of spongiosis hepatis as a benign neoplasm is based on these findings that endorse and extend previous considerations on the preneoplastic or neoplastic nature of this lesion. Irrespective of the classification of spongiosis hepatis as a benign neoplastic or a preneoplastic lesion, there is compelling evidence for its reliability as a sensitive marker for (hepato)carcinogenic effects in rats and fish. The data collected by Karbe and Kerlin support rather than contradict the reliability of spongiosis hepatis as an effect marker for carcinogens.

Abstract  BARBER(1 934) reported the death of five factory workers, who were employed in processes involving the use of dioxan. The principal lesions found at autopsy were a central zonal necrosis of the liver and a symmetrical necrosis of the cortex of the kidneys. The similarity of the renal condition to that found in the cortical necrosis of pregnancy first prompted the present investigation.