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The purpose of this article is to review previous chronic inhalation studies in rats with refractory ceramic fiber (RCF), the mathematical modeling efforts to describe the deposition, clearance, and retention of RCF fiber in the rat and human, and the concept of ''overload,'' and to assess the possibility that the maximum tolerated dose (MTD) was exceeded. Lastly, based on recent biopersistence and pulmonary clearance studies of several investigators with a particulate-free RCF, we examine the potential impact on the chronic RCF rat bioassay of coexposure to both RCF particulate and RCF fibers. The review concludes, inter alia, that RCF particulate coexposure probably had a major impact on the observed chronic adverse effects, that the MTD was probably exceeded at the highest exposure concentration of 30 mg/m3 in the rat bioassay, and that inclusion of the highest dose in the risk assessment process may overstate human health risk if a linear rather than nonlinear model is used. [ABSTRACT FROM AUTHOR]

Octamethylcyclotetrasiloxane, D4, is a low viscosity, silicone fluidconsisting of four dimethyl-siloxy units ((CH3)2SiO)4 in a cyclic structure. It is primarily used as a building block in the industrial synthesis of long chain silicone polymers. The combination of D4 with decamethylcyclopentasiloxane (D5) is commonly referred to as cyclomethicone which has a wide range of applications as a formulation aid in personal care products. To extend the existing database regarding the biological activities of D4, a 28 day whole body vapor inhalation study was conducted using Fischer 344 rats at 0 (room air), 7, 20, 60, 180 and 540 ppm for 6 hours/day, 5 days/week. Parameters measured included body weights, organ weights, gross pathology, histopathology, serum chemistries, and urinalysis. In addition to these standard toxicological endpoints, the ability of D4 exposed animals to mount an IgM antibody response was evaluated by a splenic antibody forming cell (AFC) assay and a serum enzyme-linked immunosorbant assay (ELISA). The results of this 28-day inhalation study indicate that D4 exposure caused no adverse effects on body weight, food consumption, orurinalysis parameters. In addition, there were no exposure related histopathological alterations at any site for any exposure group. A statistically significant increase in liver weight and the liver to body weight ratio was observed in both male (180-540 ppm) and female (20-540 ppm) rats, which was not observed in the 14-day recovery group animals. There were no other significant organ weight changes. Although statistically significant changes were observed in several hematological and serum chemistry parameters in both the terminal and 14-day recovery animals, the changes were marginal and within the normal range of values for the rat. Under these experimental conditions, there were no alterations noted in immune system function at any of the D

Schizochytrium sp. dried microalgae (DRM) contains oil rich in highly unsaturated fatty acids (PUFAs). Docosahexaenoic acid (DHA n-3) is the most abundant PUFA component of the oil. DHA-rich oil extracted from Schizochytrium sp. is intended for use as a nutritional ingredient in foods. As part of a comprehensive safety assessment program, the reproductive toxicity of DRM was examined in Sprague-Dawley-derived rats Crl:CD(SD)BR (30/sex/group) provided DRM in the diet at concentrations of 0, 0.6, 6.0, and 30%. These dietary levels corresponded to overall average dosages of approximately 400, 3900, and 17,800 mg/kg/day for F0 males (premating) and 480, 4600, and 20,700 mg/kg/day for F0 females, respectively. Prior to mating, males and females of the F0 generation were treated for 10 and 2 weeks, respectively. Treatment of males continued throughout mating and until termination (approximately 3 weeks after mating). Treatment of the females was continued throughout gestation and through lactation day 21. The females were killed after raising their young to weaning at 21 days of age. Food consumption was measured weekly throughout the study (except during mating) and body weights were recorded at least weekly during premating, gestation, and lactation. Reproductive parameters including estrus cycle duration, mating performance, fertility, gestation length, parturition, and gestation index were evaluated. Litter size and offspring body weights were recorded, offspring viability indices were calculated, and physical development (vaginal opening and preputial separation) was assessed for the F1 generation. All adult F0 and F1 animals were subjected to a detailed necropsy. DRM treatment had no effect on estrus cycles or reproductive performance including mating performance, fertility, gestation length, parturition, or gestation index. Litter size, sex ratio, and offspring viability indices were similarly unaffected and there were no effects of DRM treatment on the physical development of F1 animals., (Copyright 2001 Academic Press.)

Refractory ceramic fiber (RCF) is an energy-efficient, high-temperature insulation, used principally in industrial furnaces, heaters, and reactors. Prior to the 1980s, there were few publications dealing with the potential health effects of this material. However, with the advent of higher energy costs and the need for thermally efficient high-temperature insulating materials, production of RCF grew rapidly, as did interest in its potential health effects. This article provides a comprehensive and integrated review of the toxicology (in vitro and in vivo), epidemiology, and risk analysis literature of RCF. Based on the available literature, we conclude that an occupational exposure of 0.5 fibers per cubic centimeter (cm(3)) [8-h time-weighted average (8-h TWA)] results in an occupational health risk no greater than 9.1 x 10(-5).

Isofrax and Insulfrax are two new synthetic vitreous fibers (SVFs) developed for high-temperature insulation (1800-2300 degrees F) applications. In an attempt to significantly reduce or eliminate the potential of adverse health effects, these two fibers were specifically designed to have high solubility and, thus, low in vivo biodurability. In this paper, we review the effects of chemical composition on biodurability, in vitro fiber dissolution rates (K(dis)), and the relevance and relationship of K(dis) to pulmonary fibrosis and lung tumors in chronic rat inhalation studies. We also examine the correlations between K(dis) and weighted in vivo half-life (t(0.5)) of long fibers (>20 microm) and their relation to pulmonary effects in chronic rat inhalation bioassays. Predictions for outcomes of inhalation bioassays and development of nonsignificant risk levels of exposure are provided. Additionally, justification for the use of inhalation versus noninhalation animal data is provided as is a brief review of human health effects of SVFs. We conclude, inter alia, that Isofrax and Insulfrax have low biodurability, would not be expected to produce either pulmonary fibrosis or lung tumors in a well-designed animal inhalation bioassay, have weighted half-lives beneath the threshold established by the European Union for classification as a carcinogen, and based on epidemiological data for SVFs would not be expected to result in incremental cancer in human cohorts. Finally, it is estimated that approximately 90% of workplace exposure concentrations of these materials would be beneath 1 f/cc. At a concentration of 1 f/cc, neither fiber would be expected to result in an incremental working lifetime cancer risk greater than 10(-5)., (Copyright 1999 Academic Press.)

D5 is a low-molecular-weight cyclic siloxane used for industrial and consumer product applications. The objective of the present study was to evaluate the subchronic toxicity of D5 following a 3-month nose-only inhalation exposure. In addition, animals from both sexes of the control and high dose groups were allowed a 4-week recovery period to observe reversibility, persistence, or delayed occurrence of any potential adverse effects. Male and female Fischer 344 rats were exposed for 6 h/day, 5 days/week for 3 months to target concentrations of 0 (30/sex/group), 26 (20/sex/group), 46 (20/sex/group), 86 (20/sex/group), and 224 (30/sex/group) ppm D5. Recovery groups (0 and 224 ppm) comprised 10 rats/sex/group. Body weights and food consumption were monitored at least twice weekly over the course of exposures. Approximately 16 h preceding euthanasia, animals were transferred into metabolism caging for urine collection and were fasted. Rats were anesthetized with pentobarbital and euthanized by exsanguination. Blood was collected for hematological and clinical biochemical analyses. Selected organ weights were measured and a complete set of tissues was taken for histopathological examination. There were several minor changes observed in clinical biochemistry parameters; the most notable was an increase in gamma glutamyl transferase (gamma-GT) in both sexes at the high dose. In females, this effect was dose-related (46-224 ppm) and did not recover upon cessation of exposure. Additionally, there was an decrease in serum lactate dehydrogenase (LDH) observed in females at 86 and 224 ppm which was not resolved during recovery. There was an increase in absolute and/or relative liver weight in rats of both sexes. Taken together, these data suggest that the female rat is more sensitive to the actions of D5 on the liver. Exposure-related increases in absolute and relative lung weights were observed in both sexes at terminal necropsy. This observation was not noted in males in the recovery phase, but was still present in females. Finally, histopathological evidence indicated the primary target organ following D5 inhalation exposure is the lung, with an increase in focal macrophage accumulation and interstitial inflammation in the lungs of male and female rats exposed to 224 ppm D5. This observation did not appear to resolve at the end of a 1-month period of nonexposure. The incidence of these changes was also slightly increased in rats of both sexes exposed to 86 ppm D5. These data suggest that nose-only D5 vapor inhalation provokes minimal changes in the lung which are similar in incidence and severity to spontaneously occurring changes in control animals after nose-only exposures. There were no histopathological findings noted in the livers which support this organ as a target in this study, despite the observed changes in organ weight and in some serum chemistry parameters.

D5 is a low-molecular-weight cyclic siloxane used for industrial and consumer product applications. The objective of the present study was to assess potential toxic and immunomodulatory consequences of inhalation exposure to D5. Male and female Fischer 344 rats (25/group) were exposed by whole body inhalation to 0, 10, 25, 75, or 160 ppm D5 6 h/day, 7 days/week for 28 days. Clinical signs, body weights, and food consumption were recorded. On the day following the final exposure, 10 rats/group/sex were euthanized and a complete necropsy performed. Following a 14-day nonexposure recovery period, the remaining 5 rats/sex/group were necropsied. Body and organ weights were obtained and a complete set of tissues was taken for histopathology. Samples were also collected for serum chemistry, hematology, and urinalysis. Immunotoxicology-designated rats (10/sex/group) were immunized with sheep erythrocytes (sRBC) 4 days prior to euthanasia and cyclophosphamide (CYP) was administered i.p. to positive controls on days 24 through 28. The anti-sRBC antibody-forming cell (AFC) response was evaluated in a standard plaque assay. Blood was also collected for examination in the anti-sRBC enzyme-linked immunosorbant assay (ELISA). D5 exposure did not modulate humoral immunity, while the internal control, CYP, produced the expected suppression of the AFC response. D5 exposure caused no adverse effects on body weight, food consumption, or urinalysis parameters. Serum alkaline phosphatase (SAP) was significantly decreased in females at terminal (12%, 160 ppm) and recovery sacrifice. A significant increase in the liver-to-body weight ratio was observed in female animals at the end of exposures (13%, 160 ppm), but was not noted in recovery animals from the same exposure group. In males, significant increases in liver-to-body weight (5%) and thymus-to-body weight (14%) ratios were also noted at the high dose at terminal sacrifice and were not present at recovery. At recovery only, a significant increase in spleen-to-body weight ratios (14 and 17%; 25 and 160 ppm, respectively) was noted. At the end of exposure, histopathological analysis indicated an increased incidence and severity of nasal (Level 1) goblet cell proliferation. Focal macrophage accumulation in the lung was also observed to be increased in incidence in both sexes at 160 ppm. At the end of the recovery period, the effects in both of these organs appeared to be reversible. In summary, D5 inhalation exposure did not alter humoral immunity and caused only minor, transient changes in hematological, serum chemistry, and organ weight values. Histopathological changes were confined to the respiratory tract and appeared to be reversible. The no observed effect level for systemic toxicity, based primarily on the liver weight changes, was 75 ppm.

Repeated inhalation exposure to octamethylcyclotetrasiloxane (D4) produces a reversible and dose-related hepatomegaly and proliferation of hepatic endoplasmic reticulum in rats. However, the effects of D4 on the expression of cytochrome P450 enzymes have not been evaluated. In the present study, the time course for changes in hepatic microsomal cytochrome P450 enzyme expression following repeated inhalation exposure to D4 vapors was determined in male and female Fischer 344 rats. Animals were exposed to D4 vapor at concentrations of 70 and 700 ppm, via whole body inhalation for 6 h/day, 5 days/week for 4 weeks. Specified animals were euthanized on exposure days 3, 7, 14, 21, and 28. Microsomal fractions were prepared from fresh liver by differential centrifugation. Enzyme activity as well as immunoreactive protein levels of several cytochrome P450 enzymes (CYP), epoxide hydrolase, and UDP-glucuronosyltransferase (UDPGT) were evaluated. The time course for enzyme induction was monitored by measuring 7-ethoxyresorufin O-deethylase (EROD) and 7-pentoxyresorufin O-depentylase (PROD) activities on days 3, 7, 14, 21, and 28. CYP1A1/2 activity, as determined by EROD activity, was increased approximately 2- to 3-fold over the exposure period. However, an examination of immunoreactive protein revealed no induction of CYP1A1 and a suppression of CYP1A2 in the 700 ppm D4 group. In comparison, CYP2B1/2 enzyme activity, as determined by PROD, was significantly increased as early as day 3 in both the 70 and 700 ppm D4 groups of male and female rats. Overall, PROD activity on day 28 was induced more than 10-fold in the 70 ppm D4 groups and more than 20-fold in the 700 ppm D4 groups. The increase in PROD activity was paralleled by a comparable increase in CYP2B1/2 immunoreactive protein. There was a modest (2- to 3-fold) increase in CYP3A1/2 activity and immunoreactive protein, as determined by 6 beta-hydroxylation of testosterone and Western blot analysis. Expression of CYP enzymes was at or near maximum by day 14 and remained relatively constant throughout the exposure period. On day 28, epoxide hydrolase activity and immunoreactive protein were induced (2- to 3-fold) in a dose-dependent manner. Only slight changes in the expression and activity of UDPGT were detected, and these did not appear to be dose related. Thus, repeated inhalation exposure to D4 induces CYP enzymes and epoxide hydrolase in a manner similar to that observed for phenobarbital (PB). Therefore, D4 can be described as a "PB-like" inducer of hepatic microsomal enzymes in the Fischer 344 rat.

A mathematical retention model has been developed to predict the lung burden and size distribution of kaolin refractory ceramic fibers (RCF) in the pulmonary region of the human lung during exposure. Fiber dissolution, breakage, and differential clearance are considered in this model; rates for these processes are obtained by extrapolation from available data on laboratory rats. The lung burden predicted by this model is in general agreement with fiber counts from three factory workers. An important prediction from this study is that clearance of RCF is not significantly impaired at a fiber concentration beneath 10 f/cm3 during occupational exposure.

Chronic exposure and postexposure experiments have been recently performed in rats to evaluate the biological responses of inhaled refractory ceramic fibers (RCF) at different concentration levels. The lung burden data in the accessory lobe of the rat lung were collected during and after different exposure and postexposure periods. The size distribution of retained fibers in the lung at different time points was also measured. We used these data to develop a mathematical model of fiber clearance from the rat lung. It was found that the clearance rate did not depend significantly upon fiber size but there was a clear dependence on lung burden. As lung burden increased, the clearance rate was found to decrease. An empirical equation was derived for the clearance rate as a function of lung burden. At low burdens, rats had a retention half-time of about 126 days for RCF compared to a typical half-time of about 60 days for insoluble nonfibrous particles.

The Workshop on Approaches to Evaluating the Toxicity and Carcinogenicity of Man-Made Fibers (MMF) was held in Durham, North Carolina, on November 11-13, 1991. The goal of the workshop was to reach a consensus, or to determine the extent to which a consensus existed, in two areas. Participants were asked to identify scientifically sound approaches for evaluating the toxicity and carcinogenicity of man-made fibers based on today's science and to determine research appropriate for study during the next 5 years that can provide an improved scientific basis for future revisions of approaches used to evaluate man-made fiber toxicity and carcinogenicity. During the first day, a series of "state of knowledge" presentations were made to provide all participants with a common data base from which to interact and discuss scientific issues. The workshop participants were assigned to one of four discussion groups, which met separately in three half-day sessions following the first day of presentations. All groups discussed the same topics: exposure assessment, hazard identification, and dose-response information needed to integrate to characterize risk in the first session; approaches to obtaining the needed information in the second session; and recommended approaches and guidelines for evaluating the toxicity and carcinogenicity of MMF and research needs in the third session. The workshop participants reconvened as a whole after each discussion session, and one member from each group reported the group's conclusions. A closure period was also included at the end of the workshop for review and discussion of items that had been considered during the workshop. The primary conclusions reached were the following: -All fiber types capable of depositing in the thorax are not alike in their pathogenic potential. -Only fiber samples with dimensions similar to those to which humans can inhale should be tested. -A complete characterization (i.e., dimensions, fiber number, mass, and aerodynamic diameter) of the fiber aerosol and retained dose is essential. -Appropriate aerosol generation methods must be used for inhalation studies in order to preserve fiber lengths. -A tiered approach to toxicity evaluation is recommended that includes: 1. In vitro screening for durability, surface properties, cytotoxicity, and similar properties, etc; 2. Short-term inhalation or other in vivo studies; 3. That chronic inhalation studies are the "gold standard" (i.e., provide most appropriate data for risk characterization). -The rat is the most appropriate species for inhalation studies. -In chronic inhalation studies, animals should be retained to at least 20% survival after 2-year exposure. -Serial lung burden analyses are an essential component of inhalation studies and are essential for understanding exposure-dose-response relationships. -Studies oriented to understanding mechanisms of toxicity and carcinogenicity are important adjuncts to traditional toxicity studies. -Histopathological analyses of tissues of the respiratory tract represent primary endpoints for evaluating effects of inhaled fibers. Major effects include pulmonary fibrosis, lung tumors, and mesotheliomas. Experimental tissues should be archived for future studies; wherever possible, handling and preservation of tissues should be done in a way that maximizes their future use in mechanistic studies. -Potential human exposures throughout the entire life-cycle of the fiber must be considered and fibrous material for toxicologic studies prepared accordingly. -Intracavity studies are inappropriate for risk characterization but can play a useful screening role in assessing fiber toxicity.(ABSTRACT TRUNCATED AT 400 WORDS)

Male and 13.5- and 17.5-day pregnant Swiss-Webster mice were administered 120 mg/kg [2,3-14C]acrylamide orally. The male mice were frozen 0.33, 1, 3, 9, 24, 72, and 216 hr later, and the pregnant mice at each gestational period were frozen at 3 and 24 hr. Whole-body autoradiographs from the male mice at early time intervals revealed accumulation of radioactivity in the contents of the gastrointestinal tract, liver, pancreas, testis, brain and gallbladder, and epithelia of oral cavity, esophagus, and bronchi. The distribution appears to be similar in the male and pregnant mice. Absorption from the stomach was virtually complete by 3 hr; renal and hepatic elimination was essentially complete at 24 hr. Radioactivity in the male reproductive tract appeared in the parenchyma of the testis at 1 hr, moved to the seminiferous tubules and head of the epididymis at 9 hr, and by 9 days remained only in the tail of the epididymis and the crypts of the epithelium of the glans penis. This movement parallels that of spermatids. The 13.5-day fetuses were uniformly labeled except for a slightly increased uptake in fetal brain. The distribution of radioactivity in the 17.5-day fetal tissues resembled that in maternal tissues; the remarkable exception was an intense accumulation in fetal skin. This study indicates that acrylamide is efficiently absorbed from the stomach and eliminated by the liver, kidney, and possibly the pancreas. A previously unrecognized affinity of acrylamide or a metabolic product was demonstrated for fetal skin in late gestation and for adult epithelia of oral cavity, esophagus, forestomach, and bronchi. Also, acrylamide or a metabolite appears to bind to spermatids at a specific stage near maturation.

The metabolism, excretion and disposition of melamine were determined after administration of a single oral dose of 0.025 mCi (0.38 mg) [14C]melamine to adult male Fischer 344 rats. Within the first 24 hr, 90% of the administered dose was excreted in the urine. Negligible radioactivity appeared in breath and faeces. There was little difference in blood, liver or plasma concentrations of 14C, suggesting that melamine distributes in body water. The only organs showing radioactivity levels much higher than plasma were the kidney and bladder. The bladder level was by far the highest, a finding probably due either to back diffusion from urine or to contamination of bladder tissue with urine. Virtually no residual radioactivity was observed in tissues examined at 24 hr or later. The elimination-phase half-life calculated from plasma data, 2.7 hr, was in good agreement with the urinary-excretion half-life of 3.0 hr. The renal clearance of melamine was 2.5 ml/min. Radioactivity in plasma or urine co-chromatographed with that of the dosing solution, indicating that melamine is not metabolized in the male Fischer 344 rat.

Male and female Fischer 344 rats were maintained on treated drinking water providing dosages of 0 (controls), 0.01, 0.1, 0.5, or 2.0 mg acrylamide/kg body wt/day for 2 years to assess the chronic toxicity and oncogenic potential of the chemical. The mean body weights of male and female rats receiving 2.0 mg/kg/day and of male rats receiving 0.5 mg/kg/day were minimally decreased when compared with controls. During the last 4 months of the study, there was an increase in mortality among male and female rats receiving 2.0 mg/kg/day. A target organ effect, characterized by degeneration of peripheral nerves, was observed in rats receiving 2.0 mg/kg/day. The incidence of several tumor types was increased in the rats receiving 2.0 mg/kg/day when compared with controls. In females, increased tumor incidences were observed in the mammary gland, central nervous system, thyroid gland-follicular epithelium, oral tissues, uterus, and clitoral gland. In males the incidence of tumors of the thyroid gland-follicular epithelium and scrotal mesothelium was increased. Male rats receiving 2.0 mg/kg/day also had increased incidence of central nervous system tumors when compared to historical controls but not when compared to concurrent controls. The only tumor incidence which was significantly increased at the 0.5 mg/kg/day level was scrotal mesothelioma. There was no statistically significant increase of any tumor type at the 0.1 or 0.01 mg/kg/day dose levels. However, the incidence of scrotal mesothelioma at the 0.1 mg/kg/day level was greater than that observed in the control group or historically reported in this laboratory.