Abstract  Objectives Investigating the role of occupational exposure to solvents in the occurrence of lymphoid neoplasms (LNs) in men. Methods The data were generated by a French hospital-based case-control study, conducted in six centres in 2000–2004. The cases were incident cases aged 18–75 years with a diagnosis of LN. During the same period, controls of the same age and gender as the cases were recruited in the same hospitals, mainly in the orthopaedic and rheumatological departments. Exposure to solvents was assessed using standardised occupational questionnaires and case-by-case expert assessment. Specific quantification of benzene exposure was attempted. The analyses included 491 male patients (244 cases of non-Hodgkin's lymphoma (NHL), 87 of Hodgkin's lymphoma, 104 of lymphoproliferative syndrome and 56 of multiple myeloma) and 456 male controls. Unconditional logistic regressions were used to estimate OR and 95% CI. Results Solvent exposure, all solvents considered together, was marginally associated with NHL (OR=1.4 (1.0 to 2.0) p=0.06), but not with other LNs. No association with the main chemical series of solvents was observed. There was no trend with the average intensity or frequency of exposure. Exposure to pure benzene was not significantly related to NHL (OR=3.4 (0.8 to 15.0)). The highest maximum intensities of benzene exposure were associated with diffuse large cell lymphoma (OR=2.1 (1.0 to 4.6)). Conclusion The results of the present study provide estimates compatible with the hypothesis that exposures to pure benzene and high benzene intensities may play a role in some NHL. There was no evidence for a role of other organic solvents in the occurrence of LN.

Abstract  OBJECTIVES: This community based case-referent study was initiated to investigate aetiological factors for squamous cell carcinoma of the upper gastrointestinal tract. METHODS: The study was based on all Swedish men aged 40-79 living in two regions of Sweden during 1988-90. Within that base, efforts were made to identify all incident cases of squamous cell carcinoma of the oral cavity, oropharynx and hypopharynx, larynx, and oesophagus. Referents were selected as a stratified (age, region) random sample of the base. The response was 90% among cases and 85% among referents. There were 545 cases and 641 referents in the final study group. The study subjects were interviewed about several lifestyle factors and a life history of occupations and work tasks. The exposure to 17 specific agents were coded by an occupational hygienist. The relative risk (RR) of cancer was calculated by logistic regression, standardising for age, geographical region, and alcohol and tobacco consumption. RESULTS: Exposure to asbestos was associated with an increased risk of laryngeal cancer, and a dose-response relation was present. The RR was 1.8 (95% confidence interval (95% CI) 1.1 to 3.0) in the highest exposure group. More than eight years of exposure to welding fumes was associated with an increased risk of pharyngeal cancer (RR 2.3 (1.1 to 4.7)), and laryngeal cancer (RR 2.0 (1.0 to 3.7)). There were indications of a dose-response for duration of exposure. Associations were also found for high exposure to polycyclic aromatic hydrocarbons (PAHs) and oesophageal cancer, RR 1.9 (1.1 to 3.2). Exposure to wood dust was associated with a decreased risk of cancer at the studied sites. CONCLUSIONS: Some of the present findings confirm known or suspected associations--such as asbestos and laryngeal cancer. The study indicates that welding may cause an increased risk of pharyngeal as well as laryngeal cancer. The findings corroborate an association between exposure to PAHs and oesophageal cancer.

Abstract  Samples of mother's milk were collected from Bayonne, NJ; Jersey City, NJ; Pittsburgh, PA; Baton Rouge, LA; and Charleston, WV, and analyzed for volatile (purgeables) and semivolatile (extractable) organics using glass capillary gas chromatography/mass spectrometry/computer. In the volatile fraction, 26 halogenated hydrocarbons, 17 aldehydes, 20 ketones, 11 alcohols, 2 acids, 3 ethers, 1 epoxide, 14 furans, 26 other oxygenated compounds, 4 sulfur-containing compounds, 7 nitrogen-containing compounds, 13 alkanes, 12 alkenes, 7 alkynes, 11 cyclic hydrocarbons, and 15 aromatics were found, including major peaks for hexanal, limonene, dichlorobenzene, and some esters. The levels of dichlorobenzene appeared to be significantly higher in the samples from Jersey City and Bayonne than in samples from other sites. Jersey City samples also appeared to have significantly higher levels of tetrachloroethylene. Charleston and Jersey City samples appeared to have significantly higher levels of chloroform; however, chloroform was observed in the blanks at about 20% of that in the samples. Due to the small sample size and lack of control over the solicitation of sample donors, the data cannot be used to extrapolate to the general population. Fewer semivolatile compounds of interest were found. Polychlorinated naphthalenes, polybrominated biphenyls, chlorinated phenols, and other compounds were specifically sought and not detected (limit of detection about 20-100 ng/mL milk). Polychlorinated biphenyls (PCBs) and DDE were found.

Abstract  As evidenced by the recent report of the Commission of the European Communities (CEEC) project (Detection of Aneugenic Chemicals-CEEC project, 1993), there currently is a great deal of effort towards developing and validating assays to detect aneuploidy-inducing chemicals. In this report, we describe the utility of the Syrian hamster embryo (SHE) cell transformation assay for detecting carcinogens with known or suspected aneuploidy-inducing activity. The following carcinogens were tested: asbestos, benomyl, cadmium chloride, chloral hydrate, diethylstilbestrol dipropionate, and griseofulvin. Thiabendazole, a noncarcinogen, was also tested. Chemicals of unknown or inconclusive carcinogenicity data, colcemid, diazepam, econazole nitrate, and pyrimethamine were also evaluated. All of the above chemicals except thiabendazole induced a significant increase in morphological transformation (MT) in SHE cells. Based on these results as well as those published in the literature previously, the SHE cell transformation assay appears to have utility for detecting carcinogens with known or suspected aneuploidy-inducing ability.

Abstract  Results on 105 cases with histopathologically confirmed non-Hodgkin's lymphoma (NHL) and 335 controls from a previously published case-control study on malignant lymphoma are presented together with some extended analyses. No occupation was a risk factor for NHL. Exposure to phenoxyacetic acids yielded, in the univariate analysis, an odds ratio of 5.5 with a 95% confidence interval of 2.7-11. Most cases and controls were exposed to a commercial mixture of 2,4-dichlorophenoxyacetic acid and 2,4,5-trichlorophenoxyacetic acid. Exposure to chlorophenols gave an odds ratio of 4.8 (2.7-8.8) with pentachlorophenol being the most common type. Exposure to organic solvents yielded an odds ratio of 2.4 (1.4-3.9). These results were not significantly changed in the multivariate analysis. Dichlorodiphenyltrichloroethane, asbestos, smoking, and oral snuff were not associated with an increased risk for NHL. The results regarding increased risk for NHL following exposure to phenoxyacetic acids, chlorophenols, or organic solvents were not affected by histopathological type, disease stage, or anatomical site of disease presentation. Median survival was somewhat longer in cases exposed to organic solvents than the rest. This was explained by more prevalent exposure to organic solvents in the group of cases with good prognosis NHL histopathology.

Abstract  The nephrotoxin S-(1,2-dichlorovinyl)-L-cysteine (DCVC) is cleaved in the renal tubules to produce a reactive electrophilic intermediate. If this intermediate is responsible for the toxicity, addition of the nucleophilic scavenger glutathione (GSH) should decrease toxicity, and depletion of tubular GSH should enhance toxicity. GSH was added to isolated rabbit renal tubules simultaneously with, 15 min before, and 15 min after the addition of DCVC. The active accumulation of the organic anion para-aminohippuric acid (PAH) and organic cation tetraethylammonium bromide (TEA) was used as an index of renal toxicity. Incubation of renal tubules with 0.01-1 mM DCVC for 15 min decreased active transport, with complete inhibition at 1 mM. This was accompanied by a 50% decrease in non-protein sulfhydryl concentration. The addition of GSH (6 mM) simultaneously with DCVC completely prevented any decrease in active transport. The addition of GSH (6 mM) to tubules in which active transport was inhibited by DCVC reversed the inhibition to 80% of control. Similar enhancement of active transport occurred when tubules isolated 1 h after in vivo exposure to DCVC at 20-100 mg kg-1 were incubated with GSH (6 mM). Preincubation of renal tubules with GSH (5-15 mM) made them more refractory to the DCVC-induced decreased PAH and TEA transport. The inhibition of active transport by DCVC is enhanced if the tubular non-protein sulfhydryl is first lowered by diethyl maleate or glycidol. Thus, the tubular GSH concentration appears to be an integral component in regulating the alterations in active transport caused by DCVC.

Abstract  A retrospective cohort study was carried out in a cardboard factory in Germany to investigate the association between exposure to trichloroethene (TRI) and renal cell cancer. The study group consisted of 169 men who had been exposed to TRI for at least 1 year between 1956 and 1975. The average observation period was 34 years. By the closing day of the study (December 31, 1992) 50 members of the cohort had died, 16 from malignant neoplasms. In 2 out of these 16 cases, kidney cancer was the cause of death, which leads to a standard mortality ratio of 3.28 compared with the local population. Five workers had been diagnosed with kidney cancer: four with renal cell cancers and one with a urothelial cancer of the renal pelvis. The standardized incidence ratio compared with the data of the Danish cancer registry was 7.97 (95% CI: 2.59-18.59). After the end of the observation period, two additional kidney tumors (one renal cell and one urothelial cancer) were diagnosed in the study group. The control group consisted of 190 unexposed workers in the same plant. By the closing day of the study 52 members of this cohort had died, 16 from malignant neoplasms, but none from kidney cancer. No case of kidney cancer was diagnosed in the control group. The direct comparison of the incidence on renal cell cancer shows a statistically significant increased risk in the cohort of exposed workers. Hence, in all types of analysis the incidence of kidney cancer is statistically elevated among workers exposed to TRI. Our data suggest that exposure to high concentrations of TRI over prolonged periods of time may cause renal tumors in humans. A causal relationship is supported by the identity of tumors produced in rats and a valid mechanistic explanation on the molecular level.

Abstract  In order to identify nonadditive effects on development, three compounds were combined using five dosages of each agent (a 5 x 5 x 5 full-bacterial design). Trichloroethylene (TCE), di(2-ethylhexyl) phthalate (DEHP), and heptachlor (HEPT), in corn oil, were administered by gavage to Fischer-344 rats on Gestation Days 6-15. Dose levels were 0, 10.1, 32, 101, and 320 mg/kg/day for TCE; 0, 24.7, 78, 247, and 780 mg/kg/day for DEHP; and 0, 0.25, 0.8, 2.5, and 8 mg/kg/day for HEPT. The dams were allowed to deliver and their pups were weighed and examined postnatally. Maternal death showed no main effects but DEHP and HEPT were synergistic. For maternal weight gain on Gestational Days 6-8, main effects for all three agents were observed, as well as 6-8 main effects for all three agents were observed, as well as TCE-DEHP synergism, and DEHP-HEPT antagonism. Maternal weight gain on Gestational Days 6-20 adjusted for litter weight showed main effects for TCE and HEPT, but no interactions. Main effects for all three agents were evident for full-litter resorptions and prenatal loss. The HEPT main effects were unexpected and were interpreted as reflecting potentiation by HEPT of the other agents. For full-litter loss, the TCE-HEPT and DEHP-HEPT interactions were antagonistic, perhaps due to a “ceiling” effect. For prenatal loss, the TCE-DEHP interaction was synergistic. Postnatal loss showed DEHP and HEPT main effects but no interactions. Analysis of pup weights on Day 1 revealed TCE and DEHP main effects and DEHP-HEPT antagonism; on Day 6, DEHP and HEPT main effects, DEHP-HEPT antagonism, and TCE-DEHP synergism were evident. Microphthalmia and anophthalmia incidences revealed TCE and DEHP main effects but no interactions. This extensive examination of a full-factorial design elucidates the complexities of studying and interpreting mixture toxicity. The data are available for further analysis.

Abstract  Risk assessment procedures can be improved through better understanding and use of tissue dose information and linking tissue dose level to adverse outcomes. For volatile organic compounds, such as toluene and trichloroethylene (TCE), blood and brain concentrations can be estimated with physiologically based pharmacokinetic (PBPK) models. Acute changes in the function of the nervous system can be linked to the concentration of test compounds in the blood or brain at the time of neurological assessment. This set of information enables application to a number of risk assessment situations. For example, we have used this approach to recommend duration adjustments for acute exposure guideline levels (AEGLs) for TCE such that the exposure limits for each exposure duration yield identical tissue concentrations at the end of the exposure period. We have also used information on tissue concentration at the time of assessment to compare sensitivity across species, adjusting for species-specific pharmacokinetic differences. Finally this approach has enabled us to compare the relative sensitivity of different compounds on a tissue dose basis, leading to expression of acute solvent effects as ethanol-dose equivalents for purposes of estimating cost-benefit relationships of various environmental control options. © 2005 Elsevier B.V. All rights reserved.

Abstract  We tested the impact of three features of a job-exposure matrix on risk estimates in a case-control study that evaluated the association of methylene chloride and astrocytic brain cancer. These features were probability of use of the agent; the consideration of decade of predominant use of methylene chloride within each occupation; and the use of a more specific industrial-occupational coding system. We compared the risk estimates obtained with and without these features. The introduction of each feature had a striking effect on the estimate of relative risk. The odds ratio ranged from 1.47 with none of these features, to 2.47 with high probability of exposure within industry and occupation, to 4.15 with high probability of exposure and specific industrial-occupational coding, to 6.08 with the three features together. These results indicate that the degree of exposure misclassification can be reduced by the introduction of these features into the job-exposure matrix.

Abstract  Dichloroacetate (DCA) is a by-product of drinking water chlorination. Administration of DCA in drinking water results in accumulation of glycogen in the liver of B6C3F1 mice. To investigate the processes affecting liver glycogen accumulation, male B6C3F1 mice were administered DCA in drinking water at levels varying from 0.1 to 3 g/l for up to 8 weeks. Liver glycogen synthase (GS) and glycogen phosphorylase (GP) activities, liver glycogen content, serum glucose and insulin levels were analyzed. To determine whether effects were primary or attributable to increased glycogen synthesis, some mice were fasted and administered a glucose challenge (20 min before sacrifice). DCA treatments in drinking water caused glycogen accumulation in a dose-dependent manner. The DCA treatment in drinking water suppressed the activity ratio of GS measured in mice sacrificed at 9:00 AM, but not at 3:00 AM. However, net glycogen synthesis after glucose challenge was increased with DCA treatments for 1-2 weeks duration, but the effect was no longer observed at 8 weeks. Degradation of glycogen by fasting decreased progressively as the treatment period was increased, and no longer occurred at 8 weeks. A shift of the liver glycogen-iodine spectrum from DCA-treated mice was observed relative to that of control mice, suggesting a change in the physical form of glycogen. These data suggest that DCA-induced glycogen accumulation at high doses is related to decreases in the degradation rate. When DCA was administered by single intraperitoneal (i.p.) injection to naïve mice at doses of 2-200 mg/kg at the time of glucose challenge, a biphasic response was observed. Doses of 10-25 mg/kg increased both plasma glucose and insulin concentrations. In contrast, very high i.p. doses of DCA (> 75 mg/kg) produced progressive decreases in serum glucose and glycogen deposition in the liver. Since the blood levels of DCA produced by these higher i.p. doses were significantly higher than observed with drinking water treatment, we conclude that apparent differences with data of previous investigations is related to substantial differences in systemic dose and/or dose-time relations.

Abstract  The disinfection of water, required to make it safe for human consumption, leads to the presence of halogenated organic compounds. Three of these carcinogenic 'disinfection by-products', dichloroacetic acid (DCA), trichloroacetic acid (TCA) and chloral hydrate (CH) have been widely evaluated for their potential toxicity. The mechanism(s) by which they exert their activity and the steps in the etiology of the cancers that they induce are important pieces of information that are required to develop valid biologically-based quantitative models for risk assessment. Determining whether these chemicals induce tumors by genotoxic or nongenotoxic mechanisms (or a combination of both) is key to this evaluation. We evaluated these three chemicals for their potential to induce micronuclei and aberrations as well as mutations in L5178Y/TK +/- (-)3.7.2C mouse lymphoma cells. TCA was mutagenic (only with S9 activation) and is one of the least potent mutagens that we have evaluated. Likewise, CH was a very weak mutagen. DCA was weakly mutagenic, with a potency (no. of induced mutants/microgram of chemical) similar to (but less than) ethylmethanesulfonate (EMS), a classic mutagen. When our information is combined with that from other studies, it seems reasonable to postulate that mutational events are involved in the etiology of the observed mouse liver tumors induced by DCA at drinking water doses of 0.5 to 3.5 g/l, and perhaps chloral hydrate at a drinking water dose of 1 g/l. The weight-of-evidence for TCA suggest that it is less likely to be a mutagenic carcinogen. However, given the fact that DCA is a weak mutagen in the present and all of the published studies, it seems unlikely that it would be mutagenic (or possibly carcinogenic) at the levels seen in finished drinking water.

Abstract  This article addresses the evidence that trichloroethylene (TCE) or its metabolites might mediate tumor formation via a mutagenic mode of action. We review and draw conclusions from the published mutagenicity and genotoxicity information for TCE and its metabolites, chloral hydrate (CH), dichloroacetic acid (DCA), trichloroacetic acid (TCA), trichloroethanol, S-(1, 2-dichlorovinyl)-l-cysteine (DCVC), and S-(1, 2-dichlorovinyl) glutathione (DCVG). The new U.S. Environmental Protection Agency proposed Cancer Risk Assessment Guidelines provide for an assessment of the key events involved in the development of specific tumors. Consistent with this thinking, we provide a new and general strategy for interpreting genotoxicity data that goes beyond a simple determination that the chemical is or is not genotoxic. For TCE, we conclude that the weight of the evidence argues that chemically induced mutation is unlikely to be a key event in the induction of human tumors that might be caused by TCE itself (as the parent compound) and its metabolites, CH, DCA, and TCA. This conclusion derives primarily from the fact that these chemicals require very high doses to be genotoxic. There is not enough information to draw any conclusions for trichloroethanol and the two trichloroethylene conjugates, DCVC and DCVG. There is some evidence that DCVC is a more potent mutagen than CH, DCA, or TCA. Unfortunately, definitive conclusions as to whether TCE will induce tumors in humans via a mutagenic mode of action cannot be drawn from the available information. More research, including the development and use of new techniques, is required before it is possible to make a definitive assessment as to whether chemically induced mutation is a key event in any human tumors resulting from exposure to TCE

Abstract  Long-term rodent bioassays with chemicals administered at maximum tolerated doses identify noncarcinogens as well as carcinogens. Thirty-one chemicals recently evaluated for carcinogenic potential by the National Toxicology Program provide unique data on the relationships between mutagenicity, toxicity, and carcinogenicity. Twenty-two substances were classified as carcinogens, and nine showed no evidence of carcinogenicity. Although cellular proliferation does play an intrinsic role in neoplastic processes, the responses associated with chronic toxicity in these studies were not always sufficient to induce neoplasia. Regardless of their mutagenic potential, 19 carcinogens induced toxic effects at sites that did not show neoplastic changes; similar toxic lesions were also seen among the mutagenic and nonmutagenic noncarcinogens. Although many nonmutagens induced neoplasia at sites that showed toxic effects, some of the same chemicals also exhibited toxicity at other site

Abstract  Peroxisome proliferator-activated receptor alpha (PPARalpha) is responsible for peroxisome proliferator-induced pleiotropic responses, including the development of hepatocellular carcinoma in rodents. However, it remains to be determined whether activation of PPARalpha only in hepatocytes is sufficient to induce hepatocellular carcinomas. To address this issue, transgenic mice were generated that target constitutively activated PPARalpha specifically to hepatocytes. The transgenic mice exhibited various responses that mimic wild-type mice treated with peroxisome proliferators, including significantly decreased serum fatty acids and marked induction of PPARalpha target genes encoding fatty acid oxidation enzymes, suggesting that the transgene functions in the same manner as peroxisome proliferators to regulate fatty acid metabolism. However, the transgenic mice did not develop hepatocellular carcinomas, even though they exhibited peroxisome proliferation and hepatocyte proliferation, indicating that these events are not sufficient to induce liver cancer. In contrast to the transgenic mice, peroxisome proliferators activate proliferation of hepatic non-parenchymal cells (NPCs). Thus, activation of hepatic NPCs and/or associated molecular events is an important step in peroxisome proliferators-induced hepatocarcinogenesis.

Abstract  The relationship between the concentration of trichloroethylene (TCE) in the brain and changes in brain function, indicated by the amplitude of steady-state pattern-elicited visual evoked potentials (VEP), was evaluated in Long-Evans rats. VEPs were recorded from visual cortex following stimulation of the eyes and, thus, reflect the function of the afferent visual pathway and, in broad terms, may be indicative of overall brain function. The concentration of TCE in the brain at the time of VEP testing (i.e., momentary brain concentration) was hypothesized to predict the amplitude of the VEP across a range of inhalation concentrations, both during and after exposure. Awake restrained rats were exposed to clean air or TCE in the following combinations of concentration and duration: 500 ppm (4 h), 1000 ppm (4 h), 2000 (2 h), 3000 ppm (1.3 h), 4000 ppm (1 h), and 5000 ppm (0.8 h). VEPs were recorded several times during the exposure session, and afterward for experimental sessions of less than 4 h total duration (i.e., concentrations from 2000 to 5000 ppm). The sample collection time for each VEP was about 1 min. Brain concentrations of TCE were predicted using a physiologically based pharmacokinetic (PBPK) model. VEP waveforms were submitted to spectral analysis, and the amplitude of the largest response component, occurring at twice the temporal stimulation rate (F2), was measured. Exposure to all air concentrations of TCE in the study reduced F2 amplitude. The reduction of F2 amplitude was proportional to momentary brain TCE concentration during and after exposure. A logistical function fit to the combined data from all exposure conditions described a statistically significant relationship with 95% confidence limits between brain TCE concentration and F2 amplitude. The results support the hypothesis that momentary brain concentration of TCE is an appropriate dose metric to describe the effects of acute TCE inhalation exposure on rat VEPs. The combination of the PBPK model predicting brain TCE concentration from the exposure conditions with the logistical function predicting F2 amplitude from the brain TCE concentration constitute a quantitative exposure-dose-response model describing an acute change in neurological function following exposure to an important hazardous air pollutant.

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 Hazardous Air Pollutant Exposure Model, version 5 (HAPEM5) User’s Guide is designed to assist exposure analysts with running and interpreting results from HAPEM5. Throughout the User’s Guide, the input file names and file types are in lowercase italics and program names are in all uppercase letters for easier identification. Likewise, model variables are presented in bold italics. When presented, input and output data and program source codes will be presented in a single lined box, indicating that the text inside the box is shown exactly as it exists in its electronic form. In addition, shaded text boxes appear throughout the document providing useful information and tips to users.

Abstract  Potential risk factors in renal cell carcinoma (RCC) were studied in a case-control study of 315 RCC cases and 313 hospital and 336 population controls. Risk factors included medical history, radiation exposure, predominant lifetime occupation, exposure to high-risk industries, and summary of important risk factors by a linear logistic regression model based on the comparison of RCC cases and controls selected from hospitals and the general population for 33 variables. A significant increase in urologic, cardiovascular, malignant, digestive, and metabolic disease was observed among cases over population controls. Exposure to radiation increased the risk, especially in females. A predominant lifetime occupation as a professional decreased the risk, whereas work as an operative increased the risk significantly. Work in petroleum-related and dry-cleaning industries were associated with elevated risk. Multivariate analysis comparing cases with each of the control groups for males and females identified obesity as the most important risk factor in RCC. Weight control at an early age might help to prevent the occurrence of a significant proportion of this rare but increasing malignant disease.

Abstract  THIO, used in the production of pesticides, polymers, and pharmaceuticals, and as a food additive, was tested for developmental toxicity in Sprague-Dawley rats (25/group) and New Zealand White rabbits (15-26/group). THIO was given po in corn oil to rats (0, 20, 35, or 50 mg/kg/day; gestational days (gd) 6-15) or rabbits (0, 10, 30 or 40 mg/kg/day; gd 6-19). Maternal body wt., food and water consumption (rats) were recorded. On gd 20 (rats) or 30 (rabbits), maternal organs and fetuses were weighed, and fetuses were examined for malformations (external, visceral, and skeletal). In rats, maternal body wt. change and food consumption were depressed in all THIO-treated groups on gd. 6-9. Gravid uterine wt. was decreased, and relative maternal liver wt. was increased at 50 mg/kg/day; kidney wt. was unaffected. Increased postimplantation loss and incidence of external malformations, and decreased live litter size were observed at 50 mg/kg/day. Female fetal body wt. was decreased at 35 mg/kg/day. In rabbits, maternal food intake tended to be lower, and body wt. change was decreased at 30 and 40 mg/kg/day on gd 12-15. Gravid uterine wt., liver and kidney wt. were unaffected. Postimplantation loss, litter size, average fetal body wt. and morphological development were unaffected. In summary, for rats, 20 mg/kg/day THIO was the low observed adverse effect level (LOAEL) for maternal toxicity, based on transient decreases in maternal wt. gain and food intake. A maternal no observed adverse effect level (NOAEL) was not determined. The developmental NOAEL in rats was 20 mg/kg/day; clear evidence of developmental toxicity was seen at greater than or equal to 35 mg/kg/day. In rabbits, the maternal NOAEL was 10 mg/kg/day. Maternal toxic effects at greater than or equal to 30 mg/kg/day were minor. The developmental NOAEL was greater than or equal to 40 mg/kg/day.

Abstract  Since statistical analysis proved the intercorrelation of tissue-gas partition coefficients of chemicals with similar chemical structures, bioavailability is controlled by one parameter dependent on the physicochemical properties of the chemicals and two constants distinguishing the tissues. Oil-gas partition coefficients are suggested to describe the biosolubility of volatile halogenated aliphatic chemicals. Tissue-gas partition coefficients derived from oil-gas partition coefficients were substituted in a pharmacokinetic model in order to study the effect of biosolubility on uptake, distribution, and elimination of inhaled chemicals. The simulation was focused on occupational exposures (8 h/day, 5 days/wk). Desaturation curves for all tissues show three exponential decays. The analysis of the simulation data indicates three patterns in behavior of inhaled vapors and gases in the body. Tissue uptake of poorly soluble chemicals (oil-gas partition coefficient less than 10) is flow limited at the beginning of exposure, but the partial pressures of such chemicals in the body equilibrate very rapidly with ambient air. Increased pulmonary uptake compensates for metabolic clearance. The rapid response of tissue concentrations to changes in exposure concentrations indicates that the toxic effect can easily be induced by short-term increase of exposure concentration, and that emergence from the reversible effect is rapid when exposure ceases. Tissue uptake of chemicals with oil-gas partition coefficients between 10 and 10(4) is flow limited during the entire 8-h exposure. Tissue concentrations increase slowly. Pulmonary uptake, being restricted by alveolar ventilation, compensates at steady state only for the amount of chemical removed by metabolic clearance. Therefore, tissue concentrations at steady state are lower than biosolubility. Accumulation during occupational exposure is obvious. Dumping of inhaled chemicals in adipose tissue protects the target organ from the occasional short-term increases in the exposure concentration. Tissue uptake of highly soluble chemicals (oil-gas partition coefficients greater than 10(4)) is limited by alveolar ventilation and exposure concentration. The rising and declining of tissue concentrations is very slow, half-times being in the magnitude of months and years. Metabolism reduces the half-time significantly. A lagging acute toxic effect can develop as the chemical accumulates in the body; the effect is most likely to persist long after the termination of the exposure.

Abstract  This paper models general survival and the distribution of tumor onset times for various tumors in the data base of control animals developed by the National Toxicology Program. For general survival, a modified Weibull model is shown to give an adequate fit for both Fischer 344 rats and C57BL/6 x C3H F1 mice. In addition, data from control animals in a lifetime study of asbestos are used to support the extension of these survival curves beyond 2 years in Fischer rats. The distributions of tumor onset times are modeled using a two-parameter Weibull model. For many common tumor types, this model yielded a very good fit to the data. Finally, a summary measure of the contribution of a tumor to mortality is given.

Abstract  Previous studies have demonstrated that various compounds, including the common groundwater contaminants trichloroethylene (TCE) and chloroform (CHCl3), can produce a synergistic toxic response when coadministered with the model hepatotoxicant carbon tetrachloride (CCl4). This phenomenon has not, however, been demonstrated following administration of these compounds in drinking water. Initial experiments indicated that Fischer 344 (F-344) rats were significantly more sensitive to these effects than the more commonly utilized Sprague-Dawley strain. To establish the suitability of this strain as a model, a variety of indicators of hepatotoxicity was evaluated and compared to histological evidence of injury 24 hr after dosing with CCl4 or a combination of CCl4 + TCE. Plasma alanine aminotransferase (ALT) activity was the most reliable indicator of hepatic injury and was well-correlated with the histologic data. Dose-response studies utilizing simultaneous ip dosing confirm the sensitivity of the F-344 rat, demonstrating synergistic toxicity at doses as low as 0.165 mmol/kg of CCl4 and 0.6 mmol/kg of TCE. Synergism was also detected following simultaneous ip administration of 1 mmol/kg CCl4 and 0.5 mmol/kg of CHCl3. To evaluate the effects of drinking water exposure, rats were pretreated for 3 days with solutions containing TCE (0-40 mM) or CHCl3 (0-8 mM) stabilized with 1% Emulphor (EL-620P) as their only source of fluids. A single, ip dose of CCl4 (1 mmol/kg) was then administered and 24 hr later animals were killed for examination of liver histology and determination of ALT activity. Although none of the pretreatments were detectably hepatoxic, rats which drank 15 and 40 mM TCE or 8 mM CHCl3 exhibited an enhanced response to CCl4.

Abstract  Simultaneous administration of trichloroethylene (TCE), at an oral dose of 0.5 ml/kg, resulted in a marked potentiation of liver injury caused by an oral dose of carbon tetrachloride (CCl4, 0.05 ml/kg). Hepatic glutathione levels were depressed at 24 hr only in the rats given TCE and CCl4. Using serum enzyme (ALT and SDH) as indicators of hepatotoxicity, potentiation of CCl4-injury was most apparent at 24 hr. Upon histological examination of H&E stained liver sections, the differences between livers obtained from TCE and CCl4-treated rats versus CCl4-treated rats were most apparent at later time points (48 and 72 hr). At 48 hr after CCl4, livers showed a distinctive and uniform pattern of injury with regeneration features predominating over necrosis. At this time, livers from TCE and CCl4-treated rats were characterized by extensive zone 3 coagulative necrosis. Inflammatory infiltrations were less prominent. At 72 hr, morphological features of livers from TCE and CCl4 rats were similar to those from rats given CCl4 alone at 48 hr. From the results obtained, it appears that the regenerative activity of the liver may be delayed in rats simultaneously administered TCE and CCl4 as compared to rats administered only CCl4.

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