Abstract  OBJECTIVES: Trichloroethylene (TCE) is suspected of association with elevated risk of cervical cancer. A case-control study was performed in a geographical area in which occupational TCE exposure is high. The study objective was to analyze the correlation between occupational TCE exposure and cervical cancer (including precancerous conditions).

METHODS: Case and control subjects were recruited by gynecologists. General and occupational data were collected by telephonic interviews. An industrial hygienist assessed occupational TCE exposure on a task-exposure matrix. Analysis focused on occupational TCE exposure at various levels and on cumulative dose. Multivariate analysis was performed to take account of the various risk factors.

RESULTS: In total, 67 case and 67 age-matched control subjects were included. Mean age was 36 years in both groups. Five of the possible general risk factors correlated significantly with cervical dysplasia or cancer: number of partners, history of genital or anal wart, interval between first period and first sexual relation, parity, and body mass index, the last three showing inverse correlation. Elevated risk was found in women who had had jobs as manual workers according to the PCS French classification (professions and socioprofessional categories), and production and related workers according to ISCO classification (International Standard Classification of Occupations), with odds ratios (ORs), adjusted on general and medical risk factors, of 7.68 [95% confidence interval (CI): 1.39-42.54] and 7.48 (1.30-43.24), respectively, among skilled service sector workers; the adjusted OR was close to significance, at 4.67 (95% CI: 0.92-23.67). No occupational sectors were significantly associated with elevated risk. In all, 17 (25.4%) case and 15 (22.4%) control subjects were exposed to TCE: raw OR = 1.17 (95% CI: 0.54-2.52), adjusted OR = 1.51 (95% CI: 0.42-5.41). There was no significant correlation between cumulative dose and exposure time.

CONCLUSIONS: The study found no significantly increased risk of cervical dysplasia or cancer associated with occupational TCE exposure.

Abstract  Clinical symptoms reported in humans exposed to 1,2-dichloroethene (= 1,2-dichloroethylene) in air include depression of the central nervous system (drowsiness, fatigue, intracranial pressure), nausea and eye irritation. One fatality has been reported. No information is available on toxicity upon ingestion or dermal contact and carcinogenic effects have not been studied. Long-term human health effects are unknown. Glossary.

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  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  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  The Report on Carcinogens (RoC) is a scientific and public health document mandated by Congress in 1978. The RoC identifies and discusses substances, chemicals, mixtures, or exposure circumstances (collectively called substances) that may pose a cancer hazard to human health and to which persons in the United States are exposed. Nominations to the RoC go through a rigorous review process with multiple opportunities for public comment. The RoC is a compilation of substance profiles and each new edition replaces the previous one. Each substance profile in the RoC identifies a substance as known or reasonably anticipated to be a human carcinogen and provides information on (1) the scientific evidence that supports the listing (human epidemiological studies, cancer studies in experimental animals, and toxicokinetic, genotoxic, and mechanistic data), (2) the potential for human exposure, such as data on use, production, environmental occurrence, occupational exposure, and exposure to the general population, and (3) current Federal regulations to limit exposure.

Abstract  The massive exploitation of natural resources, of which tobacco and asbestos are two conspicuous, though very different examples, and the synthesis of industrial chemicals have generated new hazards and new carcinogens which have been added to older ones. The majority of the over 50 agents that have been firmly identified so far as being human carcinogens belong to the relatively new hazards, that is environmental chemicals or chemical mixtures to which humans have been exposed only during the last century and a half. They are of more importance for cancer occurring in men than in women, and there is no evidence so far that they are related to cancers occurring at some of the most common target sites in either sex. It would be mistaken to believe that complete cancer prevention could be achieved solely by controlling these new, or relatively new, carcinogenic agents, but it would be similarly wrong to deny the importance of trying to control them and of continuing to do so. The experimental approach for the identification of carcinogens has an irreplaceable role to play in preventing the dispersal into our environment of new hazards and in identifying among the chemicals already in use, those that are carcinogenic. That a closer integration between the epidemiological and the experimental approaches may succeed in substantially reducing the size of the unknown region within the spectrum of cancer-causing factors, is today's hope that awaits confirmation. At the same time, advances in the understanding of the mechanisms underlying the different steps of the process leading to the clinical manifestation of cancer may help in the uncovering of agents and risk factors that the approaches used, at least in the way they have been used until now, may not have been apt to identify.

Abstract  Leydig cell adenomas are observed frequently in studies evaluating the chronic toxicity of chemical agents in laboratory animals. Doubts have been raised about the relevance of such responses for human risk assessment, but the question of relevance has not been evaluated and presented in a comprehensive manner by a broad group of experts. This article reports the consensus conclusions from a workshop on rodent Leydig cell adenomas and human relevance. Five aspects of Leydig cell biology and toxicology were discussed: 1) control of Leydig cell proliferation; 2) mechanisms of toxicant-induced Leydig cell hyperplasia and tumorigenesis; 3) pathology of Leydig cell adenomas; 4) epidemiology of Leydig cell adenomas; and 5) risk assessment for Leydig cell tumorigens. Important research needs also were identified. Uncertainty exists about the true incidence of Leydig cell adenomas in men, although apparent incidence is rare and restricted primarily to white males. Also, surveillance databases for specific therapeutic agents as well as nicotine and lactose that have induced Leydig cell hyperplasia or adenoma in test species have detected no increased incidence in humans. Because uncertainties exist about the true incidence in humans, induction of Leydig cell adenomas in test species may be of concern under some conditions. Occurrence of Leydig cell hyperplasia alone in test species after lifetime exposure to a chemical does not constitute a cause for concern in a risk assessment for carcinogenic potential, but early occurrence may indicate a need for additional testing. Occurrence of Leydig cell adenomas in test species is of potential concern as both a carcinogenic and reproductive effect if the mode of induction and potential exposures cannot be ruled out as relevant for humans. The workgroup focused on seven hormonal modes of induction of which two, GnRH agonism and dopamine agonism, were considered not relevant to humans. Androgen receptor antagonism, 5?-reductase inhibition, testosterone biosynthesis inhibition, aromatase inhibition, and estrogen agonism were considered to be relevant or potentially relevant, but quantitative differences may exist across species, with rodents being more sensitive. A margin of exposure (MOE; the ratio of the lowest exposure associated with toxicity to the human exposure level) approach should be used for compounds causing Leydig cell adenoma by a hormonal mode that is relevant to humans. For agents that are positive for mutagenicity, the decision regarding a MOE or linear extrapolation approach should be made on a case-by-case basis. In the absence of information about mode of induction, it is necessary to utilize default assumptions, including linear behavior below the observable range. All of the evidence should be weighed in the decision-making process.

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  Rats, guinea pigs, dogs, rabbits, and monkeys were exposed to trichloroethylene, carbon tetrachloride, 1,1,1-trichloroethane, dichlorodifluoromethane, and 1,1-dichloroethylene. Two types of inhalation experiments were conducted: continuous exposure for 90 days and 8-hour exposures, 5 days a week, for a total of thirty exposures. The parameters studied included mortality, visible signs of toxicity, and hematologic, biochemical, pathologic, and body weight changes. Throughout this entire study which encompassed 17 separate exposures over a period of nearly four years, no visible signs of toxicity were noted in any species exposed to these materials. Significant mortality was found in both the repeated (515 mg/m3) and continuous (61 mg/m3) exposures to carbon tetrachloride as well as in the continuous exposures to 1,1-dichloroethylene at 189, 101, and 61 mg/m3. Growth depression in varying degrees was found in all continuous exposures involving trichloroethylene, carbon tetrachloride, and 1,1-dichloroethylene and in the repeated exposures to carbon tetrachloride. No significant hematologic alterations were noted in any of the studies. No biochemical studies were done in the earlier years and hence no biochemical data were obtained from the animals exposed to trichloroethylene and dichlorodifluoromethane. Serum urea nitrogen levels were within control limits in all of the exposures to carbon tetrachloride, 1,1-dichloroethylene, and 1,1,1-trichloroethane in which determinations were made. Liver lipid contents in guinea pigs were found to be significantly elevated following repeated exposure to 515 mg/m3 of carbon tetrachloride. Significant elevations of serum glutamic-pyruvic transaminase and liver alkaline phosphatase activities were found in rats and guinea pigs following continuous exposure to 189 mg/m3 of 1,1-dichloroethylene. Histopathologic study revealed liver damage following continuous exposures to high levels of dichlorodifluoromethane (3997 mg/m3), and to lower levels of carbon tetrachloride (61 mg/m3), and 1,1-dichloroethylene (189 mg/m3). Similar liver damage was also found in the repeated exposures to the two latter materials at 515 mg/m3 and 395 mg/m3, respectively.

Abstract  Comparison has been made of injury to the rat pulmonary alveolar parenchyma evoked by intravenous injection of N-nitrosomethylurethane, intratracheal instillation of 3-methylcholanthrene or repeated inhalation for up to 15 days of carbon tetrachloride, trichloroethylene or gasoline vapour. Biochemical analyses, including assessment of rates of RNA and DNA synthesis and secretion of pulmonary surfactant, were correlated with morphological changes determined by electron microscopy. Single doses of N-nitrosomethylurethane or 3-methylcholanthrene inhibited incorporation of [14C] orotate into lung RNA 1--3 days after treatment. Daily exposure for 30 min to carbon tetrachloride or trichloroethylene vapour caused less marked reduction in orotate incorporation. Ultrastructural examination revealed that 3-methylcholanthrene toxicity was characterised by cytoplasmic change including disruption of surfactant lamellaie of Type 2 pneumocytes and variable degenerative changes Type 1 pneumocytes. Eight to ten days after treatment, the morphological evidence of hypertrophy/hyperplasia and transformation of Type 2 pneumocytes correlated well with biochemical evidence of stimulated incorporation of [3H]thymidine. Inhalation of carbon tetrachloride or trichloroethylene vapour produced milder responses including occasional degenerative changes in Type 1 pneumocytes, reduced numbers of surfactant lamellae in Type 2 pneumocytes and no change in [3H]thymidine incorporation. In contrast to the gradation of injury produced by the various chemicals, all procedures caused a marked and reproducible reduction in secretion of pulmonary surfactant as determined by endobronchial lavage. Following solvent inhalation, reduced recovery of surfactant was detected within 5 days of repeated exposure and thereafter no further change in this depressed level resulted from continued exposure for a further 10 days. The data are discussed in terms of a generalised pattern of response by pulmonary alveolar tissue to chemical injury and the apparent sensitivity of surfactant secretion as an indicator of damage to the lung.

Abstract  A number of short-term methods have been developed in recent years to test chemical compounds and other agents for metagenic activity. These tests involve a number of species, both mammalian and nonmammalian, and are conducted both in vivo and in vitro. A correlation has been shown between the mutagenicity and the carcinogenicity of a compund. It has been estimated that approximately 80% (B.N. Ames, pers. comm.; M.S. Legator, pers. comm.) of all mutagenic compounds are also carcinogenic, although not all carcinogens are mutagens. Therefore, the value of tests to determine the mutagenicity of a compound is important in that these tests may, at least in some cases, give some indication of the carcinogenicity of that chemical as well. The mutagenicity tests alone, however, cannot difinitively identify a carcinogen. However, some of these test can be used for monitoring at-risk population groups and to aid in the evaluation of acceptable exposure standards. Mutational events may occur either at the gene level, where they result in mutant alleles, or at the chromosome level, where they cause chromosomal aberrations (usually the deletions or addition of some part of the chromosome arm). These may occur either during meiosis (in germ cells resulting in possible genetic transmission of that mutation) or during mitosis (occurring in somatic cells and not hereditary). Chromosomal aberrations may be either numerical or structural. Numerical abberations affect the whole chromosome set by the addition or deletion of one or more chromosomes from the cell. Structural anomalies, however, are generally deletions, breaks, gaps, or translocations in choromosomes and do not affect the chromosome number. Although many of these mutational events may result in cellular death, many may be repaired. In addition to the genetic end points of gene mutation or chromosomal aberration primary DNA damage may result from chemical mutagenesis. There are a number of tests that evaluate damage-induced genetic recombination. These include mitotic crossing over, gene coversion, sister chromatid exchange, and unscheduled DNA synthesis, as well as others.

Abstract  In recent years physiologically based pharmacokinetic models have come to play an increasingly important role in risk assessment for carcinogens. The hope is that they can help open the black box between external exposure and carcinogenic effects to experimental observations, and improve both high-dose to low-dose and interspecies projections of risk. However, to date, there have been only relatively preliminary efforts to assess the uncertainties in current modeling results. In this paper we compare the physiologically based pharmacokinetic models (and model predictions of risk-related overall metabolism) that have been produced by seven different sets of authors for perchloroethylene (tetrachloroethylene). The most striking conclusion from the data is that most of the differences in risk-related model predictions are attributable to the choice of the data sets used for calibrating the metabolic parameters. Second, it is clear that the bottom-line differences among the model predictions are appreciable. Overall, the ratios of low-dose human to bioassay rodent metabolism spanned a 30-fold range for the six available human/rat comparisons, and the seven predicted ratios of low-dose human to bioassay mouse metabolism spanned a 13-fold range. (The greater range for the rat/human comparison is attributable to a structural assumption by one author group of competing linear and saturable pathways, and their conclusion that the dangerous saturable pathway constitutes a minor fraction of metabolism in rats.) It is clear that there are a number of opportunities for modelers to make different choices of model structure, interpretive assumptions, and calibrating data in the process of constructing pharmacokinetic models for use in estimating “delivered” or “biologically effective” dose for carcinogenesis risk assessments. We believe that in presenting the results of such modeling studies, it is important for researchers to explore the results of alternative, reasonably likely approaches for interpreting the available data—and either show that any conclusions they make are relatively insensitive to particular interpretive choices, or to acknowledge the differences in conclusions that would result from plausible alternative views of the world.

Abstract  Toluene and 5 aliphatic chlorinated hydrocarbons of wide industrial use were injected into the air space of fertilized chicken eggs at 2,3 and 6 days of incubation. The embryotoxicity was evaluated as survival and death incidences after 14 days of incubation, and also the the weights and lengths of the embryo were recored. The approximate LD50 value for trichloroethylene and trichlorethanes varied between 50 and 100 μmol/egg while for toluene, tetrachlorethylene and methylene chloride it was over 100 μmol/egg. Macroscopic malformations of various kinds were produced with doses of 5–100 μmol/egg. The teratogenic potential of the tested compounds decreased in the following order: 1,1,1-trichloroethane > trichloroethylene > methylene chloride, tetrachloroethylene, 1,1,2-trichloroethane > toluene > olive oil control.

Abstract  The acute toxicity (96-hr median lethal concentrations (LC50s) of ten chlorinated isomers of benzene, phenol, ethane, and ethylene to the American flagfish (Jordanella floridae) were determined in both static and flow-through systems. Chronic toxicity to embryo-larval fish was also estimated from hatching success and post-hatch survival as well as fry growth rates and survival. Maximum acceptable toxicant concentrations (MATC) were estimated where possible. In general, for both acute and chronic toxicity tests, the order of increasing relative toxicity based on the water-borne exposure concentrations was: chloroethanes, chloroethylenes, chlorobenzenes, and chlorophenols. Within groups, more highly chlorinated isomers were usually more toxic. The presence of suspended or colloidal 1,2,4,5-tetrachlorobenzene was observed in acute toxicity testing and affected toxicity estimates.

Abstract  Animals (rats, gerbils and guinea pigs) were exposed to various common solvents. The brain lipids were extracted and analysed. In particular the fatty acid pattern of a major phospholipid, ethanolamine, phosphoglyceride was studied. A major finding was that some chlorinated solvents, trichloroethylene, perchloroethylene and 1,1,1-trichloroethane, had effects on the ethanolamine phosphoglyceride fatty acid pattern, while most other solvents, like toluene, xylene, white spirit and Freon 11 lacked this effect. Relatively small, but significant, changes were observed in the proportions of the polyunsaturated fatty acids of both the n-6 and n-3 series. The selective effect of the chlorinated solvents might indicate that they have a specific effect on the enzymatic regulation of membrane fatty acid composition. However, the lack of effects of other solvents might also be explained by low blood levels, due either to a low uptake (Freon 11, white spirit) or an extensive metabolism (toluene, xylene). Intrauterine exposure of guinea pigs to perchloroethylene (160 ppm) during the last half of gestation had minor effects on the ethanolamine phosphoglyceride fatty acid pattern. Thus it appears that animals during the period of rapid brain growth are equally sensitive to exposure as adult animals.

Abstract  Data derived from studies with vinylidene chloride (1,1-dichloroethylene)and 1,1,2-trichloroethylene suggest that similar mutagenic and tumorogenic properties in mice may be attributable to rearrangement of the 2 haloalkene-derived haloepoxides, respectively, into chloroacetyl chloride and dichloroacetyl chloride. On the other hand, the relative harmlessness of 1,1,2-trichloroethylene in rats and man is due to alternative rearrangement of 1,1,2-trichloroethylene oxide into chloral and the further products of its metabolism. The identification in mice of the new 1,1,2-trichloroethylene metabolite, dichloroacetic acid (in addition to trichloroacetic acid) strongly supports this supposition. The small proportion of dichloroacetic acid in relation to the large proportion of trichloroacetic acid in the urine of the treated mice is consistent with a spill-over model that is now tentatively proposed for 1,1,2-trichloroethylene metabolism in these animals.