Abstract  The relationship between inhaled dichloromethane (DCM) and percentage of carboxyhemoglobin (% COHb) in blood has been investigated in rabbits. After a single 20-min exposure to DCM, % COHb rose to a maximum within 2–3 hr and usually declined to basal values within 8 hr. The maximum COHb concentration and the time to reach that value were DCM concentration-dependent. In rabbits given a 4-hr exposure to DCM, % COHb increased over the first 2–3 hr, reaching a peak by about 4 hr with a return to basal levels within 24 hr. Studies were carried out to determine whether treatment with modifiers of hepatic mixed-function oxidase changed the % COHb response after DCM exposure. Of the compounds investigated, only CCl4 and phenobarbital altered % COHb resulting from DCM inhalation. As expected, CCl4, a potent hepatotoxin, reduced the % COHb resulting from DCM inhalation. Contrary to expectations phenobarbital also lowered the COHb response from DCM inhalation although the decrease was not as marked as that caused by CCl4.

Abstract  The possible mutagenicity of the organic solvent dichloromethane was investigated with the mutation test as described by Ames et al. The compound was mutagenic in both tester strains used, namely TA98 and TA100. The administration of rat-liver homogenate did not appear to be essential though it slightly increased the number of mutations.

Abstract  Five patients presented to the emergency department (ED) following exposure in an enclosed space to methylene chloride (dichloromethane), used for removing paint. Two workers and three rescuers were involved. Two rescuers complained only of dizziness and mild nausea, and were subsequently discharged from the ED. One rescuer was asymptomatic. Worker no. 1 arrived in cardiac arrest and eventually died in the ED despite resuscitation efforts. Worker no. 2 also presented to the ED in cardiac arrest, and was successfully resuscitated to pulse and blood pressure. However, he never regained consciousness or spontaneous respirations, and died on the fourth day. Of interest is that worker no. 2's carboxyhemoglobin level increased from 2% to 8% over the 9 hours following admission, despite administration of 40% to 50% oxygen by endotracheal tube. Among the conclusions that can be drawn are (1) the cause of death in these patients was not carbon monoxide poisoning, but solvent-induced narcosis; (2) carboxyhemoglobin levels may continue to rise following cessation of exposure, despite administration of high flow oxygen; (3) rescuers can easily become victims if proper protective clothing and respirators are not worn.

Abstract  Acute effects of inhaled dichloromethane on the spontaneous electroencephalogram (EEG) and sensory-evoked potentials (EPs) were characterized and compared to previously observed effects of toluene; both solvents are common components of abused solvent mixtures. Twelve adult male Fischer-344 rats with chronic epidural electrode implants served as subjects. Each rat was exposed for 60 min to 5,000, 10,000, and 15,000 ppm dichloromethane while held in a plastic restrainer that also served as a head-only exposure chamber. The sequence of exposures was counterbalanced across rats, and the exposures were separated by about one week. To characterize the time course of any changes, somatosensory and flash EPs were recorded every 5 min during the first 45 min of the exposures. As was the case with toluene, electrophysiologic waveforms recorded from different sensory systems, and components of these waveforms, reacted in different ways to dichloromethane. With respect to the FEP and SEP the two solvents produced quite different effects. Toluene increased the amplitudes of early FEP components, eliminated late components, induced oscillations in visual cortex, and had no discernible effects on component latencies. In contrast, dichloromethane eliminated the N1 component, at moderate exposure had little or no effects on amplitudes of the later components (N3 through N4), did not induce oscillations, and had significant effects on latencies. Whereas toluene dramatically increased SEP component amplitudes at moderate concentrations with diminishing effect at higher concentrations and exposure times, dichloromethane rather uniformly decreased SEP amplitude in a simple concentration-related way. Toluene and dichloromethane had similar effects on BAER component latencies. They both caused component (P1 through P5) latencies and the P1-P5 interwave time to increase. However, whereas toluene increased early and late (but not middle) component amplitudes, dichloromethane decreased the amplitudes of early and late components and increased the amplitudes of middle components. These results emphasize the acute pharmacologic specificity of different solvents and suggest that differences in chronic neurotoxicity might also be found; they also suggest that predictable interactions might be found with acute and chronic exposure to mixtures that contain such solvents.

Abstract  A variety of low molecular weight aliphatic chlorinated hydrocarbons have a history of use in the processing of foods, and their presence in potable water supplies has also been demonstrated. In this study, the relative uptake of four different aliphatic chlorinated hydrocarbons (methylene chloride, dichloroethane, chloroform and trichioroethylene) was studied after administration, by intragastric intubation, at the same dose level as corn-oil or aqueous solutions. Serial blood samples were collected over a 5-h period and uptake was assessed as the calculated area under blood concentration-time curves. A significant decrease in the rate and extent of uptake was observed for the compounds when administered as an oil solution as compared with an aqueous solution. Lower peak concentrations and an increase in the time taken to reach peak concentration, after dosing with corn oil solutions, was also observed.

Abstract  The developmental expression of the alpha, mu and pi class glutathione S-transferases has been defined in human liver using radioimmunoassay and immunohistochemistry. Expression of alpha and mu class isoenzymes increased significantly at birth, while that of the pi isoenzyme declined during the first trimester. Mu-class isoenzymes (GST1 1, GST1 2, GST1 2-1) were expressed in hepatocytes but not in other liver cell types.

Abstract  There has been much discussion in recent years regarding the most appropriate follow-up testing in vivo when positive results are obtained in vitro but the in vivo micronucleus (MN) test (traditionally the most widely-used test) is negative. Not all rodent carcinogens give positive results in the micronucleus test, and so it has been common practice to include a second in vivo assay such as the unscheduled DNA synthesis (UDS) test. This has proved useful but is usually limited to analysis of rodent (usually rat) liver. With the increased evaluation and use of other in vivo assays, e.g. for transgenic mutations (TG) and DNA damage (Comet assay) it was important to investigate their usefulness. We therefore examined the published in vivo UDS, TG and Comet-assay results for 67 carcinogens that were negative or equivocal in the micronucleus test. Between 30 and 41 chemicals were evaluated in each of the three in vivo tests, with some overlap. In general, the UDS test was disappointing and gave positive results with <20% of these carcinogens, some of which induced tumours in rat liver and produced DNA adducts in vivo. The TG assay gave positive responses with >50% of the carcinogens, but the Comet assay detected almost 90% of the micronucleus-negative or equivocal carcinogens. This pattern of results was virtually unchanged when the in vitro profile (gene mutagen or clastogen) was taken into account. High sensitivity (ability to detect carcinogens as positive) is only really useful when the specificity (ability to give negative results with non-carcinogens) is also high. Based on small numbers of publications with non-carcinogens, the TG and Comet assays gave negative results with non-carcinogens on 69 and 78% of occasions, respectively. Although further evaluation of the Comet and TG assays, particularly with non-carcinogens, is needed, these data suggest that they both should play a more prominent role in regulatory testing strategies than the UDS test.

Abstract  Precise age-specific average body weight estimates are necessary for deterministic risk assessments, and an accurate body weight distribution is equally important in probabilistic risk assessments. Age-specific body weight distributions for U.S. residents are estimated using NHANES (National Health and Nutrition Examination Survey) data collected in four surveys over the last 24 years. The weighted mean and standard deviation of natural log-transformed body weights are computed for single-year age groups and population age-specific weight patterns further described using piece-wise polynomial spline functions and nonparametric age-smoothed trend lines. These functions are used to compare distributional changes in age-specific body weight in the United States from the first NHANES survey in 1976?1980 to the most recent in 1999?2002. Analysis demonstrates that age- and sex-specific average body weight changes over this time period are not uniform. Use of these functions to compute body weight distributions for selected child-age categories is demonstrated.

Abstract  OBJECTIVES: To extend the follow up of a cohort of 14,457 aircraft maintenance workers to the end of 1990 to evaluate cancer risks from potential exposure to trichloroethylene and other chemicals. METHODS: The cohort comprised civilians employed for at least one year between 1952 and 1956, of whom 5727 had died by 31 December 1990. Analyses compared the mortality of the cohort with the general population of Utah and the mortality and cancer incidence of exposed workers with those unexposed to chemicals, while adjusting for age, sex and calendar time. RESULTS: In the combined follow up period (1952-90), mortality from all causes and all cancer was close to expected (standardised mortality ratios (SMRs) 97 and 96, respectively). Significant excesses occurred for ischaemic heart disease (SMR 108), asthma (SMR 160), and cancer of the bone (SMR 227), whereas significant deficits occurred for cerebrovascular disease (SMR 88), accidents (SMR 70), and cancer of the central nervous system (SMR 64). Workers exposed to trichloroethylene showed non-significant excesses for non-Hodgkin's lymphoma (relative risk (RR) 2.0), and cancers of the oesophagus (RR 5.6), colon (RR 1.4), primary liver (RR 1.7), breast (RR 1.8), cervix (RR 1.8), kidney (RR 1.6), and bone (RR 2.1). None of these cancers showed an exposure-response gradient and RRs among workers exposed to other chemicals but not trichloroethylene often had RRs as large as workers exposed to trichloroethylene. Workers exposed to solvents other than trichloroethylene had slightly increased mortality from asthma, non-Hodgkin's lymphoma, multiple myeloma, and breast cancer. CONCLUSION: These findings do not strongly support a causal link with trichloroethylene because the associations were not significant, not clearly dose-related, and inconsistent between men and women. Because findings from experimental investigations and other epidemiological studies on solvents other than trichloroethylene provide some biological plausibility, the suggested links between these chemicals and non-Hodgkin's lymphoma, multiple myeloma, and breast cancer found here deserve further attention. Although this extended follow up cannot rule out a connection between exposures to solvents and some diseases, it seems clear that these workers have not experienced a major increase in cancer mortality or cancer incidence.

Abstract  The in vivo-in vitro hepatocyte DNA repair assay has been shown to be useful for studying genotoxic hepatocarcinogens. In addition, measurement of S-phase synthesis (SPS) provides an indirect indicator of hepatocellular proliferation, which may be an important mechanism in rodent carcinogenesis. This assay was used to examine 24 chemicals for their ability to induce unscheduled DNA synthesis (UDS) or SPS in Fischer-344 rats or B6C3F1 mice following in vivo treatment. Hepatocytes were isolated by liver perfusion and incubated with 3H-thymidine following in vivo treatment by gavage. UDS was measured by quantitative autoradiography as net grains/nucleus (NG). Controls from both sexes of both species yielded less than 0.0 NG. Chemicals chosen for testing were from the National Toxicology Program (NTP) genetic toxicology testing program and most were also evaluated in long-term animal studies conducted by the NTP. 11-Aminoundecanoic acid, benzyl acetate, bis(2-chloro-1-methylethyl)ether (BCMEE), C.I. Solvent Yellow 14, cinnamaldehyde, cinnamyl anthranilate, dichloromethane, dichlorvos, glutaraldehyde, 4,4'-methylenedianiline (MDA), 4-nitrotoluene, 4,4'-oxydianiline, a polybrominated biphenyl mixture (PBB), reserpine, 1,1,2,2-tetrachloroethane, 1,1,2-trichloroethane, trichloroethylene, and 2,6-xylidine all failed to induce UDS in rats and/or mice. Dinitrotoluene and Michler's Ketone induced positive UDS response in rat, while N-nitrosodiethanolamine and selenium sulfide induced equivocal UDS results in mouse and rat, respectively. BCMEE, bromoform, chloroform, PBB, 1,1,2-trichloroethane, and trichloroethylene were all potent inducers of SPS in mouse liver, while C.I. Solvent Yellow 14, and 1,1,2,2-tetrachloroethane yielded equivocal SPS results in rat and mouse, respectively. These results indicate that most of the test compounds do not induce UDS in the liver; however, the significant S-phase responses induced by many of these compounds, especially the halogenated solvents, may be an important mechanism in their hepatocarcinogenicity.

Abstract  1. Inhalation of low concentrations of carbon monoxide (CO) by pregnant rats (75 and 150 p.p.m. from day 0 to day 20 of gestation) leads to changes in mesolimbic dopaminergic transmission associated with an impairment of sexual behaviour in male offspring. 2. Eighty day old males exposed in utero to CO (150 p.p.m.) exhibited a significant increase in mount/ intromission latency as well as a significant decrease in mount/intromission frequency. A significant decrease in ejaculation frequency was also found in CO (150 p.p.m.)-exposed animals. 3. The acute administration of amphetamine, at a dose (0.5 mg kg(-1) s.c.) stimulating copulatory activity in control rats, failed to reduce mount/intromission latency and did not increase mount frequency in 80-day offspring exposed to CO (150 p.p.m.) during gestation. 4. These behavioural alterations were paralleled by neurochemical changes (in vivo microdialysis) showing that prenatal CO exposure, at concentrations (150 p.p.m.) that did not affect basal extracellular levels of dopamine in the nucleus accumbens, blunted the amphetamine (0.5 mg kg(-1) s.c.)-induced increase in dopamine release in 80-day old male rats. 5. No significant changes in either behavioural or neurochemical parameters were observed in 10-month old rats exposed prenatally to CO. 6. Since the alterations in sexual behaviour and dopaminergic transmission have been produced by prenatal exposure to CO levels resulting in maternal blood carboxyhaemoglobin concentrations equivalent to those maintained by human cigarette smokers, the present data further point out the large risk that the smoking mother poses for her offspring.

Abstract  These guidelines revise and replace the U.S. Environmental Protection Agency’s (EPA’s, or the Agency’s) Guidelines for Carcinogen Risk Assessment, published in 51 FR 33992, September 24, 1986 (U.S. EPA, 1986a) and the 1999 interim final guidelines (U.S. EPA, 1999a; see U.S. EPA 2001b). They provide EPA staff with guidance for developing and using risk assessments. They also provide basic information to the public about the Agency's risk assessment methods.

Abstract  Acetylene, C2H2, is a highly reactive, commercially important hydrocarbon. Its reactivity is related to its triple bond between carbon atoms and, as a consequence, its high positive free energy of formation. Because of its explosive nature, long distance shipping or pressurized storage is not recommended. Thus acetylene is generally used as it is produced without shipping or storage. Commercially, acetylene is used primarily as a raw material for the synthesis of a variety of organic chemicals. In the United States, this accounts for ∼90% of acetylene usage, with the balance being used for metal welding and cutting. Worldwide acetylene production peaked in the mid-1960s, after which it declined dramatically as processes were developed to substitute lower cost olefins and paraffins for the acetylene feedstock. 1,4-Butanediol production accounts for 90% of the demand for acetylene for chemical production. Although acetylene production in Japan, China, and Eastern Europe is still based on the calcium carbide process, the large producers in the United States, Western Europe, and Russia now rely principally on the partial oxidation of natural gas. However, much of the incremental growth in production is based on producing acetylene as a coproduct of ethylene in the steam cracking process. As a coproduct, acetylene is much less costly than as produced from partial oxidation or calcium carbide.

Abstract  Dihaloalkanes are of toxicological interest because of their high-volume use in industry and their abilities to cause tumors in rodents, particularly dichloromethane and 1,2-dichloroethane. The brominated analogues are not used as extensively but are known to produce more toxicity in some systems. Rats and mice were treated i.p. with (14)C-dichloromethane, -dibromomethane, -1,2-dichloroethane, or -1,2-dibromoethane [5 mg (kg body weight)(-1)], and livers and kidneys were collected to rapidly isolate DNA. The DNA was digested using a procedure designed to minimize processing time, because some of the potential dihalomethane-derived DNA-glutathione (GSH) adducts are known to be unstable, and the HPLC fractions corresponding to major adduct standards were separated and analyzed for (14)C using accelerator mass spectrometry. The level of liver or kidney S-[2-(N(7)-guanyl)ethyl]GSH in rats treated with 1,2-dibromoethane was approximately 1 adduct/10(5) DNA bases; in male or female mice, the level was approximately one-half of this. The levels of 1,2-dichloroethane adducts were 10-50-fold lower. None of four known (in vitro) GSH-DNA adducts was detected at a level of >2/10(8) DNA bases from dibromomethane or dichloromethane. These results provide parameters for risk assessment of these compounds: DNA binding occurs with 1,2-dichloroethane but is considerably less than from 1,2-dibromoethane in vivo, and low exposure to dihalomethanes does not produce appreciable DNA adduct levels in rat or mouse liver and kidney of the doses used. The results may be used to address issues in human risk assessment.

Abstract  Sixty-one sets of clearance (CL) values in animal species were allometrically scaled for predicting human clearance. Unbound fractions (f(u)) of drug in plasma in rats and humans were obtained from the literature. A model was developed to predict human CL: CL=33.35 ml/min x (a/Rf(u))(0.770), where Rf(u) is the f(u) ratio between rats and humans and a is the coefficient obtained from allometric scaling. The new model was compared with simple allometric scaling and the "rule of exponents" (ROE). Results indicated that the new model provided better predictability for human values of CL than did ROE. It is especially significant that for the first time the proposed model improves the prediction of CL for drugs illustrating large vertical allometry.

Abstract  A TLV-TWA of 50 ppm (174 mg/m3) is recommended for occupational exposure to dichloromethane is part by analogy to the TLVs for trichloroethylene and the more potent CNS depressant, tetrachloroethylene. This value is intended to minimize the potential for elevation of carboxyhemoglobin and central nervous system (CNS) depression. Dichloromethane is considered a weak animal carcinogen based on liver and lung cancer in mice and benign mammary gland tumors in rats after chronic inhalation at high concentrations ( > = 1000 ppm). Accordingly, an A3, Confirmed Animal Carcinogen with Unknown Relevance to Humans, is assigned. Sufficient data were not available to recommend Skin or SEN notations or a TLV-STEL. Dichloromethane is a substance for which Biological Exposure Indices (BEIs) have been recommended (see BEI Documentation for Dichloromethane)

Abstract  PURPOSE: To update the mortality experience of employees of a factory that produced cellulose triacetate film base at Brantham in the United Kingdom and generate information on the effects of exposure to methylene chloride, in particular, mortality from cardiovascular disease and cancers of the lung, liver and biliary tract, pancreas and brain. METHODS: All 1,785 male employees with a record of employment at the film factory in 1946-1988 were followed through 2006, including 1,473 subjects exposed to methylene chloride on average for 9 years at a concentration of 19 ppm (8 h time-weighted average). RESULTS: A total of 559 deaths occurred during the follow-up period. In the subcohort of workers exposed to methylene chloride, substantially reduced mortalities compared with national and local rates were found for all causes, all cancers, and all the principal cancer sites of interest except for brain cancer. There was a small excess of brain cancer deaths (8 observed and 4.4 expected), but no evidence of an association with exposure to methylene chloride. Lung cancer mortality was significantly reduced in exposed workers, even compared to the low mortality rate in the local population (SMR 55). In contrast, mortality from ischaemic heart disease in exposed workers was slightly increased compared with local rates (SMR 102), but was lower in active employees (SMR 94; local rates), where a direct effect of exposure to methylene chloride should be concentrated. CONCLUSIONS: The study provided no indication that employment at the plant, or exposure to methylene chloride, had adversely affected the mortalities of workers.

Abstract  The major aspects that must be considered in studies of the health effects of environmental pollutants are: the direct damage due to the exposure, the role of pre-existing disease, and effects of the exposure on the response to secondary stresses. In experimental studies at concentrations of air pollutants found in urban environments frank toxicological responses are rarely observed. However, exposure to a secondary stress, i.e. respiratory challenge with infectious bacteria, can exacerbate the response of the experimental host. Changes in the resistance to respiratory infections provide a highly sensitive experimental animal model system, which is increasingly used in studies of health effects of air pollutants. This model indicates the impairment of the basic defense mechanisms of the respiratory system by the combined exposure to low concentrations of pollutants and the superimposed bacterial infection. Changes in the resistance to respiratory infections were studied in various species of laboratory animals. S. pyogenes and K. pneumoniae are the bacteria of choice to induce the pulmonary infection. Included in the studies are short-term single and multiple exposures as well as long-term exposures to gaseous pollutants such as O3 and NO2 and particulate pollutants such as sulfates and nitrates. Changes in the resistance are measured as excess mortalities and reduced survival time as compared to those in infected animals not exposed to the pollutants. Other parameters measured ranged from changes in the immune response to changes in retention rates of bacteria in lungs.

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 neurobehavioral effects of 10 known toxicants were examined as part of a multidisciplinary screening battery. The toxicants included carbaryl (CAR), triadimefon (TDM), heptachlor (HEP), chlordane (CDN), diethylhexyl phthalate (DEHP), carbon tetrachloride (CCl4), phenol, trichloroethylene (TCE), tetrachloroethylene (PER or perchlorethylene), and dichloromethane (DCM or methylene chloride). A functional observational battery and motor activity measurements were conducted before exposure, at specified times after an acute exposure, and during and after 14-d exposure. Severity scoring analysis was used to generate profiles of effect. The pesticides, CAR, TDM, HEP, and CDN, displayed the most acute neurotoxicity and were active at lower proportions of their respective acute LD50 values than were the solvents or the industrial chemicals. Although CAR and TDM showed little or no neurobehavioral effects with repeated dosing, cumulative neurotoxicity and lethality were evident with HEP and CDN. Phenol produced acute convulsive effects, and the most prominent finding with repeated exposure was lethality. DEHP displayed no neurobehavioral toxicity. The organic solvents, TCE, PER, CCl4, and DCM, produced various degrees of general nervous system depression following acute administration of high dose levels. Repeated dosing produced little or no effect with TCE or PER, marked physiological changes with CCl4, and cumulative toxicity and lethality with DCM. Some results of these studies were unexpected and should provide impetus for further research. Overall, these findings illustrate the utility of these screening methods.

Abstract  Epidemiological studies provide the only definitive information on the degree of cancer risk to man. Since malignant diseases are clearly of multifactorial origin, their investigation in man has become increasingly complex, and epidemiological and statistical studies on cancer require a correspondingly complex and rigorous methodology. The past 15 years have seen rapid developments of the analytic tools available to epidemiologists. These advances now permit a more flexible and quantitative approach to the use of epidemiological data, and thus greatly enhance the utility of such data for the primary purpose of disease prevention. For society now expects that if preventive measures are to be introduced, then quantitative assessments of the expected benefit should be available. The first volume in this series focused on case-control studies, reflecting the concentration on this approach in the 1970s for the identification of cancer hazards. Attention has recently turned to the more basic line of attack provided by cohort studies, and the more general modelling of risk that can ensue. This second volume gives an authoritative account of the methods now available for the interpretation of the results from this type of study. The two volumes together give a comprehensive development of the principles and concepts underlying the design and analysis of both types of study currently used in analytic cancer epidemiology, and a detailed treatment of the quantitative methods now available. The IARC hopes that this text will be of value to the epidemiological and statistical community for many years to come.

Abstract  We investigated the effects of oral administration of 28 organic chemical agents, all of which possess neurotoxicity and most of which are used as industrial solvents, on monoamine neurotransmitters and metabolites in the rat brain. Each chemical was administered to rats singly at a dose of one-quarter the LD50 value. Two hours after administration, acetylcholine, 3, 4-dihydroxyphenylalanine (DOPA), dopamine, 3, 4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), norepinephrine, 3-methoxy-4-hydroxyphenylglycol (MHPG), serotonin, and 5-hydroxyindoleacetic acid (5HIAA) contents in the small-brain regions were measured. Twenty-one of the 28 chemicals increased acetylcholine in the hippocampus, a ratio (21/28) far higher than the 0.5 expected were these chemicals to have no tendency to increase or decrease acetyl-choline. This ratio was calculated for each brain substance. Large differences from 0.5 were also obtained for DOPAC (higher), and for 5HIAA and three neurotransmitters (dopamine, norepinephrine, and serotonin) in the hypothalamus (all lower). The ratios for MHPG and 5HIAA in the medulla oblongata were very high. In the hypothalamus, the concentrations of brain substances were easily altered by the test chemicals, and the turnover rates of hypothalamic norepinephrine and serotonin in the medulla oblongata