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  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  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  Upper respiratory tract (URT) absorption of several compounds with differing water solubilities and potentials to cause lesions of the nasal mucosa were studied in rats. Absorption of propylene glycol monomethyl ether (PGME), PGME acetate (PGMEAc), ethyl acrylate (EA), epichiorohydrin (EPI), styrene (STY), nitroethane (NE), ethylene dibromide (EDB), and methylene chloride (MeCl2) vapors by the isolated URT was compared to that by the isolated lower respiratory tract (LRT) and the intact animal. Neatly all PGME and PGMEAc and 30-70% of EA, EPI, STY, NE, and EDB were absorbed when passed through the. URT. In general, similar levels were absorbed by both the isolated LRT and intact animal. It was estimated that intact animals received more than 90% of their total dose of PGME and PGMEAc. and 50% of EA, NE, EPI, and EDB via the URT. Further, the dosage per Unit of surface area in the URT may be 5000-6000 times that of the LRT. However, the extent of URT absorption was not related to the ability to cause lesions of the nasal mucosa. Absorption of compounds by the URT was not a simple function of water solubility or of blood or water/air partitioning coefficients suggesting that a more complex mechanism for controlling absorption may exist. In one case. it was demonstrated that URT enzymatic activity could influence the absorption of certain compounds by the URT.

Abstract  Methylene chloride (dichloromethane) is used in a variety of industrial applications. To date, there has been no formal assessment of immunotoxicity attributed to methylene chloride. Studies were undertaken to examine whether methylene chloride has any potential to influence the integrity of immune function. For this purpose, Sprague-Dawley rats of both genders were exposed by inhalation to a single high dose (5000 ppm) of methylene chloride for 6 h/d, 5 d/wk for 28 d. This was considered the relevant route of administration, as not only is inhalation a primary route for human exposure to methylene chloride, but, also, the chemical is absorbed rapidly via the lungs. Under these conditions of exposure, methylene chloride failed to influence absolute or relative thymus weights in either gender and produced a significant reduction in relative, but not absolute, spleen weight in female rats only. Immunocompetence was measured as a function of the ability of treated animals to mount immunoglobulin M (IgM) antibody responses to sheep red blood cells (SRBC) as determined by enzyme-linked immunosorbent assay (ELISA). Exposure to methylene chloride did not affect antibody production. Evidence indicates that under these conditions of exposure, methylene chloride did not compromise immune function.

Abstract  Maternal smoking is a known risk factor for orofacial clefts. We investigated whether risk is greater among offspring who lack the genetic capacity to produce glutathione S-transferase enzymes relevant to detoxification of chemicals in cigarette smoke.

Using a population-based case-control design, we genotyped 423 California infants with an isolated cleft and 294 nonmalformed controls for null variants of the glutathione S-transferases GSTT1 and GSTM1.

If a mother smoked during pregnancy and her fetus was homozygous null for GSTT1, the risk of isolated cleft lip with or without cleft palate was tripled (odds ratio = 2.9; 95% confidence interval = 1.2-7.2). For fetuses who were homozygous null for GSTM1 and whose mothers smoked >/=20 cigarettes per day, we found nearly a 7-fold increased risk (6.8; 0.82-57). Combined absence of GSTM1 and GSTT1 enzymes among the offspring of smoking mothers was associated with a nearly 6-fold increased risk for cleft lip (6.3; 1.3-42). A similar increased risk for cleft palate was associated with absence of GSTM1, but not for absence of GSTT1.

Maternal smoking during pregnancy increases risks for clefts among fetuses lacking enzymes involved in the detoxification of tobacco-derived chemicals.

Abstract  The objective of this study is to predict clearance of drugs in humans from animals which are excreted in the bile. Clearance (CL) of eight drugs known to be excreted in the bile were randomly selected from the literature. Scaling of CL was performed using at least three animal species. Using simple allometry, CL x mean life-span potential (MLP) or CL x brain weight, CLs of studied drugs were predicted in humans. The choice of one of the methods depended on the 'rule of exponents' as described by Mahmood and Balian. A 'correction factor' was calculated by adjusting bile flow rate based on the species body weight (bile flow = mL/day/kg body weight) or liver weight (bile flow = mL/day/kg liver weight). Using the 'rule of exponents' and combining it with the 'correction factor', the CLs of biliary excreted drugs were predicted in humans. Predicted CLs in humans from animals using simple allometry were several times higher for all eight drugs (% error [range] = 46-1703). Using the 'rule of exponents' and combining it with a 'correction factor' as described in this report provided a substantial improvement (% error [range] = 5-91) in the prediction of CL for biliary excreted drugs. The results of this study indicate that the CL of a biliary excreted drug may be overpredicted in humans and by applying the 'correction factor' employed here, the predictability of drug CL in humans from animal data may be significantly improved.

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  Many organic solvents are considered probable carcinogens. We carried out a population-based case-control study including 790 incident cases of childhood acute lymphoblastic leukemia and as many healthy controls, matched on age and sex. Maternal occupational exposure to solvents before and during pregnancy was estimated using the expert method, which involves chemists coding each individual's job for specific contaminants. Home exposure to solvents was also evaluated. The frequency of exposure to specific agents or mixtures was generally low. Results were generally similar for the period ranging from 2 years before pregnancy up to birth and for the pregnancy period alone. For the former period, the odds ratio (OR), adjusted for maternal age and sex, for any exposure to all solvents together was 1.11 [95% confidence interval (CI), 0.88-1.40]. Increased risks were observed for specific exposures, such as to 1,1,1-trichloroethane (OR = 7.55; 95% CI, 0.92-61.97), toluene (OR = 1.88; 95% CI, 1.01-3.47), and mineral spirits (OR = 1.82; 95% CI, 1.05-3.14). There were stronger indications of moderately increased risks associated with exposure to alkanes (C5-C17; OR = 1.78; 95% CI, 1.11-2.86) and mononuclear aromatic hydrocarbons (OR = 1.64; 95% CI, 1.12-2.41). Risk did not increase with increasing exposure, except for alkanes, where a significant trend (p = 0.04) was observed. Home exposure was not associated with increased risk. Using an elaborate exposure coding method, this study shows that maternal exposure to solvents in the workplace does not seem to play a major role in childhood leukemia

Abstract  BACKGROUND: A number of studies have shown possible associations between occupational exposures, particularly solvents, and lymphomas. The present investigation aimed to evaluate the association between exposure to solvents and lymphomas (Hodgkin and non-Hodgkin) in a large population-based, multicenter, case-control study in Italy. METHODS: All newly diagnosed cases of malignant lymphoma in men and women age 20 to 74 years in 1991-1993 were identified in 8 areas in Italy. The control group was formed by a random sample of the general population in the areas under study stratified by sex and 5-year age groups. We interviewed 1428 non-Hodgkin lymphoma cases, 304 Hodgkin disease cases, and 1530 controls. Experts examined the questionnaire data and assessed a level of probability and intensity of exposure to a range of chemicals. RESULTS: Those in the medium/high level of exposure had an increased risk of non-Hodgkin lymphoma with exposure to toluene (odds ratio = 1.8; 95% confidence interval = 1.1-2.8), xylene 1.7 (1.0-2.6), and benzene 1.6 (1.0-2.4). Subjects exposed to all 3 aromatic hydrocarbons (benzene, toluene, and xylene; medium/high intensity compared with none) had an odds ratio of 2.1 (1.1-4.3). We observed an increased risk for Hodgkin disease for those exposed to technical solvents (2.7; 1.2-6.5) and aliphatic solvents (2.7; 1.2-5.7). CONCLUSION: This study suggests that aromatic and chlorinated hydrocarbons are a risk factor for non-Hodgkin lymphomas, and provides preliminary evidence for an association between solvents and Hodgkin disease

Abstract  Fourteen subjects were exposed to about 870 and 1,740 mg/m3 of methylene chloride in the air during rest and physical exercise on a bicycle ergometer. The duration of each exposure period was 30 min. Each subject was exposed during four periods. The concentration of methylene chloride in the alveolar air increased in the beginning but had a tendency to level off at the end of each period. There was a high correlation between the alveolar and arterial concentration of methylene chloride. The uptake of methylene chloride was about 55 % of the supplied amount at rest, about 40% at a work load of 50 W, and about 30 and 35 % at 100 and 150 W, respectively. The concentration of carboxyhemoglobin (COHb) increased both during and after exposure. With exposure to 1,740 mg/m3 a concentration of COHb in the blood of about 0.85 g/100 ml was reached. This value corresponds to about 5.5 % COHb.

Abstract  The accumulation of methylene chloride and its metabolites in different organs and tissues was studied in an experimental series comprising 10 rats. Each rat was exposed for 1 h to radioactive methylene chloride (14C) in a concentration amounting to 1,935 mg/m3 in inspiratory air. Radioactive carbon atoms were found in the isolated carbon monoxide after exposure. There was also a close correlation between the activity of carbon monoxide extracted from the blood sample and the amount of carboxyhemoglobin (COHb) in the specimen. The largest concentration of methylene chloride and its metabolites per gram of tissue was found in white adipose tissue. This concentration had declined by more than 90% 2 h after exposure, whereas the concentration in the liver declined by about 25% during the same period. The amount accumulated in the brain displayed a decline of about 75% 2 h after exposure. Thus the examination showed that the increased concentration of COHb in the blood during exposure to methylene chloride is due to the metabolism of methylene chloride into carbon monoxide.

Abstract  HEEP COPYRIGHT: BIOL ABS. Well-controlled experimental exposures to methylene chloride vapor lasting for 2 or 4 hr were performed in human beings and dogs. The exposure concentrations ranged from 100 to 1000 ppm in the dogs and from 100 to 200 ppm in man. Serial breath and blood curves from both species were directly proportional to the magnitude of exposure. The average 24-hr urinary excretions of methylene chloride for the 100- and 200- ppm exposures in man were approximately 23 mug and 82 mug, respectively. During comparable exposures, the dog absorbed substantially more methylene chloride vapor than man. Prolonging the exposure from 2 to 4 hr did not result in a substantial increase in solvent absorption. It is possible to make accurate extrapolations to human exposures from animal experiments provided the appropriate attention is given to factors such as the exposure duration, the time of collection after the exposure, the extent of metabolic involvement and kinetic parameters. In such extrapolations, it is sometimes necessary to correct the experimental die-away curves because of changes in muscular exercise during the exposure.

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

Abstract  Physiologically based pharmacokinetic (PB-PK) models describe the dynamic behavior of chemicals and their metabolites in individual tissues of living animals. Because PB-PK models contain specific parameters related to the physiological and biochemical properties of different species as well as the physical chemical characteristics of individual chemicals, they are useful tools for performing high dose/low dose, dose route, and interspecies extrapolations in hazard evaluations. An example of such extrapolation has been presented by M. E. Andersen, H. J. Clewell III, M. L. Gargas, F. A. Smith, and R. H. Reitz (Toxicol. Appl. Pharmacol. 87, 185-205, 1987), who employed a PB-PK model for methylene chloride (CH2Cl2) to estimate the chronic toxicity of this material. However, one limitation of this PB-PK model was that the metabolic rate constants for the glutathione-S-transferase (GST) pathway in humans were estimated by allometric scaling rather than from experimental data. In this paper we report studies designed to estimate the in vivo rates of metabolism of CH2Cl2 from in vitro incubations of lung and liver tissues from B6C3F1 mice, F344 rats, Syrian Golden hamsters, and humans. A procedure for calculating in vivo metabolic rate constants from the in vitro studies is presented. This procedure was validated by making extrapolations with mixed function oxidase enzymes (MFO) acting on CH2Cl2, where both in vitro and in vivo rates of metabolism are known. The in vitro rate constants for the two enzyme systems are consistent with the hypothesis presented by Andersen et al. that metabolism of CH2Cl2 occurs in vivo by two competing pathways: a high-affinity saturable pathway (identified as MFO) and a low-affinity first-order pathway (identified as GST). The metabolic rate constants for GST obtained from these studies are also consistent with the hypothesis of Andersen et al. that production of large quantities of glutathione/CH2Cl2 conjugates in vivo may increase the frequency with which lung and liver tumors develop in some species of animals (e.g., B6C3F1 mouse). When in vivo studies in humans are unavailable, in vitro enzyme assays provide a reasonable method for estimating metabolic rate constants.

Abstract  Maternal blood dichloromethane concentrations were higher than fetal blood dichloromethane concentrations and maternal and fetal blood carbon monoxide concentrations were the same in pregnant rats exposed to 500 ppm of dichloromethane. Fetal blood carbon monoxide concentrations were higher than maternal blood carbon monoxide concentrations in pregnant rats exposed to 20 ppm of carbon monoxide. These results show that maternal exposure to dichloromethane is accompanied by fetal exposure to both dichloromethane and carbon monoxide.

Abstract  Inhalation of low concentrations (75 and 150 ppm) of carbon monoxide (CO) by pregnant rats from days 0 to 20 of gestation leads to alterations in habituation and working memory in young adult male offspring subjected to the novel exploration object test. In particular, lack of habituation upon the second presentation of the objects and failure in the ability to discriminate between the novel and the familiar object were found in CO (75 and 150 ppm)-exposed offspring. These alterations were not accompanied by changes in spontaneous motor activity (open field test). The subtle behavioral deficits observed in the present study have been produced by prenatal exposure to CO levels resulting in maternal blood carboxyhaemoglobin (HbCO) concentrations equivalent to those observed in human cigarette smokers.

Abstract  A new system has been developed to determine enzyme activities of glutathione transferase theta (GSTT1-1) based on radiometric product detection resulting from the enzymic reaction of methyl chloride with 35S-labelled glutathione. In principle, the method is universally applicable for determination-of glutathione transferase activities towards a multiplicity of substrates. The method distinguishes between erythrocyte GSTT1-1 activities of human 'non-conjugators', 'low conjugators' and 'high conjugators'. Application to cytosol preparations of livers and kidneys of male and female Fischer 344 and B6C3F1 mice reveals differential GSTT1-1 activities in hepatic and renal tissues. These ought to be considered in species-specific modellings of organ toxicities of chlorinated hydrocarbons.