This paper discusses the use of psychological performance tests to assess the effects of environmental stressors. The large number and the variety of performance tests are illustrated, and the differences between performance tests and other psychological tests are described in terms of their design, construction, use, and purpose. The stressor emphasis is on the effects of drugs since that is where most performance tests have found their main application, although other stressors, e.g., fatigue, toxic chemicals, are mentioned where appropriate. Diazepam is used as an example. There is no particular performance emphasis since the tests are intended to have wide applicability. However, vehicle-driving performance is discussed because it has been the subject of a great deal of research and is probably one of the most important areas of application. Performance tests are discussed in terms of the four main underlying models--factor analysis, general information processing, multiple resource and strategy models, and processing-stage models--and in terms of their psychometric properties--sensitivity, reliability, and content, criterion, construct, and face validity. Some test taxonomies are presented. Standardization is also discussed with reference to the reaction time, mathematical processing, memory search, spatial processing, unstable tracking, verbal processing, and dual task tests used in the AGARD STRES battery. Some comments on measurement strengths and appropriate study designs and methods are included.
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With the sequencing of the human genome completed, the question becomes: what now? Many common diseases are known to be associated with genetic variants, or changes in single nucleotides of the DNA making up the human genome. However, scientists still have many questions about how individual gene variants, and interactions between variants and environmental factors, contribute to an individual’s risk of developing common diseases such as cancer, obesity, and heart disease.
Some scientists believe the only way to answer those questions is through a large prospective cohort study, collecting DNA samples and information about exposure to a variety of environmental factors from 500,000 to 1 million participants and following this random sampling of the population over a number of years. But such a study would require a huge investment of time, effort, and money; the DHHS Secretary’s Advisory Committee on Genetics, Health, and Society (SACGHS) estimates the cost at roughly $3 billion, possibly more. In addition, such an endeavor would likely raise significant social, legal, and ethical issues concerning privacy, consent, public involvement, and communication.
Now a new draft report by the SACGHS examines the policy issues related to such a study. The report concludes that, although conducting a large prospective study presents major challenges, it also has the potential to result in significant health benefits.
Ozone is a potent photochemical oxidant that produces transient, reversible decrements in the lung function of acutely exposed individuals. A recent study provided previously unavailable clinical data for 30 healthy young adults exposed to O(3) at 0.06 ppm. That study showed significant effects of 0.08 ppm on lung function, confirming the findings of others. However, exposure to 0.06 ppm O(3) was not reported to significantly affect lung function.
We conducted this analysis to reevaluate the existing lung function data of the volunteers previously exposed to 0.06 ppm O(3).
We obtained pre- and postexposure data on forced expiratory volume in 1 sec (FEV(1)) for all subjects who were previously exposed for 6.6 hr to filtered air or to 0.06 ppm or 0.08 ppm O(3). We used standard statistical methods appropriate for paired comparisons to reanalyze FEV(1) responses after exposure to 0.06 ppm O(3) relative to filtered air.
Controlling for filtered air responses, 24 of the 30 subjects experienced an O(3)-induced decrement in FEV(1). On average, 0.06 ppm O(3) exposure caused a 2.85% reduction in FEV(1) (p < 0.002), which was consistent with the predicted FEV(1) response from existing models. Although the average response was small, two subjects had > 10% FEV(1) decrements.
Exposure to 0.06 ppm O(3) causes a biologically small but highly statistically significant decrease in mean FEV(1) responses of young healthy adults.
Atrazine is the most commonly used herbicide in the United States and probably the world. Atrazine contamination is widespread and can be present in excess of 1.0 ppb even in precipitation and in areas where it is not used. In the current study, we showed that atrazine exposure (> or = to 0.1 ppb) resulted in retarded gonadal development (gonadal dysgenesis) and testicular oogenesis (hermaphroditism) in leopard frogs (Rana pipiens). Slower developing males even experienced oocyte growth (vitellogenesis). Furthermore, we observed gonadal dysgenesis and hermaphroditism in animals collected from atrazine-contaminated sites across the United States. These coordinated laboratory and field studies revealed the potential biological impact of atrazine contamination in the environment. Combined with reported similar effects in Xenopus laevis, the current data raise concern about the effects of atrazine on amphibians in general and the potential role of atrazine and other endocrine-disrupting pesticides in amphibian declines.
The two-stage clonal expansion model for a single, less-than-lifetime period of dosing is formulated and applied to the liver and bladder tumor data from the ED01 study. The model successfully predicts liver tumor incidence for time points beyond termination of dosing with 2-acetylaminofluorene, but it is unsuccessful for bladder tumor incidence. A discontinued dosing version of the Weibull model is proposed and is shown to predict successfully both liver and bladder tumor incidences for time points after termination of dosing.
1,1-Dichloroethylene is reported to produce renal tumors in male mice. It is an hepatotoxin in fasted rats after inhalation. We found that trichloropropane epoxide, an inhibitor of epoxide hydrase, enhances hepatic injury as measured by serum sorbitol dehydrogenase elevation. A significant elevation of hepatic citric acid concentration was seen in fasted but not fed rats. We hypothesized that mitochondrial injury was associated with inhibition of the tricarboxylic acid cycle and postulated that monochloroacetic acid was a toxic metabolite of 1,1-DCE. Fluoroacetic acid and chloroacetic acid were similar in their ability to inhibit oxygen uptake when pyruvic and malic acids were substrates in isolated mitochondria supplemented with adenosine diphosphate.
In experiments where 1,1-DCE metabolism was estimated, no difference between the rate of uptake in a 2-hr period was detected between fed and fasted animals. Urinary output of radioactivity at 26 hr for fed and fasted rats was similar. Water-soluble (i.e. TCA-soluble) 1,1-DCE metabolites were found in tissues of fasted rats in excess of that seen in fed rats. The kidney had the largest concentration of total metabolites. Tissue-bound, or TCA-insoluble, radioactivity was associated with the mitrochondrial and microsomal fraction of fasted rats in excess of that seen in fed rats. The disappearance of TCA-insoluble radioactivity from the mitochondrial and microsomal fractions was comparable in rate between fed and fasted rats respectively. These results suggest that 1,1-DCE is metabolized quite rapidly in the organism to TCA-soluble components which are excreted by the kidneys. Metabolites of 1,1-DCE may enter the metabolic pool, since a reasonably short turnover of 14C-labeled, bound material was observed. The metabolite of 1,1-DCE appears to inhibit the mitochondria so that citric acid accumulates. This may occur by a process of lethal synthesis.
Within 2 hr after 1,1-dichloroethylene administration, the following phenomena occur in livers of fasted rats: dilation and disruption of bile canaliculi, plasma membrane invagination and loss of microvilli, cytoplasmic vacuolation, and loss of density in mitochondrial matrices. Early, selective loss of enzyme activities was localized by histochemical staining to bile canalicular, and inner and outer mitochondrial membranes. Biliary permeability to inulin increased, a change suggestive of the breakdown of junctions between hepatocytes. Endoplasmic reticulum and lysosomes appeared spared. In addition, scattered, individual hepatocytes exhibited changes characteristic of apoptosis by 2 hr: chromatin aggregation and margination, nucleolar coarse granulation and enlargement, rounded blebs and proturberances on cell surfaces, and the separation of these cells from surrounding parenchyma. In contrast, evidence of plasma membrane leakiness to K+, Ca2+ and soluble cytoplasmic enzymes was not detected until after 2 hr. Based on these observations, we propose that 1,1-dichloroethylene may initiate apoptosis-like cell degradation in selected parenchymal cells prior to or coincident with centrolobular necrosis.
Mortality curves for groups of fasted male rats treated with single, oral doses of 1,1-dichloroethylene (1,1-DCE, vinylidene chloride) were not monotonically increasing sigmoids, but were complex with maxima or extended plateaus in the region of dose between 100 and 700 mg of 1,1-DCE/kg. The exact shape was a function of the size (age) of the rat used. When groups of rats of various sizes were dosed with 50 mg/kg, mortality and hepatotoxicity were greatest for those groups whose average weight was between 100 and 150 g. Smaller and larger male rats were less susceptible to 1,1-DCE intoxication. The toxicity of 1,1-DCE was less severe in female rats and there was no significant effect of rat size on 1,1-DCE toxicity in females. In rats of both sexes the dose dependence of the hepatotoxic response was complex, possessing a threshold level, a region of precipitous increase, and a plateau, where larger doses were ineffective in increasing hepatotoxicity. The threshold in male rats of 100-150 g occurred near 50 mg/kg, and for females it was closer to 100 mg/kg. Considered in their entirety these data suggest that 1,1-DCE is metabolized to a toxic intermediate via some saturable pathway. Based on the effects of pretreatment with microsomal enzyme inhibitors and activators on 1,1-DCE toxicity in rats of various sizes, it appears that there are at least two microsomal reactions involved in 1,1-DCE metabolism.
The presumed halothane metabolite, 2-bromo-1,1-difluoroethylene, produces both base substitution and frameshift mutations in Salmonella typhimurium. Direct mutagenesis of isolated DNA also was observed by using a Bacillus subtils transformation assay to score the production of mutagenic lesions in transforming DNA.
Halothane (1,1,1-trifluoro-2-bromo-2-chloroethane) is a safe, clinically useful inhalation anesthetic. Rare, unpredictable cases of liver necrosis have been reported following its use. Although the mechanism of this reaction in man is unknown the most plausible is biotransformation to reactive intermediates compounds. The oxidative metabolism of halothane appears to be benign. There is early evidence that reductive (nonoxygen dependent) may be harmful. Since the bromine atom of halothane appears to possess weak bond energy, the reduced, debrominated derivative of halothane, 1,1,1-trifluoro-2-chloroethane, was synthesized and tested for hepatotoxicity in the rat. The derivative is unstable and thus was prepared anaerobically and trapped in propylene glycol solvent. Injection of small amounts of this compound into the portal vein of rats produces extensive liver necrosis. It is postulated that biotransformation of halothane via a reductive pathway could produce this reactive intermediate metabolite.
In this study, we integrated our understanding of biochemistry, physiology, and metabolism of three commonly used organic solvents with computer simulation to present a new approach that we call "in silico" toxicology. Thus, we developed an interactive physiologically based pharmacokinetic (PBPK) model to predict the individual kinetics of trichloroethylene (TCE), perchloroethylene (PERC), and methylchloroform (MC) in humans exposed to differently constituted chemical mixtures of the three solvents. Model structure and parameterization originate from the literature. We calibrated the single-compound PBPK models using published data and described metabolic interactions within the chemical mixture using kinetic constants estimated in rats. The mixture model was used to explore the general pharmacokinetic profile of two common biomarkers of exposure, peak TCE blood levels and total amount of TCE metabolites generated, in rats and humans. Assuming that a 10% change in the biomarkers corresponds to a significant health effect, we calculated interaction thresholds for binary and ternary mixtures of TCE, PERC, and MC. Increases in the TCE blood levels led to higher availability of the parent compound for glutathione conjugation, a metabolic pathway associated with kidney toxicity/carcinogenicity. The simulated change in production rates of toxic conjugative metabolites exceeded 17% for a corresponding 10% increase in TCE blood concentration, indicating a nonlinear risk increase due to combined exposures to TCE. Evaluation of metabolic interactions and their thresholds illustrates a unique application of PBPK modeling in risk assessment of occupational exposures to chemical mixtures.
Interest and concern regarding potentially estrogenic substances have resulted in development of model systems to evaluate mechanisms of such chemicals. Microarray studies have indicated that estradiol (E2)-stimulated uterine responses can be divided into early and late phases. Comparison of E2 uterine transcript profiles and those of other estrogenic chemicals of interest in vivo indicates mechanisms and activities of test compounds.
We compared transcript responses and mechanisms of response using mouse reproductive tracts after treatment with E2, estriol (E3), bisphenol A (BPA), and 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE).
Uterine RNA from ovariectomized wild-type mice, estrogen receptor α (ERα) knockout (αERKO) mice, and mice expressing a DNA-binding-deficient ERα (KIKO) treated with E2, E3, BPA, or HPTE for 2 or 24 hr was analyzed by microarray. Resulting regulated transcripts were compared by hierarchical clustering and correlation analysis, and response patterns were verified by reverse-transcription real-time polymerase chain reaction (RT-PCR).
Both xenoestrogens, BPA and HPTE, showed profiles highly correlated to that of E2 in the early response phase (2 hr), but the correlation diminished in the later response phase (24 hr), similar to the known weak estrogen E3. Both xenoestrogens also mimicked E2 in samples from KIKO mice, indicating that they are able to utilize the indirect tethering mode of ERα signaling. No response was detected in ERα-null uteri, indicating that ERα mediates the responses.
Our study forms a basis on which patterns of response and molecular mechanisms of potentially estrogenic chemicals can be assessed.
Excretion of mercapturic acids in the urine is indicative of the formation of electrophiles in the metabolism of xenobiotics. The determination of these mercapturic acids thus may be a useful method to estimate the exposure. We identified the nephrotoxic and mutagenic mercapturic acids N-acetyl-S-(1,2-dichlorovinyl)-L- cysteine and N-acetyl-S-(2,2-dichlorovinyl)-L-cysteine in the urine of workers exposed to 1,1,2-trichloroethene. A method to quantify these mercapturic acids by gas chromatography-mass spectrometry-selected ion monitoring was developed and appreciable amounts (2.8-3.8 mumole/L were found in human urine samples. Because deacetylation determines notably the amount of the excreted mercapturic acids, the formation of the resulting cysteine S-conjugates was comparably measured in subcellular fractions of rodent and human kidneys; significant species differences in acylase activity were found. The formation of mutagenic and nephrotoxic metabolites during 1,1,2-trichloroethene metabolism mandates a revision of the risk assessment of trichloroethene exposure.
It is concluded that, under the conditions of this bioassay 1,2-dibromoethane was carcinogenic for F344 rats, causing increased incidences of carcinomas, adenocarcinomas, adenomas of the nasal cavity, and hemangiosarcomas of the circulatory system in males and females; mesotheliomas of the tunica vaginalis and adenomatous polyps of the nasal cavity in males; and fibroadenomas of the mammary gland and alveolar/bronchiolar adenomas and carcinomas (combined) in females. 1,2-Dibromoethane was carcinogenic for B6C3F1 mice, causing alveolar/bronchiolar carcinomas and alveolar/bronchiolar adenomas in males and females; and hemangiosarcomas of the circulatory system, fibrosarcomas in the subcutaneous tissue, carcinomas of the nasal cavity, and adenocarcinomas of the mammary gland in females.
Under the conditions of this bioassay, 1,2-dibromo-3-chloropropane was carcinogenic for male and female F344 rats, causing nasal cavity tumors and tumors of the tongue in both sexes, and cortical adenomas in the adrenal gland of females. 1,2-Dibromo-3-chloropropane was carcinogenic in male and female B6C3F1 mice, inducing nasal cavity tumors and lung tumors.
Reported incidences of prostate cancer and masculinization of animals indicate a release of compounds with androgenic properties into the environment. Large numbers of environmental pollutants have been screened to identify such compounds; however, not until recently was 1,2-dibromo-4-(1,2-dibromoethyl)cyclohexane (TBECH) identified as the first potent activator of the human androgen receptor (hAR). TBECH has been found in beluga whales and bird eggs and has also been found to be maternally transferred in zebrafish.
In the present study we investigated interaction energies between TBECH diastereomers (alpha, beta, gamma, and delta) and the hAR, and their ability to activate the receptor and induce prostate-specific antigen (PSA) expression in vitro.
We performed computational modeling to determine interaction energies between the ligand and the AR ligand-binding site, and measured in vitro competitive binding assays for AR by polarization fluorometry analysis. We used enzyme-linked immunosorbent assays to determine PSA activity in LNCaP and HepG2 cells.
We found the gamma and delta diastereomers to be more potent activators of hAR than the alpha and beta diastereomers, which was confirmed in receptor binding studies. All TBECH diastereomers induced PSA expression in LNCaP cells even though the AR present in these cells is mutated (T877A). Modeling studies of LNCaP AR revealed that TBECH diastereomers bound to the receptor with a closer distance to the key amino acids in the ligand-binding domain, indicating stronger binding to the mutated receptor.
The present study demonstrates the ability of TBECH to activate the hAR, indicating that it is a potential endocrine disruptor.
When cells or DNA is exposed to ionizing radiation, the radicals produced in the irradiated sample will modify the base-pair region of the double strands. Effects of 1,2-dihydroxy-9,10-anthraquinone (DHA) and its Cu(II) complex on the radiation-induced modification of double-strands in calf thymus DNA were studied using ethidium bromide as a fluorescent probe. Our results show that the Cu(II)-DHA complex is more efficient in modifying the base-pair region in double-stranded DNA compared to free DHA.
Stromal cells from DBA/2 mouse bone marrow have been shown to be susceptible to cytotoxicity induced by several redox-active metabolites of benzene, including hydroquinone (HQ). Treatment with HQ also alters the composition of stromal cell populations by preferentially killing stromal macrophages compared to stromal fibroblasts. This cytotoxicity can be prevented by 1,2-dithiole-3-thione (DTT) as a result of the induction of quinone reductase (QR), a quinone-processing enzyme, and glutathione. The inductive activities of DTT protected stromal cells against HQ-induced cytotoxicity and against HQ-induced impairment of stromal cell ability to support myelopoiesis. In vivo feeding of DTT to DBA/2 mice increased QR activity within the bone marrow compartment and protected bone marrow stromal cells isolated from the DTT-fed animals from ex vivo HQ challenge. Thus, the inducibility of cellular defense mechanisms and xenobiotic-processing enzymes by chemoprotective agents such as DTT may be a useful strategy for protecting against chemically induced bone marrow toxicities.
3-Amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) and 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole (Glu-P-1) are potent mutagen/carcinogens isolated from pyrolyzates of tryptophan and glutamic acid, respectively, and they have been found to exist in many cooked foods. Trp-P-2 and Glu-P-1 bind to DNA covalently after metabolic activations. The compounds are oxidized to the corresponding hydroxylamines (N-OH-Trp-P-2 and N-OH-Glu-P-1) by microsomes. N-OH-Trp-P-2 and N-OH-Glu-P-1 are the proximate forms of Trp-P-2 and Glu-P-1, respectively. They are further activated by cytosol to the O-acyl derivatives, which bind covalently with DNA. The structures of the modified nucleic acid bases were identified as 3-(C8-guanyl)amino-1-methyl-5H-pyrido[4,3-b]indole (Gua-Trp-P-2) and 2-(C8-guanyl)amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole (Gua-Glu-P-1). These initial events caused by Trp-P-2 and Glu-P-1 were established chemically, both in vitro and in vivo.
2-Amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole (Glu-P-1) binds covalently to DNA after metabolic activation to give 2-(C8-guanyl)amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole (Gua-Glu-P-1). The importance of the intercalative ability of the Glu-P-1 skeleton into DNA base pairs for this reaction is emphasized. The reactive form of Glu-P-1, N-acetoxy-Glu-P-1 (N-OAc-Glu-P-1), reacts preferentially at the C8 position of guanine residues in G-C-rich regions of DNA.
Studies were conducted on inhalation pharmacokinetics of 1,3-butadiene and of its primary reactive metabolic intermediate 1,2-epoxybutene-3 in rats (Sprague-Dawley) and mice (B6C3F1). Investigations of inhalation pharmacokinetics of 1,3-butadiene revealed saturation kinetics of 1,3-butadiene metabolism in both species. For rats and mice linear pharmacokinetics apply at exposure concentrations below 1000 ppm 1,3-butadiene; saturation of 1,3-butadiene metabolism is observed at atmospheric concentrations of about 2000 ppm. The estimated maximal metabolic elimination rates were 400 mumole/hr/kg for mice and 200 mumole/hr/kg for rats. This shows that 1,3-butadiene is metabolized by mice at about twice the rate of rats. Investigations of inhalation pharmacokinetics of 1,2-epoxybutene-3 revealed major differences in metabolism of this compound between both species. No indication of saturation kinetics of 1,2-epoxybutene-3 metabolism could be observed in rats up to exposure concentrations of 5000 ppm, whereas in mice the saturation of epoxybutene metabolism became apparent at atmospheric concentrations of about 500 ppm. The estimated maximal metabolic rate for 1,2-epoxybutene-3 was 350 mumole/hr/kg in mice and greater than 2600 mumole/hr/kg in rats. When the animals are exposed to high concentrations of 1,3-butadiene, 1,2-epoxybutene-3 is exhaled by rats and mice. For rats 1,2-epoxybutene-3 concentration in the gas phase of the system reaches a plateau at about 4 ppm. For mice, 1,2-epoxybutene-3 concentration increases with exposure time until, at about 10 ppm, signs of acute toxicity are observed. Under these conditions hepatic nonprotein sulfhydryl compounds are virtually depleted in mice but not in rats.(ABSTRACT TRUNCATED AT 250 WORDS)
We treated pregnant rats with 1 microg/kg body weight/day 1,2,3,4,6,7-hexachlorinated naphthalene (1,2,3,4,6,7-HxCN) on days 14-16 of gestation and examined the effects on the reproductive systems of their male offspring at various phases of sexual maturation. Sperm count in the cauda epididymidis did not change in 1,2,3,4,6, 7-HxCN-treated rats on postnatal day 89, the age of sexual maturity, but the sperm count in the cauda epididymidis did increase to approximately 180% of the control value on postnatal day 62. In addition, homogenization-resistant testicular spermatids increased to approximately 160% of the control value on postnatal day 48, and the percent of postmeiotic tubules increased to approximately 190% of the control value on postnatal day 31 in this group. These results indicate that the onset of spermatogenesis was accelerated in the 1,2,3,4,6,7-HxCN rats. Serum concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) had already reached the maximum level on postnatal day 31 in the 1,2,3,4,6, 7-HxCN group, suggesting that the onset of LH and FSH secretions from the pituitary gland was also accelerated and that this endocrine disruption was the cause of early onset of spermatogenesis in this group. In the fat of 1,2,3,4,6,7-HxCN-treated dams, 5.75+/-2.81 ppb 1,2,3,4,6,7-HxCN was detected when offspring were weaned. This concentration was 5-10 times higher than that found in human adipose tissue.
Although benzene is known to be myelotoxic and to cause myeloid leukemia in humans, the mechanism has not been elucidated.
We focused on 1,2,4-benzenetriol (BT), a benzene metabolite that generates reactive oxygen species (ROS) by autoxidation, to investigate the toxicity of benzene leading to leukemogenesis.
After exposing HL-60 human myeloid cells to BT, we investigated the cellular effects, including apoptosis, ROS generation, DNA damage, and protein damage. We also investigated how the cellular effects of BT were modified by hydrogen peroxide (H2O2) scavenger catalase, hypochlorous acid (HOCl) scavenger methionine, and 4-aminobenzoic acid hydrazide (ABAH), a myeloperoxidase (MPO)-specific inhibitor.
BT increased the levels of apoptosis and ROS, including superoxide (O2•-), H2O2, HOCl, and the hydroxyl radical (•OH). Catalase, ABAH, and methionine each inhibited the increased apoptosis caused by BT, and catalase and ABAH inhibited increases in HOCl and •OH. Although BT exposure increased halogenated DNA, this increase was inhibited by catalase, methionine, and ABAH. BT exposure also increased the amount of halogenated tyrosines; however, it did not increase 8-oxo-deoxyguanosine.
We suggest that BT increases H2O2 intracellularly; this H2O2 is metabolized to HOCl by MPO, and this HOCl results in possibly cytotoxic binding of chlorine to DNA. Because myeloid cells copiously express MPO and because halogenated DNA may induce both genetic and epigenetic changes that contribute to carcinogenesis, halogenative stress may account for benzene-induced bone marrow disorders and myeloid leukemia.
This paper describes a physiologically based toxicokinetic model for 1,3-butadiene uptake, distribution, and metabolic clearance in mice. Model parameters for metabolic activity were estimated from the correspondence between computer simulation studies and experimental results as published in the literature. The parameterized model was validated with independent literature data. With the resulting model, the relative importance of lung metabolism as compared to metabolism in the liver increased with decreasing ambient air concentrations. This was due to saturation of metabolism in the alveolar area of the lung, which occurred in the simulations at ambient air concentrations well below current threshold limit values. At higher air concentration, liver metabolism became relatively more important. The tendency toward increased importance of lung metabolism at low doses indicates the necessity of careful extrapolation of in vivo results to low doses. Moreover, this trend may also contribute to species difference in susceptibility to the carcinogenic activity of butadiene.
Researchers from the National Institute for Occupational Safety and Health (NIOSH) conducted an extent-of-exposure study of the 1,3-butadiene monomer, polymer, and end-user industries to determine the size of the exposed workforce, evaluate control technologies and personal protective equipment programs, and assess occupational exposure to 1,3-butadiene. A new analytical method was developed for 1,3-butadiene that increased the sensitivity and selectivity of the previous NIOSH method. The new method is sensitive to 0.2 microgram per 1,3-butadiene sample. Walk-through surveys were conducted in 11 monomer, 17 polymer, and 2 end-user plants. In-depth industrial hygiene surveys were conducted at 4 monomer, 5 polymer, and 2 end-user plants. Airborne exposure concentrations of 1,3-butadiene were determined using personal sampling for each job category. A total of 692 full shift and short-term personnel and 259 area air samples were examined for the presence of 1,3-butadiene. Sample results indicated that all worker exposures were well below the current OSHA PEL of 1000 ppm. Exposures ranged from less than 0.006 ppm to 374 ppm. The average exposure for all samples was less than 2 ppm. The present American Conference of Governmental Industrial Hygienists (ACGIH) threshold limit value for 1,3-butadiene is 10 ppm. To reduce the potential for occupational exposure, it is recommended that quality control sampling be conducted using a closed loop system. Also all process pumps should be retrofitted with dual mechanical seals, magnetic gauges should be used in loading and unloading rail cars, and engineering controls should be designed for safely voiding quality control cylinders.
Sources of industrial emissions of 1,3-butadiene are discussed both by process (production, consumers) and type (equipment leaks, point sources). Quantification of the emissions are presented, as reported by the U.S. Environmental Protection Agency in 1986. The reported emissions attributed to equipment leaks (also known as fugitive emissions) range from about 50 to 95% of the total, depending on the specific production process used. The methods by which these emissions were estimated are discussed, with particular emphasis on the fugitive sources. Industry studies to better quantify the fugitive emissions are described.
Studies were conducted to determine the cytotoxic and cytogenetic effects of 1,3-butadiene and two structural analogs, chloroprene and isoprene, in the bone marrow cells of B6C3F1 mice exposed to the chemicals by inhalation. In one study, animals were exposed to 1,3-butadiene concentrations of 6.25, 62.5, or 625 ppm 6 hr/day on 10 exposure days and in the second study, to the same concentrations on weekdays for 13 weeks. Chloroprene and isoprene treatments involved 6 hr/day exposures on 12 exposure days at concentrations of 0, 12, 32, 80, and 200 ppm for chloroprene and 0, 438, 1750, and 7000 ppm for isoprene. In the 10-day study, 1,3-butadiene induced significant increases in sister chromatid exchange (SCE) at 6.25 ppm, micronuclei at 62.5 ppm, and chromosomal aberrations at 625 ppm. In the 13-week study, the frequency of micronucleated normochromatic erythrocytes in the peripheral blood was significantly elevated in all exposure groups including the 6.25-ppm group. Isoprene induced both SCE and micronuclei, whereas chloroprene gave negative results for all cytogenetic end points assessed in bone marrow cells.
The 1990 Clean Air Act Amendments list several volatile organic chemicals as hazardous air pollutants, including ethylene oxide, butadiene, styrene, and acrylonitrile. The toxicology of many of these compounds shares several common elements such as carcinogenicity in laboratory animals, genotoxicity of the epoxide intermediates, involvement of cytochrome P450 for metabolic activation (except ethylene oxide), and involvement of at least two enzymes for detoxication of the epoxides (e.g., hydrolysis or conjugation with glutathione). These similarities facilitate research strategies for identifying and developing biomarkers of exposure. This article reviews the current knowledge about biomarkers of butadiene. Butadiene is carcinogenic in mice and rats, which raises concern for potential carcinogenicity in humans. Butadiene is metabolized to DNA-reactive metabolites, including 1,2-epoxy-3-butene and diepoxybutane. These epoxides are thought to play a critical role in butadiene carcinogenicity. Butadiene and some of its metabolites (e.g., epoxybutene) are volatile. Exhalation of unchanged butadiene and excretion of butadiene metabolites in urine represent major routes of elimination. Therefore, biomonitoring of butadiene exposure could be based on chemical analysis of butadiene in exhaled breath, blood levels of butadiene epoxides, excretion of butadiene metabolites in urine, or adducts of butadiene epoxides with DNA or blood proteins. Mutation induction in specific genes (e.g., HPRT) following butadiene exposure can be potentially used as a biomarker. Excretion of 1,2-dihydroxy-4-(N-acetylcysteinyl-S)butane or the product of epoxybutene with N-7 in guanine in urine, epoxybutene-hemoglobin adducts, and HPRT mutation have been used as biomarkers in recent studies of occupational exposure to butadiene. Data in laboratory animals suggest that diepoxybutane may be a more important genotoxic metabolite than epoxybutene. Biomonitoring methods need to be developed for diepoxybutane and other putative reactive butadiene metabolites. With butadiene and related compounds, the ultimate challenge is to identify useful biomarkers of exposure in which quantitative linkages between exposure and internal dose of the important DNA-reactive metabolites are established.
1,3-Butadiene and two major genotoxic metabolites 3,4-epoxybutene (EB) and 1,2:3,4-diepoxybutane (DEB) were used as model compounds to determine if genetic toxicity findings in animal and human cells can aid in extrapolating animal toxicity data to man. Sister chromatid exchange (SCE) and micronucleus induction results indicated 1,3-butadiene was genotoxic in the bone marrow of the mouse but not the rat. This paralleled the chronic bioassays which showed mice to be more susceptible than rats to 1,3-butadiene carcinogenicity. However, 1,3-butadiene did not induce unscheduled DNA synthesis (UDS) in the rat or mouse hepatocytes following in vivo exposure. Likewise, UDS in rat and mouse hepatocytes in vitro was not induced by EB or DEB. Salmonella typhimurium gene mutation (Ames) tests of 1,3-butadiene using strains TA1535, TA97, TA98, and TA100 and employing rat, mouse, and human liver S9 metabolic systems were barely 2-fold above background only in strain TA1535 at 30% 1,3-butadiene in air with induced and uninduced rat S9 and mouse S9 (uninduced). 1,3-Butadiene was negative in in vitro SCE studies in human whole blood lymphocytes cultures treated in the presence of rat, mouse, or human liver S9 metabolic activation. In general, 1,3-butadiene is genotoxic in vivo but is a weak in vitro genotoxin.
Positive carcinogenicity studies in mice and rats have led to concerns that 1,3-butadiene may be carcinogenic in humans under exposure conditions that have existed in occupational settings and perhaps exist today. The principal settings of interest are the styrene-butadiene rubber (SBR) manufacturing industry, which uses large quantities of 1,3-butadiene, and the 1,3-butadiene monomer industry. The potential for 1,3-butadiene exposure is highest during monomer transfer operations and is lowest in finishing areas of polymerization plants where the polymer products are processed. Three large cohort mortality studies have been conducted in the SBR and monomer producing industries since 1980. These studies, which examined the mortality experience of over 17,000 men employed in one monomer and 10 SBR facilities, are the subject of this review. All but one of the facilities began operations during the early 1940s. The mortality experience observed within these employee cohorts is comparable to that seen in other long-term studies of men employed in the petroleum, chemical, and rubber industries for all causes of death, total malignant neoplasms, and for the specific cancers seen in excess in the toxicologic studies. This paper discusses discrepant findings observed in more detailed analyses within individual cohorts and among employment subgroups, as well as selected limitations of the particular studies. Additional efforts to refine 1,3-butadiene exposure categories are needed. Within the context of sample size limitations inherent in these studies, there is currently inadequate evidence to establish a relationship between cancer mortality outcomes and 1.3-butadiene exposure in humans.
The petroleum-derived substance 1,3-butadiene is a known human carcinogen that is a significant contributor to cancer risk in the United States. There is evidence it causes liver, heart, lung, and hematopoietic cancers in rodents through genetic damage. But some researchers suspect it also may induce changes through other pathways, including epigenetic alterations, which occur when the function of a gene is altered while its DNA sequence remains stable. A new study provides further evidence 1,3-butadiene may indeed cause epigenetic damage [EHP 119(5):635–640; Koturbash et al.].
The authors exposed male C57BL/6J mice to inhaled 1,3-butadiene at two doses, 6.25 ppm and 625 ppm, for 2 weeks (6 hours per day, 5 days per week). The low dose is about 10–100 times higher than typical occupational and ambient exposures, respectively, while the inhalation pathway is considered the most common for human exposure. In the 5 mice exposed at each dose, the researchers found numerous dose-dependent alterations in genes linked with liver function. Compared with controls, mice in the low-dose group had 1 gene with a more than 2-fold increase in expression and 5 with a more than 2-fold decrease in expression. Mice in the high-dose group had 4 genes with a more than 2-fold increase in expression and 13 with a more than 2-fold decrease in expression. The high-dose mice also had a small but significant decrease in body weight.
The authors also found evidence of epigenetic changes that were consistent with altered gene expression in the liver. Changes in the attachment of methyl groups to DNA are a useful marker of epigenetic changes, and the researchers observed significant decreases in 5 markers of methylation in the high-dose group and smaller decreases in 4 of the 5 markers in the low-dose group. High-dose mice also had a roughly 50% decrease in another methylation indicator.
Changes in histones, proteins that help regulate gene expression, also occurred in the high-dose mice, with significant decreases in methylation based on 3 biomarkers. Expression of proteins involved in DNA methylation and histone methylation decreased while expression of a protein involved in histone demethylation increased, consistent with the observed decreases in DNA and histone methylation.
These findings fit with earlier research into epigenetic effects of other substances and are consistent with other mechanistic evidence of how such damage can play a role in the onset of various adverse health effects, the authors say. If additional studies—including studies of female mice, other mouse strains, and other animals—repeat these findings, this would indicate multiple modes of carcinogenicity for 1,3-butadiene and could lead to establishment of specific biomarkers for epigenetic damage that could be used in future toxicity and exposure assessments.
Previous studies have revealed marked differences in the incidence of leukemia between rats and mice exposed to 1,3-butadiene that do not appear to be readily explained on the basis of pharmacokinetics or metabolism. Chronic exposure to 1,3-butadiene results in a high incidence of thymic lymphoma in B6C3F1 mice that is not observed in Sprague-Dawley rats. Studies at the Chemical Industry Institute of Toxicology have focused on evaluating the potential of endogenous ecotropic retroviral background to influence susceptibility to 1,3-butadiene leukemogenesis. These studies have compared the pathogenesis and incidence of thymic lymphoma between B6C3F1 and NIH Swiss mice. Proviral ecotropic sequences are truncated in the NIH Swiss mouse, and the virus is not expressed. Chronic exposure to 1,3-butadiene (1250 ppm) for up to 1 year resulted in a fourfold difference in the incidence of thymic lymphoma between B6C3F1 and NIH Swiss mice. These results provide presumptive evidence for retrovirus involvement since NIH Swiss mice lack ecotropic viruses and appear to be relatively resistant to induction of lymphoma by 1,3-butadiene. Other explanations appear to be less likely in light of the fact that target organ toxicity has been determined to be virtually identical between the two strains during the preleukemic phase of 1,3-butadiene exposure.
In previous attempts to model disposition of 1,3-butadiene in mice and rats, parameter values for 1,2-epoxybut-3-ene metabolism were optimized to reproduce elimination of this gas from closed chambers. However, each of these models predicted much higher concentrations of circulating epoxybutene than were subsequently measured in animals exposed to butadiene. To account for this discrepancy, a previous physiologically based pharmacokinetic model of butadiene disposition was modified to describe a transient complex between cytochrome P450 and epoxide hydrolase on the endoplasmic reticulum membrane. In this model the epoxide products are directly transferred from the P450 to the epoxide hydrolase in competition with release of products into the cytosol. The model includes flow-restricted delivery of butadiene and epoxides to gastrointestinal tract, liver, lung, kidney, fat, other rapidly perfused tissues, and other slowly perfused tissues. Blood was distributed among compartments for arterial, venous, and capillary spaces. Oxidation of butadiene and epoxybutene and hydrolysis and glutathione conjugation of epoxides were included in liver, lung, and kidney. The model reproduces observed uptake of butadiene and epoxybutene from closed chambers by mice and rats and steady-state concentrations of butadiene, epoxybutene, and 1,2;3,4-diepoxybutane concentrations in blood of mice and rats exposed by nose only. Successful replication of these observations indicates that the proposed privileged access of epoxides formed in situ to epoxide hydrolase is a plausible mechanistic representation for the metabolic clearance of epoxide-forming chemicals.
1,3-Butadiene (BD) is a high-volume industrial chemical and a known human carcinogen. The main mode of BD carcinogenicity is thought to involve formation of genotoxic epoxides.
In this study we tested the hypothesis that BD may be epigenotoxic (i.e., cause changes in DNA and histone methylation) and explored the possible molecular mechanisms for the epigenetic changes.
We administered BD (6.25 and 625 ppm) to C57BL/6J male mice by inhalation for 2 weeks (6 hr/day, 5 days a week) and then examined liver tissue from these mice for signs of toxicity using histopathology and gene expression analyses. We observed no changes in mice exposed to 6.25 ppm BD, but glycogen depletion and dysregulation of hepatotoxicity biomarker genes were observed in mice exposed to 625 ppm BD. We detected N-7-(2,3,4-trihydroxybut-1-yl)guanine (THB-Gua) adducts in liver DNA of exposed mice in a dose-responsive manner, and also observed extensive alterations in the cellular epigenome in the liver, including demethylation of global DNA and repetitive elements and a decrease in histone H3 and H4 lysine methylation. In addition, we observed down-regulation of DNA methyltransferase 1 (Dnmt1) and suppressor of variegation 3-9 homolog 1, a histone lysine methyltransferase (Suv39h1), and up-regulation of the histone demethylase Jumonji domain 2 (Jmjd2a), proteins responsible for the accurate maintenance of the epigenetic marks. Although the epigenetic effects were most pronounced in the 625-ppm exposure group, some effects were evident in mice exposed to 6.25 ppm BD.
This study demonstrates that exposure to BD leads to epigenetic alterations in the liver, which may be important contributors to the mode of BD carcinogenicity.
Adverse health effects of airborne toxicants, especially small respirable particles and their associated adsorbed chemicals, are of growing concern to health professionals, governmental agencies, and the general public. Areas rich in petrochemical processing facilities (e.g., eastern Texas and southern California) chronically have poor air quality. Atmospheric releases of products of incomplete combustion (e.g., soot) from these facilities are not subject to rigorous regulatory enforcement. Although soot can include respirable particles and carcinogens, the toxicologic and epidemiologic consequences of exposure to environmentally relevant complex soots have not been well investigated. Here we continue our physico-chemical analysis of butadiene soot and report effects of exposure to this soot on putative targets, normal human bronchial epithelial (NHBE) cells. We examined organic extracts of butadiene soot by gas chromatography–mass spectrometry (GC–MS), probe distillation MS, and liquid chromatography (LC)–MS–MS. Hundreds of aromatic hydrocarbons and polycyclic aromatic hydrocarbons with molecular mass as high as 1,000 atomic mass units were detected, including known and suspected human carcinogens (e.g., benzo(a)pyrene). Butadiene soot particles also had strong, solid-state free-radical character in electron spin resonance analysis. Spin-trapping studies indicated that fresh butadiene soot in a
To date, epidemiologic research on 1,3-butadiene has consisted of cohort mortality studies of workers in the styrene-butadiene rubber (SBR) and butadiene monomer industries. These studies have been extremely useful both in defining the focus on human health effects to the lymphopoietic cancers and in providing a perspective on which to evaluate the available animal models for human risk assessment. The next step for epidemiologic research will involve a lymphopoietic cancer case control approach to enable a more precise assessment of whether there is a relationship between 1,3-butadiene exposure and lymphopoietic cancer. In addition, periodic mortality updates of the 1,3-butadiene-exposed worker cohorts will be important to monitor trends in lymphopoietic cancer rates and to ensure that other cancers with long latency do not begin to show elevated rates. This paper describes an industry-sponsored program of case-control and cohort mortality update studies along with the critical elements in research design and analysis for each study. Epidemiological studies will play an important role in testing hypotheses developed from toxicological studies about potential biological mechanisms of 1,3-butadiene carcinogenesis in humans.
A review of the toxicity of 1,3-dichlorobutene-2 (1,3-DCB), 1,4-dichlorobutene-2 (1,4-dcb), and 2-chlorobutadiene, 1,3 (beta-chloroprene) was undertaken with an emphasis on assessing the hazards of these materials in the industrial situation. 1,3-DCB is a by-product of beta-chloroprene from the acetylene route, with 1,4-DCB is an intermediate in the production of beta-chloroprene from the butadiene route, the production route used in the U.S. Presented in the review is a summary of the acute toxicity including mutagen testing, skin, eye, and inhalation testing of these compounds. In addition, subacute inhalation testing, embryotoxicity, teratogenicity, and carcinogenicity are also reviewed where the information is available.
In this paper we report DNA binding of butadiene monoepoxide, a first metabolite of 1,3-butadiene catalyzed by monooxygenases. We prepared alkylated purines as marker compounds for 32-P-postlabeling and electrochemical analysis and developed methods to measure the corresponding products. The traditional postlabeling assay was modified by incorporating a solid phase extraction column and high-performance liquid chromatography (HPLC) enrichment steps to the assay prior to labeling. The final analysis of adducted N6 adenines is based on two dimensional thin-layer chromatography (TLC) and an on-line HPLC/radioactivity analysis. The qualitative and quantitative results are based on positively identified marker compounds. Alkylated N7 guanines were released from DNA by neutral thermal hydrolysis, prepurified by HPLC, and analyzed by HPLC with a sensitive electrochemical detection procedure. By using these methods, we found alkylation of calf thymus DNA exposed to butadiene monoepoxide in vitro at adenine N6 and guanine N7 sites. Analysis of lung DNA samples from mice and rats exposed to butadiene through inhalation showed that adenine N6 adducts were formed in vivo in a dose responsive manner.
A series of studies to further evaluate the developmental and reproductive toxicity of inhaled 1,3-butadiene was sponsored by the National Toxicology Program. Pregnant Sprague-Dawley rats (24-28/group) and Swiss (CD-1) mice (18-22/group) were exposed to atmospheric concentrations of 0, 40, 200, or 1000 ppm 1,3-butadiene for 6 hr/day on days 6 through 15 of gestation (dg) and killed on dg 18 (mice) or dg 20 (rats). Subsequently, the uterine contents were evaluated; individual fetal body weights were recorded; and external, visceral, and skeletal examinations were performed. In rats, maternal toxicity was observed in the 1000-ppm group in the form of reduced extragestational weight gain and, during the first week of treatment, decreased body weight gain. Under these conditions, there was no evidence of developmental toxicity in rats. In contrast, results of the mouse developmental toxicity study indicated that the fetus may be more susceptible than the dam to inhaled 1,3-butadiene. Maternal toxicity was observed in mice at the 200- and 1000-ppm 1,3-butadiene exposure levels, whereas 40 ppm and higher concentrations of 1,3-butadiene caused significant exposure-related reductions in the mean body weights of male fetuses. Mean body weights of female fetuses were also reduced at the 200- and 1000-ppm exposure levels. No increased incidence of malformations was observed in either study. Other studies addressing male reproductive and mutagenesis end points were performed with B6C3F1 mice (sperm-head morphology) and Swiss (CD-1) mice (dominant lethal study).(ABSTRACT TRUNCATED AT 250 WORDS)
The International Agency for Research on Cancer has given the designations of "sufficient evidence" of carcinogenicity of 1,3-butadiene in experimental animals and "limited evidence" of carcinogenicity in humans. To investigate the carcinogenic effect in humans, we conducted a cohort mortality study among 364 men who were assigned to any of three 1,3-butadiene production units located within several chemical plants in the Kanawha Valley of West Virginia, including 277 men employed in a U.S. Rubber Reserve Plant which operated during World War II. The butadiene production units included in this study were selected from an index developed by the Union Carbide Corporation, which listed for each chemical production unit within their South Charleston, West Virginia and Institute, West Virginia, plants all products, by-products, and reactants. Departments included in the study were those where butadiene was a primary product and neither benzene nor ethylene oxide was present. A total of 185 deaths were observed; the standardized mortality ratio (SMR) for all causes of death was 91, reflecting lower mortality among the study population than the U.S. population. The study found a significantly elevated standardized mortality ratio (SMR) for lymphosarcoma and reticulosarcoma based on four observed cases (SMR = 577; 95% CI = 157-1480), which persisted in an analysis using county referent rates. An excess of lymphosarcoma and reticulosarcoma among all workers and among workers with routine exposure to 1,3-butadiene was also observed in the only other cohort of 1,3-butadiene production workers previously studied.(ABSTRACT TRUNCATED AT 250 WORDS)
1,3-Butadiene (BD), a suspected human carcinogen, is used as the raw material in industries to make synthetic butyl rubber and plastics. Simulation models using experimental animal data have shown that physiologic factors play an important role in the kinetic behavior of BD. However, human data are limited. The aim of this inhalation study was to identify influential human physiologic factors in the respiratory uptake of BD. We recruited 133 healthy volunteers in Boston, Massachusetts, into this study and tested them under an approved human subjects protocol. Each subject was exposed to 2 ppm (4.42 mg/m3) BD for 20 min, followed by purified air for another 40 min. Five exhaled breath samples collected during exposure were used to determine the respiratory uptake of BD, which was defined as absorbed BD (micrograms) per kilogram of body weight during exposure. Although subjects were given identical administered doses (40 ppm x min), there was a wide range of uptake, 0.6-4.9 microg/kg. Of the studied physiologic factors, the blood:air partition coefficient and alveolar ventilation were most significant in determining the respiratory uptake (p < 0.001 for each). In addition, in the multiple regression analysis, females had significantly higher respiratory uptake of BD than males on a weight basis. For all subjects, increasing age and cigarette smoking led to significantly decreased respiratory uptake of BD. The results of this human study are consistent with previous kinetic simulations and animal studies. The findings also suggest that interindividual variation in human physiologic factors that affect the exposure-internal dose relationship should be considered while also exploring exposure-disease associations in future epidemiologic research.
Examination of a profile of data already existing on 1,3-butadiene shows adequate knowledge in many areas of toxicology that are conventionally required in hazard identification. However, while much progress has been made in areas of metabolism and pharmacokinetics, further studies would be worthwhile to improve mechanistic understanding such as the examination of alternate metabolic pathways, the generation of interspecies scaling factors, and an assessment of the relevance of various tumor sites. In this respect, data pertaining to repeated and pulse exposures of rodents and primates would be helpful. Another important aspect is the need to understand any human health implications of the observed 1,3-butadiene-induction of the murine leukemia virus. In this respect, studies have been pursued that include the comparison of leukemogenesis in congenetic strains, the leukemogenicity of viral isolates in rodent carcinogenicity and human cell culture studies, and the mechanisms of activation of ecotropic proviral sequences. Molecular epidemiological and toxicological research is ongoing in rodents and primates to evaluate hemoglobin adduct formation as an index of 1,3-butadiene exposure. Challenges of specificity, sensitivity, and simplification of current procedures need to be overcome. Recent mutagenicity and metabolism data suggest that structurally-related isoprene may have carcinogenic potential. The use of interstrain comparative studies and data in a second species is discussed, as well as proposed metabolism studies.
1,3-Butadiene (BD), which is used to make styrene-butadiene rubber, is a potent carcinogen in mice and a probable carcinogen, associated with leukemia, in humans. We have previously used HPRT mutation as a biomarker to evaluate exposures to BD in a monomer production plant. We now report on a study of 49 workers in a styrene-butadiene rubber plant in which we used the concentration of the BD metabolite 1,2-dihydroxy-4-(N-acetylcysteinyl-S)-butane (M1) in urine as a biomarker of exposure and the frequency of HPRT variant (mutant) lymphocytes (Vf) as a biomarker of effect. Workers were assigned to high- and low-exposure groups based on historical information about work areas and jobs. Personal exposure to BD for one work shift was measured using a passive badge dosimeter. Each participant provided a urine specimen and blood sample at the end of the work shift and completed a questionnaire providing information on lifestyle, health, and work activities. The average BD exposures in the high- and low-exposure groups were significantly different, even after excluding two extreme values, (high 1.48 ppm; low 0.15 ppm, p < 0.002). This study was done in 1994 and 1995 before the establishment, in 1996, of the new permissible exposure limit of 1 ppm. Both the mean M1 and the HPRT Vf were more than three times greater in the high-exposure group than in the low-exposure group (p < 0.0005). The three end points correlated with each other, with sample correlation coefficients between 0.4 and 0.6. The correlations among BD exposure and the biomarkers of internal exposure and genotoxicity suggest that occupational exposure to BD, in the range of 1-3 ppm, may be associated with adverse biological effects.
1,3-Butadiene, a major ingredient of synthetic rubber, has been shown to be carcinogenic in two animal species. To assess the possible human carcinogenicity of 1,3-butadiene, a critical review was undertaken of the epidemiologic literature. An early retrospective study of 8017 males employed in tire manufacturing found excess mortality for lymphatic and hematopoietic neoplasms in production workers (standardized mortality ratio, SMR = 560); these workers were exposed to 1,3-butadiene as well as to styrene and possibly to benzene. A recently updated epidemiologic study of 2568 workers at a butadiene manufacturing plant in Texas reported low mortality overall (SMR = 84) but found excess deaths for lymphosarcoma and reticulum cell sarcoma (SMR = 229). A retrospective study of workers employed at two synthetic rubber plants in Texas found excess mortality for lymphatic and hematopoietic malignancies in the older of these facilities; the excesses for lymphosarcoma (SMR = 224) and leukemia (SMR = 278) were most significant in wartime workers. A large, recently updated retrospective study of 12,113 workers employed in eight synthetic rubber manufacturing plants in the United States and Canada found excess mortality for lymphatic and hematopoietic cancer in production workers; the SMR for other lymphatic cancers in white production workers was 230, and the SMR for all lymphatic malignancies in black production workers was 507. These updated epidemiologic results strongly suggest an etiologic association between occupational exposure to 1,3-butadiene and human cancer. It is reasonable, therefore, to conclude that there now exists at least limited evidence for the human carcinogenicity of 1,3-butadiene.
Species differences in sensitivity to carcinogenic effects from inhaled 1,3-butadiene might stem, at least in part, from differences in uptake, metabolism, and distribution of 1,3-butadiene. To examine this possibility, rats, mice, and monkeys were exposed to stepped concentrations of 14C-labeled 1,3-butadiene and the chemically related compound, isoprene. Respiratory data were collected during exposure and were used to determine fractional uptake. Rates and routes of excretion of retained radioactivity were also determined and blood levels of potentially toxic metabolites were measured. In some cases, the concentrations of hemoglobin adducts were determined. For rodents, the tissue distribution of metabolites was examined. Some results from these continuing studies to date are: a) mice achieve higher blood concentrations of reactive metabolites than do rats; b) blood levels of toxic metabolites are lower in monkeys than in rodents; c) uptake and retention of 1,3-butadiene is nonlinear in the range where long-term toxicity studies have been conducted; d) the efficiency of production of reactive metabolites decreases with increased inhaled concentrations of 1,3-butadiene; e) repeated exposure to 1,3-butadiene does not induce the metabolism of 1,3-butadiene in rodents; f) hemoglobin adducts of 1,3-butadiene are potential dosimeters of exposure; and g) rats inhaling isoprene produce reactive metabolites analogous to those produced during inhalation of 1,3-butadiene. The available data indicate that major differences in the biological fate of inhaled 1,3-butadiene occur among species, and these differences, at least in part, account for those in species sensitivity to the toxicity of inhaled 1,3-butadiene.