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PubMed1990

Occupational exposure of workers to 1,3-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.

Air Pollutants, Occupational↗
PubMed1990

Assessment of 1,3-butadiene epidemiology studies.

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.

Butadienes↗
PubMed1990

Morphology of neoplastic lesions induced by 1,3-butadiene in B6C3F1 mice.

1,3-Butadiene (CAS No. 106-99-0) was studied for potential carcinogenicity and chronic toxicity by inhalation in B6C3F1 mice. Groups of 50 mice of each sex were exposed to 0, 625, or 1250 ppm 1,3-butadiene for 6 hr/day, 5 days/week for 60 weeks (male) or 61 weeks (female). The study was scheduled for 104 weeks of exposure but was terminated early because of reduced survival related to induction of a variety of tumors in 1,3-butadiene-exposed mice. A second chronic inhalation study was conducted in which male and female mice were exposed to 0, 6.25, 20, 62.5, 200, or 625 ppm for up to 2 years. Additional groups of 50 male mice were exposed to 625 ppm for 13 or 26 weeks, 312 ppm for 52 weeks, or 200 ppm for 40 weeks, then held without exposure until scheduled sacrifice 104 weeks after initial exposure. 1,3-Butadiene-exposed mice from both studies had increased incidences of malignant lymphomas that were observed as early as week 20 in the first study and week 23 in the second study. The lymphomas were primarily lymphocytic and originated in the thymus, although generalized lymphoma was often present. Exposed mice in both studies developed cardiac hemangiosarcomas that were observed as early as week 32 in the first study and week 41 in the second study. Also present were foci of endothelial hyperplasia in the myocardium that were regarded as early evidence of developing hemangiosarcoma. Alveolar epithelial hyperplasia, alveolar/bronchiolar adenomas and alveolar/bronchiolar carcinomas represented the spectrum of proliferative lung lesions induced by exposure to 1,3-butadiene in both studies. Exposure-related proliferative forestomach lesions observed in both studies included epithelial hyperplasia, squamous cell papillomas, and squamous cell carcinomas. 1,3-Butadiene-exposed female mice in both studies developed mammary gland neoplasms at increased incidences. Most of the mammary tumors were pleomorphic adenocarcinomas, but several adenoacanthomas were also seen. Granulosa cell tumors of the ovary were exposure-related neoplasms in both studies. Occasionally the granulosa cell tumors were malignant as evidenced by vascular invasion or pulmonary metastasis. Although there was an increased incidence of hepatocellular neoplasms in exposed females in the first study, by week 65 of the second study there was not evidence of a clear response of liver neoplasms. The preliminary results of the second study indicate there was induction of tumors similar to those seen in the first study but occurring in response to lower concentrations of 1,3-butadiene.

Animals↗
PubMed1990

Inhalation pharmacokinetics of 1,3-butadiene and 1,2-epoxybutene-3 in rats and mice.

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)

Administration, Inhalation↗
PubMed1993

Carcinogenicity of 1,3-butadiene.

1,3-Butadiene, a high-production volume chemical used largely in the manufacture of synthetic rubber, is a multiple organ carcinogen in rats and mice. In inhalation studies conducted in mice by the National Toxicology Program, high rates of early lethal lymphomas occurring at exposure levels of 625 ppm or higher reduced the development and expression of later developing tumors at other sites. Use of survival-adjusted tumor rates to account for competing risk factors provided a clearer indication of the dose responses for 1,3-butadiene-induced neoplasms. An increase in lung tumors in female mice was observed at exposure concentrations as low as 6.25 ppm, the lowest concentration ever used in a long-term carcinogenicity study of this gas. Human exposures to 1,3-butadiene by workers employed at facilities that produce this chemical and at facilities that produce styrene-butadiene rubber have been measured at levels higher than those that cause cancer in animals. Furthermore, epidemiology studies have consistently revealed associations between occupational exposure to 1,3-butadiene and excess mortality due to lymphatic and hematopoietic cancers. In response to the carcinogenicity findings for 1,3-butadiene in animals and in humans, the Occupational Safety and Health Administration has proposed lowering the occupational exposure standard for this chemical from 1000 ppm to 2 ppm. Future work is needed to understand the mechanisms of tumor induction by 1,3-butadiene; however, the pursuit of this research should not delay the reduction of human exposure to this chemical.

Air Pollutants, Occupational↗
PubMed2006

Estimating ambient concentration and cancer risk for 1,3-butadiene in Japan.

A detailed assessment of 1,3-butadiene exposure was performed for the purpose of risk assessment in Japan. The concentration of 1,3-butadiene and the 1,3-butadiene-exposure-related lifetime excess cancer risk in the general environment and in the vicinity of industrial point sources were estimated using two different types of diffusion models: the National Institute of Advanced Industrial Science and Technology-atmospheric dispersion model for exposure and risk assessment (AIST-ADMER) model ver. 1.0 for the estimation of regional scale concentrations and the Ministry of Economy, Trade and Industry - low rise industrial source dispersion (METI-LIS) model ver. 2.01 for the estimation of local concentrations near industrial sources. The calculated results indicate that the annual mean concentrations of 1,3-butadiene in residential areas are generally less than 0.5 microg/m(3), but in a few area near industrial point sources they exceed 1.7 microg/m(3), corresponding to a lifetime excess cancer risk of 10(-5). Using data on exposure concentrations and cancer unit risk, the lifetime excess cancer risk for persons exposed to 1,3-butadiene in Japan was evaluated. The results indicate that an extremely small number of people have a risk of developing 1,3-butadiene-exposure-related cancer that is greater than 10(-5), while that of most of the population in Japan is between 10(-5) and 10(-6). The total 1,3-butadiene-exposure-related cancer risk in Japan was calculated as 2.0 cases/year. A large proportion of the cancer risk was associated with general environmental areas. However, the individual risks of the population living in the vicinity of industrial point sources were significantly higher than those of the population living in the general environment.

Air Pollutants↗
PubMed1991

[Genotoxic properties of 1,3-butadiene and its derivatives].

1,3-butadiene gas is widely used in manufacture of synthetic rubber and plastics. In groups of workers occupationally exposed to 1,3-butadiene secondary leukemia and lymphoma were observed. Quite frequently, in these groups combined exposure to other chemicals such as styrene and benzene was observed. Studies on bacteria suggest that 1,3-butadiene is an indirect mutagen whose mutagenic potency depends on metabolic activation. Mutagenic and carcinogenic properties of 1,3-butadiene were investigated on laboratory animals. The results have shown that 1,3-butadiene induced multiple organ cancer, as well as increase in SCE, chromosome aberrations and micronuclei in mice and rats. 1,3-butadiene and its metabolites produced an effect of growth inhibition, an increase in SCE and chromosomal aberrations in mammalian cells in vitro. Up till now is known about genotoxic and carcinogenic properties of 1,3-butadiene in humans.

Animals↗
PubMed1993

Use of haemoglobin adducts for biomonitoring exposure to 1,3-butadiene.

Measurement of specific adducts to haemoglobin can be used to establish the dosimetry of electrophilic compounds and metabolites in experimental animals and in man. Adducts of 1,2-epoxybutene with the N-terminal valine in haemoglobin were determined in male B6C3F1 mice and Sprague-Dawley rats following exposure by inhalation to low concentrations of 1,3-butadiene (0, 2, 10 or 100 ppm, 6 h/day, 5 days/week, 4 weeks; animals killed within 1 h after the last exposure). The adduct level increased linearly with butadiene concentration in the mice, whereas a deviation from linearity was observed in the rats. After exposure to 100 ppm butadiene, the adduct levels were four times higher in mice than in rats; at lower concentrations of butadiene, the species difference was less pronounced. Adduct levels of about 1-3 pmol/g globin were recorded in human subjects (nonsmokers) who worked in a production area where butadiene levels of about 1 ppm had been recorded in a survey conducted three to nine months prior to this study. Increased adduct levels were also observed in cigarette smokers (two subjects) who were not exposed occupationally to butadiene. Although preliminary, the data suggest that the adduct levels, and consequently the doses of epoxybutene per parts per million-hour of butadiene are lower in humans than in mice and rats. The adduct levels are much lower than those seen after occupational exposures to corresponding air levels of ethylene oxide and are lower than those seen after exposure to ethylene.

Adult↗
PubMed1993

Use of transgenic mice for assessing the mutagenicity of 1,3-butadiene in vivo.

We have examined the mutagenicity of 1,3-butadiene in vivo in transgenic mice constructed with lambda phage shuttle vectors that contain either lacZ or lacI as transgenes. Thus far, we have shown that butadiene is mutagenic to the lung of lacZ mice (CD2F1, 625 ppm butadiene, 6 h/day, 5 days) and to the bone marrow of lacI mice (B6C3F1, 62.5, 625, 1250 ppm butadiene, 6 h/day, 5 days/week, 4 weeks) exposed by inhalation to the same concentrations used previously in bioassays of the carcinogenicity of butadiene. Analysis of the DNA sequences of lacI mutants from the bone marrow of lacI mice demonstrated a shift in the spectrum of mutation from G:C base pairs in the control group to mutation at A:T base pairs in the exposed group. In addition, analysis of DNA sequences of mutations in three animals exposed to butadiene showed evidence of mutant clonal expansion in vivo. These results indicate that butadiene induces mutation in mouse tissues. Analysis of mutations at the level of DNA sequences is useful for examining the relationship between mutation and mutant frequencies in vivo and the spectrum of mutation in transgenic animals after exposures to carcinogens.

Animals↗
PubMed1993

Time-to-tumour risk assessment for 1,3-butadiene based on exposure of mice to low doses by inhalation.

The excess risk for cancer due to lifetime occupational exposure to 1,3-butadiene at the proposed US Occupational Safety and Health Administration standard of 2 ppm was estimated on the basis of a quantitative risk assessment. The risk assessment was based on a recent study by the US National Toxicology Program of the carcinogenicity of butadiene in B6C3F1 mice, using exposure concentrations ranging from 6.25 to 625 ppm butadiene and controls. Cancer risks were estimated using a multistage Weibull time-to-tumour model; the dose was based on the external butadiene concentration, owing to the low-dose linearity of butadiene metabolism. The parameters of the time-to-tumour model were estimated for seven tumour sites in male mice and nine in female mice. The risk estimates were extrapolated from mice to humans on the basis of body weight raised to the three-fourths power, and the median lifespan of mice was equated to a human lifespan of 74 years. Estimates of excess risk for lifetime occupational exposure (8 h/day, 5 days/week, 50 weeks/year, for 45 years) to 2 ppm butadiene ranged from 0.2 per 10,000 workers, based on female mouse heart haemangiosarcomas, to 600 per 10,000 workers, based on female mouse lung tumours. An analysis was performed to assess the effects of varying the modelling assumptions (incidental versus fatal tumours, inclusion or exclusion of the 625-ppm dose group, and basis for interspecies scaling) on the risk estimates from the female mouse lung tumour model. Depending on the assumptions, estimates of lifetime excess risk derived from the female mouse lung model ranged from 60 per 10,000 to 1600 per 10,000. These results suggest that exposures to butadiene in the work place should be reduced to the lowest feasible level.

Administration, Inhalation↗
PubMed1993

A pharmacokinetic model to describe toxicokinetic interactions between 1,3-butadiene and styrene in rats: predictions for human exposure.

Co-exposure to vapours of 1,3-butadiene and styrene occurs in the styrene-butadiene polymer manufacturing industry. Both compounds are biotransformed during a first step by cytochrome P450-dependent mono-oxygenases to epoxides--intermediates which are proven carcinogens. In a previous publication, we reported that metabolism of butadiene in rats was inhibited by simultaneous exposure to styrene, whereas butadiene had no effect on the kinetics of styrene. In order to translate these results into conditions of human exposure, we developed a physiologically based pharmacokinetic (PBPK) model, which is presented here. Maximal metabolic rates (Vmax) and Ostwald's partition coefficients were obtained using liver microsomes and tissues from rat and man. Apparent Michaelis (Km) and inhibition (Ki) constants were derived from previously published data on rats and were considered to be species-independent. The model was used to simulate human exposure to atmospheric mixtures of 5 and 15 ppm butadiene with 0.20 and 50 ppm styrene. It predicts that the presence of styrene significantly inhibits butadiene metabolism in man: At exposures up to 15 ppm, the amounts of butadiene metabolized can be expected to be reduced to 81 and 63% with co-exposure to styrene at 20 and 50 ppm, respectively.

Administration, Inhalation↗
PubMed2005

Hydrogenated 1,4-insertion of butadiene in the copolymerization with propylene using an isospecific zirconocene catalyst.

Poly(propylene-ran-1,3-butadiene) that contained pendant vinyl groups derived from 1,2-inserted butadiene units was selectively synthesized by rac-dimethylsilylbis(2-methyl-4-phenylindenyl)zirconium dichloride (Ph-Ind) activated with modified methylaluminoxane (MMAO) in the presence of hydrogen. The copolymers obtained without hydrogen had 1,2-inserted and 1,4-inserted butadiene units. The addition of hydrogen to the copolymerization improved the activity by approximately 1000-fold and gave the copolymer only with 1,2-inserted butadiene units, of which the content was equal to the copolymer obtained without hydrogen. The 13C NMR analysis of the copolymers clarified that butadiene also inserted into the copolymer as a tetramethylene unit, of which the content was almost the same as that of 1,4-inserted butadiene units observed in the absence of hydrogen. No signal that could be assigned to cyclic structures or long branched side chains was observed. These results indicate that pi-allyl species of zirconocenes formed by 1,4-butadiene insertion at the growing polymer chain ends transformed to the tetramethylene chain end by hydrogenation and continued successive propylene insertion.

Journal Article↗
PubMed1998

Epoxybutene-hemoglobin adducts in rats and mice: dose response for formation and persistence during and following long-term low-level exposure to butadiene.

Measurement of specific adducts to hemoglobin can be used to establish the dosimetry of electrophilic compounds and metabolites in experimental animals and in humans. The purpose of this study was to investigate the dose response for adduct formation and persistence in rats and mice during long-term low-level exposure to butadiene by inhalation. Adducts of 3,4-epoxy-1-butene, the primary metabolite of butadiene, with N-terminal valine in hemoglobin were determined in male B6C3F1 mice and male Sprague-Dawley rats following exposure to 0, 2, 10, or 100 ppm of 1,3-butadiene, 6 h/day, 5 days/week for 1, 2, 3, or 4 weeks. Blood samples were collected from groups of five mice and three rats at the end of each week during the 4 weeks of exposure and weekly for 3 weeks following the end of the 4-week exposure period. The increase and decrease, respectively, of the adduct levels during and following the end of the 4-week exposure followed closely the theoretical curve for adduct accumulation and removal for rats and mice, thereby demonstrating that the adducts are chemically stable in vivo and that the elimination follows the turnover of the red blood cells. The adduct level increased linearly with butadiene exposure concentration in the mice, whereas a deviation from linearity was observed in the rats. For example, after exposure to 100 ppm butadiene, the epoxybutene-hemoglobin adduct levels were about four times higher in mice than in rats; at lower concentrations of butadiene, the species difference was less pronounced. Blood concentrations of epoxybutene, estimated from hemoglobin adduct levels, were in general agreement with reported concentrations in mice and rats exposed by inhalation to 62.5 ppm. These studies show that adducts of epoxybutene with N-terminal valine in hemoglobin can be used to predict blood concentration of epoxybutene in experimental animals.

Algorithms↗
PubMed1986

Epoxidation of 1,3-butadiene in liver and lung tissue of mouse, rat, monkey and man.

When 1,3-butadiene is incubated with liver postmitochondrial fractions from mouse, rat, monkey or man and a NADPH-regenerating system the formation rate of butadiene monoxide is different in the four species. With the exception of rhesus monkey the amount of epoxide is proportional to the monooxygenase activity. The sequence of epoxide formation is B6C3F1-mouse, Sprague Dawley rat, man, rhesus monkey. The relation between mouse and monkey was about 7:1. When 1,3-butadiene is incubated with homogenates from lung tissue, only tissues from mouse and rat produces measurable butadiene monoxide concentrations. The monooxygenase activity in lung tissue of the mouse was only 1/30 that in mouse liver. By contrast, lung tissue formed the epoxide concentrations comparable to those formed by liver tissue, whereas monkey and human lung tissue did not produce any measurable levels of butadiene monoxide. The data might suggest that the results of recent rodent inhalation studies with 1,3-butadiene could not automatically be extrapolated to man.

Animals↗
PubMed1991

1,3-Butadiene and its epoxides induce sister-chromatid exchanges in human lymphocytes in vitro.

Sister-chromatid exchanges (SCEs) were induced in human lymphocytes by 1,3-butadiene and its epoxides 3,4-epoxy-1-butene and 1,2:3,4-diepoxybutane. After a pulse treatment of 2 h, 1,3-butadiene produced a weak but reproducible increase in SCEs both with and without S9 mix. The response was similar in cultures of whole blood and of isolated lymphocytes. The 2 epoxide metabolites of butadiene, studied in whole-blood lymphocyte cultures without exogenous metabolic activation, were highly active SCE inducers. The lowest effective concentrations of butadiene, monoepoxybutene, and diepoxybutane were 2000 microM, 25 microM and 0.5 microM, respectively. A slight but dose-dependent increase in SCEs was also observed without an exogenous metabolic system after a 48-h treatment with 1,3-butadiene. Already the lowest concentration tested (500 microM) was effective. Again, the response was similar in cultures of whole blood and isolated lymphocytes, suggesting that the lymphocytes are capable of metabolically activating 1,3-butadiene.

Butadienes↗
PubMed2004

Dose responses for DNA adduct formation in tissues of rats and mice exposed by inhalation to low concentrations of 1,3-[2,3-[(14)C]-butadiene.

Male Sprague-Dawley rats and B6C3F1 mice were exposed to either a single 6h or a multiple (5) daily (6h) nose-only dose of 1,3-[2,3-(14)C]-butadiene at exposure concentrations of nominally 1, 5 or 20 ppm. The aim was to compare the results with those from a similar previous study at 200 ppm. DNA isolated from liver, lung and testis of exposed rats and mice was analysed for the presence of butadiene related adducts, especially the N7-guanine adducts. Total radioactivity present in the DNA from liver, lung and testis was quantified and indicated more covalent binding of radioactivity for mouse tissue DNA than rat tissue DNA. Following release of the depurinating DNA adducts by neutral thermal hydrolysis, the liberated depurinated DNA adducts were measured by reverse phase HPLC coupled with liquid scintillation counting. The guanine adduct G4, assigned as N7-(2,3,4-trihydroxybutyl)- guanine, was the major adduct measured in liver, lung and testis DNA in both rats and mice. Higher levels of G4 were detected in all mouse tissues compared with rat tissue. The dose-response relationship for the formation of adduct G4 was approximately linear for all tissues studied for both rats and mice exposed in the 1-20 ppm range. The formation of G4 in liver tissue was about three times more effective for mouse than rat in this exposure range. Average levels of adduct G4 measured in liver DNA of rats and mice exposed to 5 x 6 h 1, 5 and 20 ppm 1,3-[2,3-(14)C]-butadiene were, respectively, for rats: 0.79 +/- 0.30, 2.90 +/- 1.19, 16.35 +/- 4.8 adducts/10(8) nucleotides and for mice: 2.23 +/- 0.71, 12.24 +/- 2.15, 48.63 +/- 12.61 adducts/10(8) nucleotides. For lung DNA the corresponding values were for rats: 1.02 +/- 0.44, 3.12 +/- 1.06, 17.02 +/- 4.07 adducts/10(8) nucleotides, and for mice: 3.28 +/- 0.32, 14.04 +/- 1.55, 42.47 +/- 13.12 adducts/10(8) nucleotides. Limited comparative data showed that the levels of adduct G4 formed in liver and lung DNA of mice exposed to a single exposure to butadiene in the present 20 ppm study and earlier 200 ppm study were approximately directly proportional across dose, but this was not observed in the case of rats. From the available evidence it is most likely that adduct G4 was formed from a specific isomer of the diol-epoxide metabolite, 3,4-epoxy-1,2-butanediol rather than the diepoxide, 1,2,3,4-diepoxybutane. Another adduct G3, possibly a diastereomer of N7-(2,3,4-trihydroxybutyl)-guanine or most likely the regioisomer N7-(1-hydroxymethyl-2,3-dihydroxypropyl)-guanine, was also detected in DNA of mouse tissues but was essentially absent in DNA from rat tissue. Qualitatively similar profiles of adducts were observed following exposures to butadiene in the present 20 ppm study and the previous 200 ppm study. Overall the DNA adduct levels measured in tissues of both rats and mice were very low. The differences in the profiles and quantity of adducts seen between mice and rats were considered insufficient to explain the large difference in carcinogenic potency of butadiene to mice compared with rats.

Administration, Inhalation↗
PubMed2006

Cancer risk assessment for 1,3-butadiene: data integration opportunities.

The US Environmental Protection Agency recently released its new guidelines for carcinogen risk assessment together with supplemental guidance for assessing susceptibility from early-life exposure to carcinogens. In particular, these guidelines encourage the use of mechanistic data in support of dose-response characterization at doses below those at which an increase in tumor frequency over background levels might be detected. In this context of the utility of mechanistic data for human cancer risk assessment, the International Life Sciences Institute (ILSI) has developed a human relevance framework (HRF) that can be used to assess the plausibility of a mode of action (MoA) described for animal models operating in humans. The MoA is described as a sequence of key events and processes that result in an adverse outcome. A key event is a measurable precursor step that is in itself a necessary element of the MoA or is a bioindicator for such an element. A number of cellular and molecular perturbations have been identified as key events whereby DNA-reactive chemicals can produce tumors. These include DNA adducts in target tissues, gene mutations and/or chromosomal alterations in target tissues and enhanced cell proliferation in target tissues. This type of data integration approach to quantitative cancer risk assessment can be applied to 1,3-butadiene, for example, using data on biomarkers in exposed Czech workers [1]. For this study, an extensive range of biomarkers of exposure and response was assessed, including: polymorphisms in metabolizing enzymes; urinary concentrations of several metabolites of 1,3-butadiene; hemoglobin adducts; HPRT mutations in T-lymphocytes; chromosomal aberrations by FISH and conventional staining procedures; sister chromatid exchanges. Exposure levels were monitored in a comprehensive fashion. For risk assessment purposes, these data need to be considered in the context of how they inform the MoA for leukemia, the tumor type reported to be increased in synthetic rubber workers exposed to 1,3-butadiene. Also, for the HRF it is necessary to establish key events for a MoA in rodents for the induction of tumors by 1,3-butadiene. There is clearly a species difference in sensitivity to tumor induction, with mice being much more sensitive than rats; key events need to explain this difference. For butadiene, the MoA is DNA-reactivity and subsequent mutagenicity and so following the EPA's cancer guidelines, a linear extrapolation is used from the point of departure (POD), unless additional data support a non-linear extrapolation. For the present case, the human bioindicator data are not informative as far as dose-response characterization is concerned. Mouse chromosome aberration data for in vivo exposures might be used for establishing a POD, with linear extrapolation from this POD. The available cytogenetic data from rodent studies appear to be sufficiently extensive and consistent for this to be a viable approach. This approach of using MoA and key events to establish the human relevance can lead to the development of specific informative bioindicators of response that can be used as surrogates to predict the shape of the tumor dose response curve at low doses. Truly informative predictors of tumor responses should be able to provide estimates of human tumor frequencies at low, environmental exposures to 1,3-butadiene.

Animals↗
PubMed2006

Measurement of acrolein and 1,3-butadiene in a single puff of cigarette smoke using lead-salt tunable diode laser infrared spectroscopy.

Acrolein and 1,3-butadiene in cigarette smoke generally are measured using two separate analytical methods, a carbonyl derivative HPLC method for acrolein and a volatile organic compound (VOC) GC/MS method for 1,3-butadiene. However, a single analytical method having improved sensitivity and real-time per puff measurement will offer more specific information for evaluating experimental carbon filtered cigarettes designed to reduce the smoke deliveries of these constituents. This paper describes an infrared technique using two lead-salt tunable diode lasers (TDLs) operating with liquid nitrogen cooling with emissions at 958.8 cm(-1) and 891.0 cm(-1) respectively for the simultaneous measurement of acrolein and 1,3-butadiene, respectively, in each puff of mainstream cigarette smoke in real time. The dual TDL system uses a 3.1l volume, 100 m astigmatic multiple pass absorption gas cell. Quantitation is based on a spectral fit that uses previously determined infrared molecular line parameters generated in our laboratory, including line positions, line strengths and nitrogen-broadened half-widths for these species. Since acrolein and ethylene absorption lines overlap and 1,3-butadiene, ethylene and propylene absorption lines overlap, the per puff deliveries of ethylene and propylene were determined since their overlapping absorption lines must be taken into account by the spectral fit. The acrolein and 1,3-butadiene total cigarette deliveries for the 1R5F Kentucky Reference cigarette were in agreement with the HPLC and GC/MS methods, respectively. The limit of detection (LOD) for 1,3-butadiene and acrolein was 4 ng/puff and 24 ng/puff, respectively, which is more than adequate to determine at which puff they break through the carbon filter. The retention and breakthrough behavior for the two primary smoke constituents depend on the cigarette design and characteristics of the carbon filter being evaluated.

Acrolein↗