Abstract  With the goal of elucidating the molecular and cellular mechanisms of chloroprene toxicity, we examined the potential DNA cross-linking of the bifunctional chloroprene metabolite, (1-chloroethenyl)oxirane (CEO). We used denaturing polyacrylamide gel electrophoresis to monitor the possible formation of interstrand cross-links by CEO within synthetic DNA duplexes. Our data suggest interstrand cross-linking at deoxyguanosine residues within 5'-GC and 5'-GGC sites, with the rate of cross-linking depending on pH (pH 5.0 > pH 6.0 > pH 7.0). A comparison of the cross-linking efficiencies of CEO and the structurally similar cross-linkers diepoxybutane (DEB) and epichlorohydrin (ECH) revealed that DEB > CEO > or = ECH. Furthermore, we found that cytotoxicity correlates with cross-linking efficiency, supporting a role for interstrand cross-links in the genotoxicology of chloroprene.

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

Abstract  Isoprene (2-methylbuta-1,3-diene) is a large-scale petrochemical used principally in the manufacture of synthetic rubbers. It is also produced by plants and trees and is the major endogenous hydrocarbon formed by mammals, probably from mevalonic acid. Isoprene is metabolised by mammals in processes that involve epoxidation by cytochrome P450-dependent monooxygenases to the isomeric mono-epoxides, (1-methylethenyl)-oxirane and 2-ethenyl-2-methyloxirane. Further metabolism of the mono-epoxides to mutagenic isoprene di-epoxides, (2, 2')-2-methylbioxiranes, can also occur. The oxidations to the mono- and di-epoxides occur enantioselectively and diastereoselectively. The mono-epoxides are hydrolysed enantioselectively to vicinal diols under catalysis by epoxide hydrolase. 2-Ethenyl-2-methyloxirane is also readily hydrolysed non-enzymatically. Because of the stereochemical possibilities for metabolites, the metabolism of isoprene is complex. The metabolism of isoprene by liver microsomes in vitro from a range of species including rat, mouse and human shows significant differences between species, strains and gender in respect of the diastereoselectivity and enantioselectivity of the metabolic oxidation and hydrolysis reactions. The impact of the extra methyl in isoprene on di-epoxide reactivity also appears to be critically important for the resulting biological effects. Isoprene di-epoxides may exhibit a lower cross-linking potential in vivo compared to butadiene di-epoxides. Differences in metabolism and reactivity of metabolites may be factors contributing to the significant differences in toxicological response to isoprene observed between species.

Abstract  Since the literature on genotoxicity of 2-chloro-1,3-butadiene (chloroprene) is controversial, the mutagenicity of this compound was reinvestigated with respect to its chemical stability. Because of the volatility of chloroprene, Ames tests with S. typhimurium TA 100 were carried out with gas-tight preincubation. Propylene oxide, a volatile direct mutagen, served as a positive control. Benzo[a]pyrene was used as a control for an indirect mutagen. Using this experimental regimen, freshly distilled chloroprene was not mutagenic. However, a mutagenic effect occurred linearly with increasing age of the chloroprene distillates. Aged chloroprene gave the same positive results whether preincubation was gas-tight or not. Analysis by gas chromatography (GC) revealed several decomposition products in aged chloroprene distillates. The direct mutagenicity towards TA 100 correlated with the integrated amounts of four of these substances; these substances always occurred in the same relative ratio. When chloroprene was kept under anaerobic conditions, products occurred with time which were partly different from those obtained under aerobic conditions. The direct mutagenicity of anaerobically aged chloroprene was only weak, but the mutagenic effect was enhanced about two- to threefold by addition of S9 mix. Partial identification of chloroprene decomposition products was done by gas chromatography-mass spectrometry (GC-MS): major byproducts of chloroprene, probably responsible for mutagenic properties of aged chloroprene samples, were cyclic chloroprene dimers.

Abstract  Using structure-reactivity relationships between reaction rate constants and ionization potentials for structural homologues, estimates are presented for the rate constants of the reactions of ozone, the hydroxyl radical, and the nitrate radical with forty toxic air contaminants for which no or little data are available. These rate constants are in turn used to estimate the atmospheric persistence of saturated aliphatics, unsaturated aliphatics, and aromatic toxic organics. The corresponding atmospheric half-lives for removal by chemical reactions range from a few hours for the most reactive toxics (chloroprene, hexachlorocyclo-pentadiene, cresols, nitrosamines, maleic anhydride) to several months for the least reactive compounds (nitrobenzene, methyl bromide, phosgene).

Abstract  Each year, the American Cancer Society estimates the number of new cancer cases and deaths expected in the United States in the current year, and compiles the most recent data on cancer incidence, mortality, and survival by using incidence data from the National Cancer Institute (NCI) and mortality data from the National Center for Health Statistics (NCHS). Incidence and death rates are age adjusted to the 2000 US standard population. In the year 2003, we estimate that 1,334,100 new cases of cancer will be diagnosed, and 556,500 people will die from cancer in the United States. Age-adjusted cancer death rates declined in both males and females in the 1990s, though the magnitude of decline is substantially higher in males than in females. In contrast, incidence rates continued to increase in females while stabilizing in males. African-American males showed the largest decline for mortality. However, African Americans still carry the highest burden of cancer with diagnosis of cancer at a later stage and poorer survival within each stage compared with Whites. In spite of the continued decline in cancer death rates in the most recent time period, the total number of recorded cancer deaths in the United States continues to increase slightly due to the aging and expanding population.

Abstract  We conducted an historical cohort study to investigate the mortality experience of industrial workers potentially exposed to chloroprene (CD) and other substances, including vinyl chloride (VC), with emphasis on cancer mortality, including respiratory system (RSC) and liver. In 1999, the International Agency for Research on Cancer (IARC) classified CD as a possible carcinogen (Group 2B); VC was classified in 1987 as a known human carcinogen (Group 1). Subjects were 12,430 workers ever employed at one of two U.S. industrial sites (Louisville, KY (n = 5507) and Pontchartrain, LA (n = 1357)) or two European sites (Maydown, Northern Ireland (n = 4849) and Grenoble, France (n = 717)), with earliest CD production dates ranging from 1942 (L) to 1969 (P). Two sites (L and M) synthesized CD with the acetylene process that produced VC exposures. We determined vital status through 2000 for 95% of subjects and cause of death for 95% of the deaths. Historical exposures for individual workers were estimated quantitatively for CD and VC. Workers ever exposed to CD ranged from 92.3% (M) to 100% (G); to VC from 5.5% (M) to 22.7% (L). We computed standardized mortality ratios (SMRs) (using national and regional standard populations) in relation to selected demographic, work history and exposure factors. We used worker pay type (white or blue collar) as a rough surrogate for lifetime smoking history. For the combined cohort, SMRs (95% CIs) for all causes combined, all cancers combined, RSC and liver cancer were, respectively, 0.72 (0.69–0.74), 0.73 (0.68–0.78), 0.75 (0.67–0.84) and 0.72 (0.43–1.13). Site-specific (L, M, P and G, respectively) SMRs were: for all cancers combined: 0.75 (0.69–0.80), 0.68 (0.56–0.80), 0.68 (0.47–0.95) and 0.59 (0.36–0.91); for RSC: 0.75 (0.66–0.85), 0.79 (0.58–1.05), 0.62 (0.32–1.09) and 0.85 (0.41–1.56); for liver cancer: 0.90 (0.53–1.44) (17 deaths), 0.24 (0.01–1.34) (1 death), 0.0 (0–2.39) (no deaths) and 0.56 (0.01–3.12) (1 death). Among all workers ever exposed to CD, SMRs were: for all cancers combined: 0.71 (0.66–0.76); for RSC: 0.75 (0.67–0.84); for liver cancer: 0.71 (0.42–1.14). We also observed no increased mortality risks among cohort subgroups defined by race, gender, worker pay type, worker service type (short/long term), time period, year of hire, age at hire, duration of employment, the time since first employment, and CD or VC exposure status (never/ever exposed). In summary, our study has many strengths and is the most definitive study of the human carcinogenic potential of exposure to CD conducted to date. We conclude that persons exposed to chloroprene or vinyl chloride at the levels encountered in the four study sites did not have elevated risks of mortality from any of the causes of death examined, including all cancers combined and lung and liver cancer, the cancer sites of a priori interest. This conclusion is corroborated by our detailed analyses of mortality in relation to qualitative and quantitative exposures to CD and VC at each of the four study sites, reported in our companion paper (Marsh et al., submitted for publication).

Abstract  As part of an historical cohort study to investigate the mortality experience of industrial workers exposed to chloroprene (CD) and other substances, including vinyl chloride monomer (VC), we analyzed mortality from all cancers combined, respiratory system (RSC) and liver cancer in relation to CD and VC exposures. Subjects were 12,430 workers ever employed at one of two U.S. sites (Louisville, KY (n = 5507) and Pontchartrain, LA (n = 1357)) or two European sites (Maydown, Northern Ireland (n = 4849) and Grenoble, France (n = 717)). Historical exposures for individual workers were estimated quantitatively for CD and VC. For sites L, M, P and G, respectively, average intensity of CD exposures (median value of exposed workers in ppm) were 5.23, 0.16, 0.028 and 0.149 and median cumulative exposures (ppm years) were 18.35, 0.084, 0.133 and 1.01. For sites L and M, respectively, average intensity of VC exposures (median value of exposed workers in ppm) was 1.54 and 0.03 and median cumulative exposures (ppm years) were 1.54 and 0.094. We performed relative risk (RR) regression modeling to investigate the dependence of the internal cohort rates for all cancers combined, RSC and liver cancer on combinations of the categorical CD or VC exposure measures with adjustment for potential confounding factors. We categorized exposure measures into approximate quartiles based on the distribution of deaths from all cancers combined. We also considered 5- and 15-year lagged exposure measures and adjusted some RR models for worker pay type (white/blue collar) as a rough surrogate for lifetime smoking history. All modeling was site-specific to account for exposure heterogeneity. We also computed exposure category-specific standardized mortality ratios (SMRs) to assess absolute mortality rates. With the exception of a one statistically significant association with duration of exposure to CD and all cancers combined in plant M, we observed no evidence of a positive association with all cancers, RSC or liver cancer and exposure to CD and/or VC using both the unlagged and lagged exposure measures: duration, average intensity or cumulative exposure to CD or VC; time since first CD or VC exposure; and duration of CD exposure or time since first CD exposure in presence or absence of VC exposure. We observed elevated and statistically significantly elevated RRs for some analysis subgroups, but these were due to inordinately low death rates in the baseline categories. With the possible exception of all cancer mortality in plant G, our additional adjustment of RRs for pay type revealed no evidence of positive confounding by smoking. We conclude that exposures to CD or VC at the levels encountered in the four study sites do not elevate mortality risks from all cancers, RSC or liver cancer. This conclusion is corroborated by our analysis of general mortality patterns among the CD cohort reported in our companion paper [G. Marsh, A. Youk, J. Buchanich, M. Cunningham, N. Esmen, T. Hall, M. Phillips, Mortality patterns among industrial workers exposed to chloroprene and other substances. I. General mortality patterns, Chem.-Biol. Interact., submitted for publication].

Abstract  Human health assessment information on a chemical substance is included in IRIS only after a comprehensive review of toxicity data by U.S. EPA health scientists from several program offices, regional offices, and the Office of Research and Development. Sections I (Health Hazard Assessments for Noncarcinogenic Effects) and II (Carcinogenicity Assessment for Lifetime Exposure) present the positions that were reached during the review process. Supporting information and explanations of the methods used to derive the values given in IRIS are provided in the guidance documents located on the IRIS website at http://www.epa.gov/ncea/iris/backgr-d.htm.

Abstract  Labor conditions of workers engaged in chloroprene rubber production are characterized by exposure to a complex of chemical compounds among which the leading part is played by chloroprene and products Of its interaction with hydroxyl radicals and atmospheric ozone. It was shown with certainty that the activity of creatine kinase and purine nucleoside phosphorylase decreases 2-fold as compared to the control in blood serum Of workers engaged in chloroprene synthesis. Changes in enzymes activity are not related to gender, age or length of service. Activity of serumal alanine aminotransferase (ALT) and aspartate aminotransferase(AST) did not revealed any changes in those workers.

Abstract  A historical cohort mortality study of 1,575 men occupationally exposed to chloroprene was conducted by the medical division of E.I. duPont de Nemours and Company (DuPont). The study was designed to evaluate the risk of lung cancer and other major causes of mortality with respect to chloroprene exposure. The study showed no association between chloroprene exposure and an increased risk of mortality from specific diseases, including lung cancer (Pell, 1978). The National Institute for Occupational Safety and Health (NIOSH) assisted DuPont in the study by providing additional epidemiologic resources. NIOSH was able to determine the vital status of 223 of 240 men in the cohort who could not be located by DuPont. This effort reduced the percentage of men lost to follow-up from 15.2% to 1.1%. 'Once the original study was completed, NIOSH was given the data by DuPont to reanalyze, using the NIOSH modified life table computer program. This report summarizes the results of the reanalysis.

Abstract  Partition coefficients are required for developing physiologically based pharmacokinetic models used to assess the uptake, distribution, tabolism, and elimination of volatile chemicals in mammals. A gas-phase vial equilibration technique is presented for determining the liquid:air and tissue:air partition coefficients for low-molecular-weight volatile chemicals. This technique was developed from two previously described medium:air methods, relied solely on measurement of chemical concentration in the gas phase, and, compared to earlier work, extends the range of chemicals and tissues examined. Partition coefficients were determined with 0.9% saline, olive oil, and blood, liver, muscle, and fat tissues from rats for 55 compounds. Human blood:air coefficients were determined for 36 compounds and several blood:air values were also determined in the mouse and for one compound in the hamster. An approach is described for predicting the tissue solubilities of untested compounds based on oil:air and saline:air coefficients using regression analyses. A similar approach is used to model fat:air coefficients in terms of oil:air values and to model human blood: air coefficients in terms of rat blood:air coefficients.

Abstract  The expanded Second Edition of Dr. Rothman's acclaimed Modern Epidemiology reflects the remarkable conceptual development of this evolving science and the engagement of epidemiologists with an increasing range of current public health concerns. This landmark work is the most comprehensive and cohesive text on the principles and methods of contemporary epidemiologic research.Coauthored by two leading epidemiologists, with 15 additional contributors, the Second Edition presents a much broader range of concepts and methods than Dr. Rothman's single-authored original edition. Coverage of basic measures and study types is more thorough and includes a new chapter on field methods. New chapters on advanced topics in data analysis, such as hierarchical regression, are also included. A new section covers specific areas of research such as infectious disease epidemiology, ecologic studies, disease surveillance, analysis of vital statistics, screening, clinical epidemiology, environmental and occupational epidemiology, reproductive and perinatal epidemiology, genetic epidemiology, and nutritional epidemiology.

Abstract  Chloroprene (1) was metabolized by liver microsomes from Sprague-Dawley rats, Fischer 344 rats, B6C3F1 mice, and humans to the monoepoxides, (1-chloro-ethenyl)oxirane (5a/5b), and 2-chloro-2-ethenyloxirane (4a/4b). The formation of 4a/4b was inferred from the identification of their degradation products. With male Sprague-Dawley and Fischer 344 rat liver microsomes, there was a ca. 3:2 preference for the formation of (R)-(1-chloroethenyl)oxirane (5a) compared to the (S)-enantiomer (5b). A smaller but distinct enantioselectivity in the formation of (S)-(1-chloro-ethenyl)oxirane occurred with liver microsomes from male mouse (R:S, 0.90:1) or male human (R:S, 0.86:1). 2-Chloro-2-ethenyloxirane was very unstable in the presence of the microsomal mixture and was rapidly converted to 1-hydroxybut-3-en-2-one (11) and 1-chlorobut-3-en-2-one (12). An additional rearrangement pathway of 2-chloro-2-ethenyloxirane gave rise to 2-chlorobut-3-en-1-al (14) and 2-chlorobut-2-en-1-al (15). Further reductive metabolism of these metabolites occurred to form 1-hydroxybutan-2-one (17) and 1-chlorobutan-2-one (18). In the absence of an epoxide hydrolase inhibitor, the microsomal incubations converted (1-chloroethenyl)oxirane to 3-chlorobut-3-ene-1,2-diol (21a/21b). When microsomal incubations were supplemented with glutathione, 1-hydroxybut-3-en-2-one was not detected because of its rapid conjugation with this thiol scavenger.

Abstract  The analysis of censored failure times is considered. It is assumed that on each individual are available values of one or more explanatory variables. The hazard function (age-specific failure rate) is taken to be a function of the explanatory variables and unknown regression coefficients multiplied by an arbitrary and unknown function of time. A conditional likelihood is obtained, leading to inferences about the unknown regression coefficients. Some generalizations are outlined.

Abstract  This assessment was conducted to review the new information that has become available since EPA’s 1985 health assessment of 1,3-butadiene. 1,3-Butadiene is a gas used commercially in the production of styrene-butadiene rubber, plastics, and thermoplastic resins. The major environmental source of 1,3-butadiene is the incomplete combustion of fuels from mobile sources (e.g., automobile exhaust). Tobacco smoke can be a significant source of 1,3-butadiene in indoor air. This assessment concludes that 1,3-butadiene is carcinogenic to humans by inhalation, based on the total weight of evidence. The specific mechanisms of 1,3-butadiene-induced carcinogenesis are unknown, however, it is virtually certain that the carcinogenic effects are mediated by genotoxic metabolites of 1,3-butadiene. Animal data suggest that females may be more sensitive than males for cancer effects; nevertheless, there are insufficient data from which to draw any conclusions on potentially sensitive subpopulations. The human incremental lifetime unit cancer (incidence) risk estimate is based on extrapolation from leukemias observed in an occupational epidemiologic study. A twofold adjustment to the epidemiologic-based unit cancer risk is then applied to reflect evidence from the rodent bioassays suggesting that the epidemiologic-based estimate may underestimate total cancer risk from 1,3-butadiene exposure in the general population. 1,3-Butadiene also causes a variety of reproductive and developmental effects in mice; no human data on these effects are available. The most sensitive effect was ovarian atrophy observed in a lifetime bioassay of female mice. Based on this critical effect and using the benchmark concentration methodology, an RfC (i.e., a chronic exposure level presumed to be “without appreciable risk” for noncancer effects) was calculated. In summary, the EPA’s conclusions about the health effects of 1,3-butadiene are: · 1,3-Butadiene is carcinogenic to humans by inhalation. · The unit cancer risk estimate is 0.08/ppm (based primarily on linear modeling and extrapolation of human data). This incorporates an adjustment factor of 2 to address concerns for sensitive populations. The corresponding estimate of the chronic exposure level of 1,3-butadiene resulting in extra cancer risk of 10-6 (i.e., 1 in a million) is 0.01 ppb. · A chronic RfC (0.9 ppb), an acute reference value (7 ppb), and a subchronic reference value (7 ppb) are presented for noncancer effects.

Abstract  Vinylidene chloride (VDC) monomer dissolved in olive oil was given orally to female BD IV rats (150 mg/kg body weight) on the 17th day of gestation. Their offspring were treated weekly with 50 mg/kg body weight VDC by stomach tube from the time of weaning for life span. Liver and meningeal tumours were more frequently observed in treated than in untreated animals, but the total number of tumour-bearing animals was not significantly different between treated and untreated animals. Chloroprene (CP) monomer dissolved in olive oil was given orally to female BD IV rats (100 mg/kg body weight) on the 17th day of gestation and their offspring were treated weekly with 50 mg/kg body weight by stomach tube from the time of weaning for life span. Total incidence of tumours was similar in treated and untreated animals. The data presented provide limited evidence of the carcinogenicity of VDC and no evidence of the carcinogenicity of CP when given by the oral route to rats

Abstract  A reproduction study with beta-chloroprene vapor was carried out, in which two successive generations of rats (F0- and F1-generation) were exposed to atmospheres containing 0, 10, 33 or 100 ppm beta-chloroprene. The F0-generation males and females were exposed 6 hours/day, 5 days/week for a period of 13 weeks, and thereafter, mated with untreated females and males respectively. Fl-generation rats were exposed 6 hours/day, 5 days/week for a 10-week period. The actual mean concentrations of beta-chloroprene in the test-atmospheres were 0, 9.80, 32.60 and 100.01 ppm for the F0-generation and 0, 9.85, 32.99 and 100.58 ppm for the F1-generation. Fertility of males and females, number of young born per litter, general condition, appearance, male/female ratio, and mortality of the young were not adversely affected by the exposure to beta-chloroprene. There was no indication of increased intrauterine mortality. Growth retardation was observed in the F0-generation at the high dose level and ln the F1-generatlon at tne mid- and high-dose levels. The relative weights of the liver and the ovaries of the high-level female rats, descendants from untreated females and treated males, were significantly higher than those of the controls. Gross and microscopic pathological examinations did not reveal any treatment-related abnormalities. It was concluded that under the conditions of the present two-generation experiment exposure to beta-chloroprene at levels up to 100 ppm had no adverse effect on the reproductive performance of rats.

Abstract  The monomer 1,3 butadiene (BD) is a product of the petrochemical industry. It is used to make several elastomers including the very high volume styrene butadiene rubber (SBR) that comprises the bulk of automobile tires. It is also used to make polybutadiene rubber that is used in parts of tires, coatings, composites and other products. The monomer can be converted to chlorobutadiene (chloroprene) and used to make polychloroprene (neoprene). BD is one of the several olefins created by cracking hydrocarbons in the presence of steam. A mixed C4 stream from the steam cracker is then sent to a BD monomer extraction unit. Modern units typically use dimethyl formamide as the extraction solvent. SBR is commonly made by the copolymerization of BD and styrene, along with various additives to control the reaction, in a water emulsion. The reaction proceeds in a continuous chain of reactors until it is ‘shortstopped’ by a strong reducing agent. After removing unreacted monomers from the stabilized latex, it is blended, coagulated and dewatered. The resulting dry rubber crumb is bailed, film wrapped and stored in crates. The polymerization of BD to make polybutadiene rubber can be conducted as a water suspension type polymerization similar to SBR or in a solvent system followed by solvent recovery and transfer into water suspension.