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.

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 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  The toxicity data of pesticides were summarized and compared amongst different animal species and types of bioassays. These comparisons showed the expected inter-species and inter-bioassay variability. After quantitative and statistical analysis of these data, it was concluded that, on the average, a 2-year dog bioassay detected toxic responses at similar doses as a 2-year rat study, and that both of these bioassays detected toxic responses at lower doses than either a rat 2-generation bioassay, a rat developmental toxicity study, or a 2-year mouse bioassay. Although these chronic dog and rat bioassays were found to detect toxic responses at lower doses than the other studies listed, this analysis does not reflect the seriousness of the effects that were compared. Within the confines of this analysis, then, it appears that a 2-year dog and rat study, reproductive and developmental bioassays are a sufficient data base on which to estimate high confidence Reference Doses (RfDs), and furthermore, that an additional uncertainty factor is needed to estimate RfDs to account for this inter-species and inter-bioassay variability when fewer than this number of bioassays are available.

Abstract  The public depends on competent risk assessment from the federal government and the scientific community to grapple with the threat of pollution. When risk reports turn out to be overblown--or when risks are overlooked--public skepticism abounds. This comprehensive and readable book explores how the U.S. Environmental Protection Agency (EPA) can improve its risk assessment practices, with a focus on implementation of the 1990 Clean Air Act Amendments. With a wealth of detailed information, pertinent examples, and revealing analysis, the volume explores the "default option" and other basic concepts. It offers two views of EPA operations: The first examines how EPA currently assesses exposure to hazardous air pollutants, evaluates the toxicity of a substance, and characterizes the risk to the public. The second, more holistic, view explores how EPA can improve in several critical areas of risk assessment by focusing on cross-cutting themes and incorporating more scientific judgment. This comprehensive volume will be important to the EPA and other agencies, risk managers, environmental advocates, scientists, faculty, students, and concerned individuals.

Abstract  A pharmacokinetic (PBPK) model has been developed for acrylamide (AMD) and its oxidative metabolite, glycidamide (GLY), in the rat based on available information. Despite gaps and limitations to the database, model parameters have been estimated to provide a relatively consistent description of the kinetics of acrylamide and glycidamide using a single set of values (with minor adjustments in some cases). Future kinetic and mechanistic studies will need to focus on the collection of key data for refining certain model parameters and for model validation, as well as for conducting studies that elucidate the mechanism of action. Development of a validated human AMD/GLY PBPK model capable of predicting target tissue doses at relevant dietary AMD exposures, in combination with expanding data on modes of action, should allow for a substantive improvement in the risk assessment of acrylamide in food.

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  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  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  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  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  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  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  The assessment of health risks due to low levels of exposure to potential environmental hazards based on the results of toxicological experiments necessarily involves extrapolation of results obtained at relatively high doses to the low dose region of interest. In this paper, different statistical extrapolation procedures which take into account both time-to-response and the presence of competing risks are compared using a large simulated data base. The study was designed to cover a range of plausible dose response models as well as to assess the effects of competing risks, background response, latency and experimental design on the performance of the different extrapolation procedures. It was found that point estimates of risk in the low dose region may differ from the actual risk by a factor of 1000 or more in certain situations, even when precise information on the time of occurrence of the particular lesion of interest is available. Although linearized upper confidence limits on risk can be highly conservative when the underlying dose response curve is sublinear in the low dose region, they were found not to exceed the actual risk in the low dose region by more than a factor of 10 in those cases where the underlying dose response curve was linear at low doses.

Abstract  The Report on Carcinogens is an informational scientific and public health document that identifies and discusses agents, substances, mixtures, or exposure circumstances that may pose a carcinogenic hazard to human health. It serves as a meaningful and useful compilation of data on the (1) carcinogenicity, genotoxicity, and biologic mechanisms of the listed substances in humans and/or animals, (2) the potential for exposure to these substances, and (3) the regulations promulgated by Federal agencies to limit exposures. The report does not present quantitative assessments of carcinogenic risk. Listing of substances in the report, therefore, does not establish that such substances present carcinogenic risks to individuals in their daily lives. Such formal risk assessments are the purview of the appropriate Federal, State, and local health regulatory and research agencies.

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  Based on analogy with butadiene and isoprene, the metabolism of beta-chloroprene (2-chloro-1,3-butadiene, CD) to reactive intermediates is likely to be a key determinant of tumor development in laboratory rodents exposed to CD by inhalation. The purpose of this study is to identify species differences in toxic metabolite (epoxide) formation and detoxification in rodents and humans. The in-vitro metabolism of CD was studied in liver microsomes of B6C3F1 mice, Fischer/344 and Wistar rats, Syrian hamsters, and humans. Microsomal oxidation of CD in the presence of NADP(+), extraction with diethyl ether, and analysis by GC-mass selective detection (MSD) indicated that (1-chloroethenyl)oxirane (CEO) was an important metabolite of CD in the liver microsomal suspensions of all species studied. Other potential water-soluble oxidative metabolites may have been present. The oxidation of CD was inhibited by 4-methyl pyrazole, an inhibitor of CYP 2E1. CEO was sufficiently volatile at 37 degrees C for vial headspace analysis using GC-MSD single ion monitoring (m/z=39). CEO was synthesized and used to conduct partition measurements along with CD and further explore CEO metabolism in liver microsomes and cytosol. The liquid-to-air partition coefficients for CD and CEO in the microsomal suspensions were 0.7 and 58, respectively. Apparent species differences in the uptake of CEO by microsomal hydrolysis were hamster approximately human>rats>mice. Hydrolysis was inhibited by 1,1,1-trichloropropene oxide, a competitive inhibitor of epoxide hydrolase. A preliminary experiment indicated that the uptake of CEO in liver cytosol by GSH conjugation was hamster>rats approximately mice (human cytosol not yet tested). In general, the results suggest that metabolism may help explain species differences showing a greater sensitivity for CD-induced tumorigenicity in mice, for example, compared with hamsters. Additional experiments are in progress to quantify the kinetic parameters of CD oxidation and CEO metabolism by enzymatic hydrolysis and conjugation by glutathione S-transferase for in cytosol. A future goal is to use the kinetic rates to parameterize a physiologically based toxicokinetic model and relate the burden of toxic metabolite to the cancer dose-response observed in experimental animals.

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.