Abstract  This article evaluates the quality and weight of evidence associated with epidemiologic studies of cancer among occupational cohorts exposed to chloroprene. The focus is on liver, lung, and lymphohematopoietic cancers, which had been increased in early studies. Literature searches identified eight morbidity/mortality studies covering seven chloroprene-exposed cohorts from six countries. These studies were summarized and their quality was assessed using the 10 criteria suggested by the U.S. Environmental Protection Agency. The limitations within this literature (primarily the early studies) included crude exposure assessment, incomplete follow-up, uncertain baseline rates, and uncontrolled confounding by factors such as smoking, drinking, and co-exposure to benzene and vinyl chloride. Four cohorts were studied by the same group of investigators, who reported no overall increased associations for any cancers. This four-cohort study was by far the most rigorous, having the most comprehensive exposure assessment and follow-up and the most detailed documentation. This study also contained the two largest cohorts, including an American cohort from Louisville, Kentucky, that ranked at or near the top for each of the 10 quality criteria. There was evidence of a strong healthy worker effect in the four-cohort study, which could have hidden small excess risks. Small increased risks were suggested by internal or company-specific analyses, but these were most likely caused by uncontrolled confounding and low baseline rates. Overall, the weight of evidence does not support any substantial link between chloroprene exposure and cancer, but inconsistencies and a lack of control for major confounders preclude drawing firmer conclusions.

Abstract  A benchmark dose (BMD) is the dose of a substance that corresponds to a prescribed increase in the response (called the benchmark response or BMR) of a health effect. A statistical lower bound on the benchmark dose (BMDL) has been proposed as a replacement for the no-observed-adverse-effect-level (NOAEL) in setting acceptable human exposure levels. A method is developed in this paper for calculating BMDs and BMDLs from continuous data in a manner that is consistent with those calculated from quantal data. The method involves defining an abnormal response, either directly by specifying a cutoff x0 that separates continuous responses into normal and abnormal categories, or indirectly by specifying the proportion P0 of abnormal responses expected among unexposed subjects. The method does not involve actually dichotomizing individual continuous responses into quantal responses, and in certain cases can be applied to continuous data in summarized form (e.g., means and standard deviations of continuous responses among subjects in discrete dose groups). In addition to specifying the BMR and either x0 or P0, the method requires specification of the distribution of continuous responses, including specification of the dose-response θ(d) for a measure of central tendency. A method is illustrated for selecting θ(d) to make the probability of an abnormal response any desired dose-response function. This enables the same dose-response model (Weibull, log-logistic, etc.) to be used for the probability of an abnormal response, regardless of whether the underlying data are continuous or quantal. Whenever the continuous responses are normally distributed with standard deviation σ (independent of dose), the method is equivalent to defining the BMD as the dose corresponding to a prescribed change in the mean response relative to σ.

Abstract  This document presents background information and justification for the Integrated Risk Information System (IRIS) Summary of the hazard and dose-response assessment of chloroprene. IRIS summaries may include oral reference dose (RfD) and inhalation reference concentration (RfC) values for chronic and other exposure durations, and a carcinogenicity assessment. The RfD and RfC, if derived, provide quantitative information for use in risk assessments for health effects known or assumed to be produced through a nonlinear (presumed threshold) mode of action. The RfD (expressed in units of mg/kg-day) is defined as an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. The inhalation RfC (expressed in units of mg/m3) is analogous to the oral RfD, but provides a continuous inhalation exposure estimate. The inhalation RfC considers toxic effects for both the respiratory system (portal of entry) and for effects peripheral to the respiratory system (extrarespiratory or systemic effects). Reference values are generally derived for chronic exposures (up to a lifetime), but may also be derived for acute (24 hours), short-term ( and amp;gt;24 hours up to 30 days), and subchronic ( and amp;gt;30 days up to 10 percent of a lifetime) exposure durations, all of which are derived based on an assumption of continuous exposure throughout the duration specified. Unless specified otherwise, the RfD and RfC are derived for chronic exposure duration. The carcinogenicity assessment provides information on the carcinogenic hazard potential of the substance in question and quantitative estimates of risk from oral and inhalation exposure may be derived. The information includes a weight-of-evidence judgment of the likelihood that the agent is a human carcinogen and the conditions under which the carcinogenic effects may be expressed.

Abstract  Beta-chloroprene (C(4)H(5)Cl, chloroprene, 2-chloro-1,3-butadiene, CASRN 126-99-8) is a volatile, flammable liquid monomer utilized primarily in the manufacture of neoprene (polychloroprene) elastomer used in belts, hoses, gloves, wire coatings, and tubing. Absorption into the body occurs primarily via the respiratory system and may occur via the gastrointestinal tract or the skin. Once absorbed, chloroprene is widely distributed as evidenced by effects in several target organs including nose and lung, liver, and skin. Chloroprene metabolism is believed to include cytochrome P450 oxidation to a monoepoxide, hydrolysis by epoxide hydrolases, and glutathione conjugation. Similar to 1,3-butadiene, the epoxide is considered to be the toxic moiety, and species differences in metabolic capacity may influence the severity of effects as well as what tissues are affected. EPA has not previously developed an assessment of chloroprene's potential for human health effects. Existing human epidemiological studies offer little data on noncancer effects, and the associations of exposure with increased cancer (liver and lung) mortality reported are inconclusive. Recent epidemiological studies (submitted for publication) could offer information that may impact chloroprene's health assessment. Multiple-site tumors have been reported in rats and mice exposed to chloroprene by inhalation; nevertheless, there are marked differences in strain sensitivities (i.e., tumors in F344 rats versus no tumors in Wistar rats). Recently developed physiologically based toxicokinetic models may allow for the resolution of species and tissue differences and sensitivities as well as exposure-dose-response relationships relevant to humans. (This presentation does not necessarily reflect EPA policy.).

Abstract  2-Chloro-1,3-butadiene (chloroprene, CBD), a major industrial chemical used in synthetic chlorinated rubber production, is acutely hepatotoxic. Fasted rats were exposed to concentrations of 100, 150, 225 and 300 ppm CBD for 4 h and killed at 24 h. Liver injury as measured by increased serum sorbitol dehydrogenase (SDH) activity was apparent in animals exposed to 225 and 300 ppm CBD. Non-protein sulfhydryl (NPSH) concentrations in liver were increased 24 h after all exposures. Lung NPSH concentrations were decreased significantly after 100 and 300 ppm exposure. Serum lactate dehydrogenase (LDH) activity was increased after exposure to 300 ppm. When this same enzyme was measured in lung lavage fluid from animals killed 24 h after exposure, no elevation was detected. Acute lung injury did not manifest itself with a release of LDH into the airway at this time. Alternatively, airway injury may have resolved by 24 h. Aroclor 1254 (PCB) pretreatment prevented liver injury (SDH elevation, liver enlargement, and NPSH rebound) following exposure to 100 and 300 ppm CBD. Lung NPSH was not decreased by CBD exposure of PCB-pretreated, fasted rats. The pattern of CBD toxicity is comparable to 1,1-dichloroethylene toxicity.

Abstract  The usual method for establishing allowable daily intake (ADI) for a chemical involves determining a no-observed-effect level (NOEL) and applying a safety factor. Even though this method has been used for many years, there appear to be no general guidelines or rules for defining a NOEL. The determination of a NOEL is particularly uncertain for lesions which occur naturally in untreated animals. NOELs also have shortcomings in that smaller experiments tend to give larger values (this should be reversed because larger experiments can provide greater evidence of safety) and that the steepness of the dose response in the dose range where effects occur plays little or no role in the determination of a NOEL. This paper proposes and illustrates the use of a "benchmark dose" (BD) as an alternative to a NOEL. A BD is a statistical lower confidence limit to a dose producing some predetermined increase in response rate such as 0.01 or 0.1. The BD is calculated using a mathematical dose-response model. This approach makes appropriate use of sample size and the shape of the dose-response curve. The BD normally will not depend strongly upon the mathematical model used because the method does not involve extrapolation far below the experimental range. Thus the method sidesteps much of the model dependency often associated with extrapolation of carcinogenicity data to low doses. The method can be applied to either "quantal" data in which only the presence or absence of an effect is recorded, or "continuous" data in which the severity of the effect is also noted.

Abstract  A walk-through industrial hygiene survey was conducted at the Pontchartrain Works of E.I. duPont de Nemours and Company in LaPlace, Louisiana on August 26, 1985. The purpose of the survey was to obtain information on the neoprene polymer production process and assess the potential for occupational exposure to 1,3-butadiene. This information will be used in determining the suitability of including this plant in an in-depth industrial hygiene survey. The plant, which opened in 1964, began producing neoprene from 1,3-butadiene in 1968. Both chloroprene and neoprene are currently produced from 1,3-butadiene at the plant. In addition to use in the synthesis of neoprene, chloroprene is also shipped by rail cars to another duPont facility. The incoming 1,3-butadiene is received by pipeline. The company maintains personnel records on current and past employees. No monitoring data was provided by the company. However, the company reported that they have conducted personal monitoring for 1,3-butadiene in those dichlorobutene and chloroprene areas where 1,3-butadiene exposure was thought likely. Of the 74 personal samples taken by duPont, 72 were less than 10 ppm. The results of the NIOSH analysis of the bulk sample of neoprene for residual 1,3-butadiene were non-detectable. The limit of detection was 0.04 ng/mg by weight. A bulk sample of chloroprene was not obtained. The facility is considered to be a potential candidate for an in-depth industrial hygiene survey for the determination of the extent of exposure to 1,3-butadiene. This consideration is based on an evaluation of the reported historical industrial hygiene data.

Abstract  The RAS protein controls signaling pathway are major player in cell growth, its regulation and malignant transformation. Any activation in RAS brings alteration in upstream or downstream signaling component. Activating mutation in RAS is found in approximately 30% of human cancer. RAS plays essential role in tumor maintenance and is therefore an appropriate target for anticancer therapy. Among the anti-RAS strategies that are under evaluation in the clinic are pharmacologic inhibitors designed to prevent: (1) association with the plasma membrane (prenylation and post prenylation inhibitors). (2) Downstream signaling (kinase inhibitor), (3) upstream pathway (kinase inhibitor and monoclonal antibody), (4) Expression of RAS or other component of pathway (siRNA and antisense oligonucleotide). Several of these new therapeutic agents are showing promising result in the clinic and many more are on the way. Here, we review the current status and new hopes for targeting RAS as an anticancer drug.