T4 - Symposium
A Chemical Mixtures Risk Assessment Approach for Four Organotin Plastic Stabilizers: Integration of the Human Exposure Evaluation, Dose-Response and Mode of Action Information, Part 1Scotland A 8:30-10:00 am
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| Chair(s): J. Lipscomb, R. Hertzberg
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Risk assessments for single chemical exposures have been undertaken for decades. In spite of the complex nature of human exposures to chemicals in the workplace and in the environment, relatively few examples of mature risk assessments exist for mixtures of chemicals. When mixtures comprise a large number of chemicals, the optimal approach may be to identify a toxicologically similar mixture, the data from which may be used as surrogate data for the mixture under evaluation. In contrast to a complex mixture exposure, at present, the risks associated with a four-component mixture of mono-and dimethyltin and mono- and dibutyltin is of interest due to the use of these compounds as stabilizers in polyvinylchloride (PVC) pipe used in drinking water delivery systems. These four compounds are priority drinking water contaminants for the US EPA. This 3-hour session will present the methods and requirements to perform a chemical mixtures risk assessment for these four organotin compounds. Seven, twenty-minute presentations will communicate the fundamentals of a component-based mixtures risk assessment approach, and the requirements for characterizing mode or mechanism of action for components and evaluating the degree of similarity or independence between modes or mechanisms of action, characterizing the anticipated human exposure to these compounds, as well as presenting the information on the tissue dosimetry and toxicity of these compounds. The session will culminate in a synopsis of the available information, and a discussion of how each piece of data fits into the approach for chemical mixture risk assessment, important data gaps and research needs.
The goal of the session is to describe approaches for mixtures risk assessment, to demonstrate the data available to inform a mixtures approach to the risk assessment of four organotin compounds, to demonstrate the adequacy of available data, to identify research needs and to foster discussion of partnerships to develop necessary but absent data. It will clearly demonstrate the need for interactions between toxicologists, exposure assessment experts and risk assessors
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T4.1 A Chemical Mixtures Approach To Evaluating Risk From Organotin Plastic Stabilizers Used In Drinking Water Distribution Systems.. Lipscomb JC, Lambert JC; US Environmental Protection Agency, Office of Research and Development, National Center for Environmental Assessment lipscomb.john@epa.gov
Abstract: The use of organotin compounds in piping for drinking water delivery systems result in human exposure to mixtures of mono- and di-substituted methyl and butyl tins. Single chemical toxicity data from rodents suggest that human exposures to these compounds may impair the immune, nervous, and reproductive systems. Because of identification of the chemicals of interest and their co-occurrence in piping, a mixtures risk assessment approach can be undertaken. No data are available on this mixture, or on a similar mixture, eliminating the application of a whole-mixture approach. Unless data are available to indicate an interaction of the risks from these chemicals, the risk assessment will be based on the assumption of additivity, and a component-based approach taken. In that case, either dose addition (i.e., relative potency factor approach) or response addition will be selected, based upon data that can inform whether these compounds act via similar or independent modes of action, respectively. The extrapolation of findings from single chemical studies using high doses of single chemicals introduces uncertainty at two points; 1) whether information on the mode of action warrants application of dose or response addition, and 2) extrapolation of the dose response relationship to lower levels of exposure (those to which humans may be exposed). Some data exist for each of the four compounds in each of the identified sensitive tissues, although some data sets only show a lack of response. A limited amount of mixture data exist for immune effects observed in vitro, potentially indicating an interaction effect (potentiation). The success and acceptance of a mixtures risk assessment depend heavily on interpretation of available mixture study results and the description of modes of action for component chemicals. This presentation will communicate mixtures risk assessment approaches and highlight the application of mode of action information.
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T4.2 Modeling Human Exposure to Organotins in Tap Water via Migration from PVC and CPVC Piping . Fristachi A*; ORISE Fellow, USEPA/NCEA fristachi.anthony@epa.gov
Abstract: Polyvinyl chloride (PVC) forms hydrochloric acid (HCl) when it degrades, causing a chain reaction which rapidly proceeds to complete loss of product strength. Organotins (OT), principally dibutyltin (DBT) and monobutyltin (MBT) are used as stabilizers in PVC pipe. Not all of the stabilizers used chemically bind to the PVC polymer chains and, as a result, unbound stabilizers may migrate from polymer chains out of the pipe into transported waters. Limited occurrence data from residential surveys show levels of MBT and DBT in the parts per trillion (ppt) range. Organotins have been shown to have developmental neurotoxicological and immunotoxicological effects in animal studies. Because of its noted toxicity and potential for occurrence in drinking water, the US Environmental Protection Agency (EPA) wants to characterize human exposures to OT via drinking water distribution systems and the risks of such an exposure. The goal of this research is to estimate OT concentrations in drinking water as a result of PVC/CPVC pipe leaching by integrating laboratory estimates of OT leaching rates and concentrations with estimates of average water distribution system parameters assuming minimal diurnal and intradistribution variability in concentrations unaffected by spikes in water quality or changes in treatment operational parameters. . Metrics of human exposure via multiple-media/multiple-pathway probabilistic models were derived, addressing the utility of physiologically based pharmacokinetic models to address multi route extrapolation within these models.
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T4.3 Dibutyltin Disposition in the Rat as Function of Dose and Route. Jeffcoat A.R.*, Hill J.M., Burka L.T.; RTI International and National Institute of Environmental Health Sciences arj@rti.org
Abstract: Dibutyltin (DBT) is a commonly used stabilizer in the manufacture of polyvinylchloride (PVC) pipes. PVC pipes, in turn, are ubiquitous in water-supply systems, and thus humans have a potential to be exposed via ingestion of drinking water to DBT that leaches from these pipes. DBT is also a metabolite of trbutyltin (TBT), a compound that until recently was used extensively as a biocide in antifouling paints for ships. Both TBT and DBT are contaminants of the marine environment worldwide and are present in marine animals that become part of the human food chain. Human exposure to DBT from the sources listed above is likely to be in the form of low-level, chronic (or periodic), oral ingestion. Previous studies of the disposition of DBT have generally been at doses greater than 1 mg/kg, considerably higher than the assumed normal human exposure. We present the results of studies of radiolabeled DBT disposition in male rats at oral and IV doses that range over 2 orders of magnitude, including doses at or below 0.1 mg/kg. At 72 hours following a single oral dose, but not 8 h post dose, the concentrations of residual DBT-derived material present in most rat tissues were proportional to the dose. Excretion rates were dependent on dose and route of dosing. In bile duct cannulated animals, secretion of the lowest oral and intravenous doses of DBT into bile was slow with relatively constant, but differing, rates throughout the 24-h collection period. The major radiolabeled component of bile was DBT. However, bile from animals dosed orally contained a higher percentage of polar DBT-derived material than did bile from animals dosed intravenously. These results suggest that risk factors associated with DBT are dependent on both dose and route of exposure.
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T4.4 General Toxicology Of Mono- and Di-alkyltin Chlorides. Murphy S.R*, Farr C.H.; Arkema Inc. sandi.murphy@arkemagroup.com
Abstract: Mono- and di-alkyltin chlorides are high production volume (HPV) chemicals used as intermediates in the production of organotin stabilizers for PVC. They are reactive, severely irritating to corrosive, materials. The available general health effects screening data were compiled or developed by the Organotin Environmental Programme Association in response to the EPA HPV Challenge program for methyltin trichloride, (MMTC, CAS# 993-16-8), dimethyltin dichloride (DMTC, CAS# 753-73-1), butyltin trichloride (MBTC, CAS# 1118-46-3) and dibutyltin dichloride (DBTC, CAS# 683-18-1). Developmental effects will be addressed separately. In repeated dose studies, these materials also represent the toxicity of the organotin stabilizers because the chlorides are formed in vivo via gastric hydrolysis when the stabilizers are ingested. These alkyltin chlorides are negative in the Ames test and negative (DMTC, MBTC) to weakly positive in the mouse micronucleus test. In 90 day feeding or drinking water studies in rats the nervous system is the primary target organ for methyltins, with signs ranging from hyperactivity to aggressiveness, convulsions and death. Microscopic lesions included neuronal necrosis and loss of perikarya in the pyramidal layer of the hippocampus and in the piriform cortex. Organ weight changes and clinical chemistry findings were also reported. No observed adverse effect levels (NOAELs) were ~10 and 0.6 mg/kg/day for MMTC and DMTC, respectively. Increased liver weights and clinical chemistry changes, but no abnormal histopathological findings were noted after 90 day dietary administration of MBTC at levels up to 525 mg/kg/day. Thymic atrophy is the primary target organ effect reported for DBTC, though liver and kidney weight changes and anemia were also reported. NOAELs were 525 (90 day) and 0.4 (28 day) mg/kg/day for MBTC and DBTC, respectively.
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