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Background

The Styrene Information and Research Center (SIRC) was formed in 1987 as the principal focal point for public information and research on the chemical styrene. SIRC also serves as a liaison between industry, federal and state government, and international agencies on health-related issues involving styrene. Located in Washington, D.C., SIRC is a special purpose group of The Society of the Plastics Industry, Inc. (SPI).

SIRC is a non-profit organization consisting of 27 Voting member companies involved in the manufacturing or processing of styrene, and 35 Associate member companies that fabricate materials from derivatives of styrene. Collectively, SIRC's membership represents approximately 95% of the North American styrene industry.

Mission & Goals

SIRC's mission is the collection, development, analysis, and communication of pertinent information on styrene. The organization's principal objectives are:

To develop sound medical, scientific, and technical information, for the guidance of industry and federal/state regulators on issues associated with styrene exposure.

To communicate this information effectively to plant managers, employees, and communities; as well as federal, state, and local officials, and to the media.

To promote fair and equitable regulations by federal and state agencies.

SIRC's Research Program and the Scientific Data on Styrene

­ General Overview

­ Carcinogenicity Issue

­ Developmental and Reproductive Toxicity Information

­ Endocrine Modulator Information

­ Genotoxicity Information

­ Metabolism and Styrene Oxide Information

­ Biodegradability

­ Ecotoxicity Research

­ Styrene in Food

­Styrene and Hearing

­ Neurotoxicity Research

General Overview

Since 1987, SIRC has undertaken a comprehensive research program to enhance understanding of the potential of styrene to affect human health, as well as the fate and effects of styrene in the environment. SIRC's approach has been to sponsor new research in areas where deficiencies and limitations in the existing data have not provided definitive conclusions. SIRC also commissions independent reviews of the health effects studies on styrene where data already exist. Research studies and literature reviews are sponsored with the intention that the final reports will be published in appropriate peer-reviewed journals.

SIRC has worked closely with the U.S. Environmental Protection Agency's (EPA) Office of Research and Development (ORD) and the National Toxicology Program (NTP) in developing protocols for both its sub-chronic and chronic animal inhalation studies, and has periodically updated ORD on the progress of these, and other, studies. Based on the importance which EPA places on these studies, the Agency has waited to conduct a quantitative risk assessment or consider a classification for styrene, but announced the beginning of this process in January 1998. SIRC already has initiated a dialogue with ORD to discuss aspects of health effects relative to this risk assessment for styrene.

While much of SIRC's work has focused on addressing styrene's carcinogenic potential, researchers also have investigated styrene's potential as a reproductive and developmental toxin, a mutagen, a genotoxin, and an environmental pollutant. This section will review the current scientific data on styrene for a variety of health effects endpoints. As this is intended as an overview only, specific references to studies or publications have been limited. More information on specific references may be obtained by contacting SIRC.

There is no conclusive evidence that indicates styrene is a carcinogen

Human Epidemiology Studies:

When evaluated together, the most recent collective cohort mortality studies, involving over 55,000 workers in styrene-related industries in the U.S. and Europe, over a 45-year period, show that exposure to styrene does not cause cancer (or any other disease). The levels of exposure to styrene encountered by some of these workers in the past were much higher than those encountered by workers today. Since workplace exposures to styrene are as much as 10,000 fold higher than environmental levels, a lack of effect in workers is an indicator that exposure of the general public to current environmental levels of styrene should not cause adverse health effects.

Prior to 1992, there were eight published epidemiology studies covering a total of 50,000 potentially-exposed workers in styrene-related industries. Collectively, these studies showed no evidence of increased cancer incidence or other long-term disease attributable to styrene exposure.

Certain limitations in those studies, however, led to a more recent SIRC-sponsored update of a study of nearly 16,000 workers in the American reinforced plastics industry, which was published in 1994 by Wong et al in Occupational and Environmental Medicine. In providing an average worker follow-up period of over 19 years (adding 12 years to an earlier study of the same cohort), this report provides comprehensive information for a longer latency period. No styrene-related increase in cancer, other long-term diseases, or death was found.

A similar study of 40,000 workers in the European reinforced plastics industry was published by Kogevinas et al in the Scandinavian Journal of Work Environment and Health, also in 1994. It provides an average worker follow-up of 13 years. This study likewise reported no styrene-related increase in cancer, other long-term diseases, or death.

Since 1994, several additional epidemiology studies were completed which found no evidence that indicated styrene is a carcinogen. Styrene-related increases in nonmalignant respiratory, genitourinary, and central nervous system diseases have been implicated. However, SIRC is investigating significant deficiencies with these studies which raise serious questions about these conclusions.

Animal Studies:

A total of twelve existing long-term animal studies using styrene, or a styrene b-nitrostyrene mixture, were reported in a review by McConnell and Swenberg published in 1993, by the International Agency for Research on Cancer (IARC). Each published study was reviewed and evaluated for adequacy of design and reported data, appropriateness of interpretation, and whether it had been peer-reviewed. The purpose of the review was to determine the strength of evidence for carcinogenic activity in animals, and to judge whether the data are adequate for drawing conclusions about carcinogenic activity. The authors concluded that:

There is no convincing evidence for carcinogenic action of styrene in animals, even though it has been studied in several species and by several routes of exposure (inhalation, gavage, in drinking water, and by intraperitoneal and subcutaneous injection).

None of the studies reviewed is well-suited for extrapolating potential carcinogenic activity in humans; all had deficiencies in design, conduct, or interpretation. An up-to-date chronic inhalation study was concluded to be necessary in order to evaluate this aspect of hazard assessment.

To address this significant data gap, SIRC, EPA/ORD, and NTP discussed and agreed upon the need to clarify the toxicology data on styrene through state-of-the-art chronic animal bioassays. Working in consultation with ORD and NTP on protocols, SIRC has sponsored 24-month inhalation studies in both the rat and mouse, conducted by Huntingdon Life Sciences (HLS) in England. Both studies have been conducted according to internationally recognized Good Laboratory Practice (GLP) standards, and the agencies have been periodically updated on the progress of the studies.

A final report on the rat study was released by HLS in 1996. The animals had been exposed to styrene at levels of 50, 200, 500, and 1000 parts per million (ppm). The results of the study show that there were no increases in tumors or other health effects attributable to styrene.

A final report on a 2-year mouse study is anticipated by mid 1998. The mice were exposed at levels of 20, 40, 80, and 160 ppm.

Styrene is not classified as a reproductive or developmental toxin

Comprehensive reviews of the developmental and reproductive data indicate that styrene is not teratogenic (i.e. causing birth defects), and provides little indication that styrene exposure could lead to any developmental or reproductive toxicity, including potential endocrine modulator effects (see below).

In 1995, SIRC sponsored an update of a published review of reproductive and developmental studies on styrene, by Dr. Nigel Brown, University of London. Dr. Brown concludes, "the potential developmental toxicity of styrene has been tested in several mammalian experimental species, but only one study is of good quality. Throughout all studies, there is no evidence for teratogenicity. There are reports of increases in embryonic, fetal, and neonatal death...but these effects are restricted to exposures that are maternally toxic. There is a lack of well-replicated studies, but the bulk of information suggests that styrene does not exert any specific developmental toxicities."

IARC, the United Kingdom (UK), and the American Conference of Governmental Industrial Hygienists (ACGIH) have reviewed the reproductive and developmental toxicity data and have not classified styrene as a reproductive or developmental toxicant.

Styrene has not been shown to be an endocrine modulator

Much attention has been focused recently on the issue of chemicals as potential endocrine modulators (also refered to as endocrine disrupters or estrogen mimics). In fact, styrene monomer has been shown to be non-estrogenic when tested against the currently accepted E-screen assay. A limited number of studies have suggested an effect on pituitary gland secretion of prolactin. Hyperprolactinemia can be associated with menstrual dysfunction. However, these studies are few in number, have limitations, and have not been replicated. Dr. Nigel Brown (see above) also has reviewed these studies and notes that, collectively, the available data on styrene do not support a conclusion that styrene acts as an endocrine modulator or disrupter.

SIRC has assembled a comprehensive review of the available relevant science on styrene. This information is being shared with regulatory agencies and other groups working to identify endocrine concerns, to ensure that styrene is not inappropriately linked with this issue.

A national committee, the Endocrine Disrupter Screening and Testing Advisory Committee (EDSTAC), currently is working to develop recommendations for defining endocrine disrupters, as well as identifying appropriate screening and testing methods. EDSTAC, which is composed of government, academic, and industry experts, will submit their recommendations to the EPA in 1998. Currently, EDSTAC has proposed defining endocrine disrupters as substances which are estrogenic/anti-estrogenic/androgenic/anti-androgenic, or which affect the thyroid. Based on this definition, styrene would not be considered an endocrine disrupter.

Styrene is of low concern for genotoxic effect

The genotoxicity studies reported since 1989 reinforce the findings from previous studies that styrene is not mutagenic (i.e. causing DNA mutations), or only weakly so.

A recently published literature review concludes that increases in cytogenetic (i.e. cell) effects reported in some studies on styrene workers are probably attributable to the presence of other chromosome-damaging agents in the workplace, and/or to inadequate investigations. Human studies reporting increased chromosomal aberrations (CA) must be viewed cautiously, since controlled exposures in rodent studies at concentrations of up to 20 times higher than workplace exposure levels did not result in CA's.

Human Studies:

A 1993 review by Scott published by IARC examined the published cytogenetic studies of reinforced plastics workers exposed to styrene, and found no positive correlation between styrene exposure levels and cytogenetic damage. His conclusion was that the findings in the human monitoring studies did not support the suggestion that styrene could be responsible for observed positive cytogenetic effects seen in workers in some studies.

Animal Studies:

SIRC sponsored a 1994 review of in vitro and animal study genotoxicity data by Scott and Preston, published in Mutation Research. The authors reported that, in the absence of metabolic activation systems, styrene is not mutagenic in most in vitro assays, and that there is no convincing evidence of styrene clastogenicity (i.e. ability to break down chromosomes) in experimental animals. They identified several rationales for why positive findings of increased chromosome damage in a minority of cytogenic studies are not compatible with a conclusion that styrene is responsible for the cytogenetic effects.

Recent in vivo cytogenetics studies in rats and mice conducted seperately at the Chemical Industry Institute of Toxicology and EPA research laboratories further confirm that styrene does not cause CA's in vivo, and suggest only marginal Sister Chromatid Exchange (SCE) responses at high doses.

Metabolism and the role of styrene oxide in tumor formation

Metabolism / Pharmacokinetics:

Much attention has been focused on styrene oxide, an intermediate metabolite of styrene. Differences in the rates at which animals and humans metabolize and eliminate styrene and its metabolites are critical to establishing a scientifically appropriate basis to extrapolate the results of animal studies to humans. Overall, the data indicate that humans produce less styrene oxide - and eliminate it more rapidly from the body - than rats or mice. For a given exposure level, rats and mice have at least a ten-fold higher level of styrene oxide in their blood than do humans.

SIRC sponsored a research program by the CIIT to examine differences in styrene metabolism between rats and mice, and provide guidance on the relevance of long-term mouse studies for human risk assessment. In studies with one, three, or five exposures, at styrene concentrations of 125, 250, and 500 parts per million (ppm), two strains of mice and one strain of rat showed distinct differences in the percentage of styrene metabolized via different pathways. The results reinforced the conclusion that mice are more susceptible to styrene toxicity than rats or humans.

SIRC currently is initiating additional research on metabolism issues relative to mice, in order to provide further perspective on the relevance of effects in mice as indicators of possible human health concerns.

Styrene Oxide Studies:

Several studies have reported that oral (gavage) administration of styrene oxide causes tumors in the forestomach of rats and mice, along with considerable tissue necrosis and regeneration. Recent research sponsored by the European Chemical Industry Ecology and Toxicology Centre (ECETOC) demonstrated that styrene oxide has an extremely low ability to react with DNA in the rat or mouse forestomach, as well as liver. Even at high doses, no reaction of styrene oxide with DNA could be found in the liver. SIRC sponsored a study of the effects of styrene oxide on cell proliferation in the rat forestomach, conducted by Stonybrook Laboratories, demonstrating a dose-related and concentration-related increase in cell proliferation from gavage administration of styrene oxide. Significantly increased cell proliferation was seen in rats exposed to doses of 50 mg/kg (of body weight) or greater, compared to control animals.

The ECETOC and SIRC data taken together strongly indicate that cell necrosis and the subsequent increased cell proliferation common to gavage studies is the major contributing cause of forestomach tumors from styrene oxide. The small amounts of styrene oxide formed from the metabolism of styrene in liver and other tissues are not likely to occur in a great enough concentration to cause cell necrosis and increased proliferation. Thus, the small levels of styrene oxide formed during metabolism are not likely to lead to the formation of tumors.

Styrene is highly biodegradable in the environment

A recently updated review of the published literature concludes that styrene is highly volatile in air. As a result of its biodegradability, transport of styrene through the air for appreciable distances (or its potential entry into water and soil) is unlikely in significant amounts from point-source emissions to the atmosphere.

In a SIRC-sponsored study, Dr. Martin Alexander of Cornell University demonstrated that styrene has a half-life of 3 or 4 hours, and rapidly breaks down (i.e. within 12 hours) to carbon dioxide and water under aerobic conditions in soil or water. The potential for anaerobic biodegradation exists, but the few data available on anaerobic biodegradation suggest that the compound may persist in subsoils, anoxic aquifers, septic tanks, or sludge.

Measured environmental concentrations of styrene in the air, water, and soil are too low to cause effects on either mammals, non-mammals, or microorganisms. Styrene's volatility and biodegradability keep exposure levels below that required for toxicity; and the compound's properties make bioconcentration at harmful levels unlikely.

Recent styrene ecotoxicity research

SIRC completed a series of standard acute ecotoxicity studies on the effects of styrene on the fathead minnow, daphnid, amphipod, and freshwater green algae; and a subacute toxicity study of earthworms. The studies demonstrated that styrene, like other alkylbenzenes, was moderately toxic to aquatic organisms under laboratory conditions where the styrene content in water and soil was continually replaced and evenly distributed. Under these closed, controlled conditions, styrene was toxic to green algae, but the effects were shown to be algistatic, not algicidal (i.e. inhibits but doesn't kill). Styrene also was found to be slightly toxic to earthworms.

While these studies maintained consistent exposure levels (i.e., worst case, closed conditions), in reality styrene readily breaks down and is eliminated from soils and water in the environment. Because such highly-controlled laboratory conditions do not represent conditions found in the environment, SIRC is further investigating these findings to better understand and apply this information. However, there was no indication of a concern for chronic toxicity based on these studies; and styrene is anticipated to have a low impact on aquatic and soil environments due to its volatility and biodegradability.

Styrene occurs naturally in food

SIRC sponsored a study to determine amounts of styrene found in common foods obtained directly from the farm, or site of import (i.e. with no potential for exposure to processing, packaging, or preparation materials). Published in the Journal of Agricultural and Food Chemistry in 1994, it showed that concentrations of styrene were present in 8 of 12 selected food types, including cinnamon, beef, coffee beans, peanuts, wheat, oats, strawberries, and peaches.

The results indicate styrene may be a natural component of many foods, and that the occurrence of styrene in processed foods cannot be assumed to be related to the use of styrene-based packaging, storage containers, or preparation materials.

Permissible levels of styrene exposure do not cause damage to hearing capacity

Studies show that styrene is not ototoxic (i.e., causing hearing damage) at levels to which humans are exposed in the workplace or the environment.

Styrene can be ototoxic when young rats are exposed to extremely high styrene concentrations of 800 ppm, but these levels are sixteen times higher than federal workplace limits. However, a study on the hearing ability of rats exposed to 200 ppm of styrene for prolonged periods showed no observable effect. Since this is four times higher than the styrene industry's voluntary workplace exposure limit endorsed by the Occupational Safety and Health Administration (OSHA), occupational exposure to styrene at or below the present 50 ppm limit should not affect hearing ability.

Recent reviews of neurotoxicity data

A critical review of representative literature on the neuroepidemiology of styrene, by Drs. Charles Rebert and Thomas Hall, was published in Critical Reviews in Toxicology in 1994. They noted that styrene, like many solvents, at certain concentrations could be expected to produce acute changes in consciousness; although they point out that such acute effects do not mean that styrene would produce reversible or irreversible damage to the nervous system. Drs. Rebert and Hall reviewed studies of workers in reinforced plastics and related industries, with emphasis on the value of those studies for setting safe exposure limits in the work place. They reported that the "results concerning styrene work place neurotoxicity are not actually as they are represented in the literature, where results are often interpreted to show that styrene is neurotoxic in workers exposed to levels typically encountered in the reinforced plastics industry." They concluded that the literature does not demonstrate that styrene is neurotoxic at levels of worker exposure, because the literature fails to meet well-recognized criteria for establishing causal relationships.

Dr. James Sheedy recently completed a review of literature investigating reports of color vision deficiencies associated with occupational exposure to styrene. Although some of the studies are inconclusive, evidence of slight decreases in color perception was noted. Such effects are associated with higher styrene concentrations, and styrene-induced color vision deficiencies improve when exposure is decreased. The research shows that the level of styrene-induced color vision effect is likely not subjectively noticeable, translating to 0.35 transpositions on the D-15 test; a test commonly used for occupational vision screening. Such effects are roughly the same differences in color perception normally found in the general population in individuals between the ages of 35 and 65. Additionally, a D-15 test score of less than one (<1) transposition represents an acceptable color perception rating for most occupational settings.

For Further Information:

Styrene Information and Research Center Website

Styrene Problem

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