The SIRC Review Journal

Ten issues of “The SIRC Review,” a periodical highlighting research and literature reviews conducted under the auspices of SIRC, have been published since 1990. Below you’ll find summaries of the various editions. Contact SIRC for more information or to request printed or PDF versions.

 

Published 1990

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1. The SIRC Review: The Need, The Purpose (Geoffrey C. Granville)

2. Styrene: Perspectives on the Carcinogen Question (Daniel P. Boyd, et al.)

The authors review and discuss the major studies to date on the possible carcinogenicity of styrene. They begin with the work of the International Agency for Research on Cancer (IARC) which in 1987 changed its classification of styrene from “not classifiable” to “possibly carcinogenic to humans”, despite the lack of any new human or animal data. They point out that several major national and international organizations have disagreed with this classification and have determined that the evidence does not support the classification or regulation of styrene as a carcinogen. They believe that significant studies currently in progress will clarify some of the issues and allow the development of improved risk estimations.

3. The Potential Mutagenicity of Styrene and its Metabolites (R. Julian Preston)

Dr. Preston discusses the published data on mutagenicity with respect to styrene and its metabolites, the adequacy of the data and their statistical significance. He concludes that styrene is not mutagenic in in vitro assays unless there is metabolic activation. Even when there is activation, however, styrene remains non-mutagenic or is only very weakly mutagenic. The metabolite styrene oxide is mutagenic without activation, but with activation its mutagenicity either does not change or is reduced. Overall, styrene is not mutagenic, but the role of styrene oxide as a mutagenic intermediary in the metabolism of styrene in vivo cannot be adequately assessed from existing evidence.

4. The Environmental Fate of Styrene (Martin Alexander)

Dr. Alexander reviews the research and substantive monitoring data on the fate of styrene in water, soil and the atmosphere. He concludes that the transport of styrene in nature is “very limited” because of its volatility from soils and surface waters, its rapid destruction in air, and its biodegradation in soils and surface and ground-waters. The most probable source for any human exposure is the atmosphere, especially urban air, where values up to 6.0 ppb have occasionally been recorded. However, because styrene is highly reactive and rapidly destroyed by ozone and hydroxl radicals, it is unlikely to be transported to any significant extent, or to be a source of styrene in waters or soils. There is little possibility of styrene occurring in drinking water or entering the food chain.

5. Carcinogen Classification Systems: A Time for Change (Robert J. Moolenaar)

The identification of a substance as a “possible”, “probable” or “reasonably anticipated to be” human carcinogen sounds many alarm bells. It raises the concerns of the public, of regulators and health officials, and of corporate executives whose companies manufacture or use the substance. It can have significant health, economic, financial and legal consequences. Yet the national and international systems used to classify carcinogenicity are confusing, contradictory, unreliable – and often arbitrary. The U.S. Environmental Protection Agency and its Science Advisory Board have recognized the deficiencies in EPA’s own classification process and are seeking ways to improve it. Dr. Moolenaar discusses the problems and recommends ways to make the classifications more accurate and more meaningful to those who depend on them.

Published 1990

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1. New Light on Some Key Health Issues

In this second issue of The SIRC Review we continue our examination of questions periodically raised — by government, industry, health specialists or other groups — with respect to the possible effects of exposure to styrene.

2. Authors in This Issue

3. Risk Assessment and Risk Management Current Regulatory Issues and Concerns

This excerpt from the recently published Regulatory Program of the United States Government, prepared by the Office of Management and Budget, is a major review of problem areas in the federal government’s current risk assessment and management practices. It points out that by continued reliance on worst-case assumptions and by incorporating hidden policy judgments within the scientific assessments of risk, the government has departed significantly from the recommendations of the National Academy of Sciences (NAS) and seriously distorted the risk process. The subsequent distortions are often of several orders of magnitude and are probably most severe in the area of cancer-risk assessment.

4. Styrene and its Metabolites: A Discussion of Results from Cytogenetic Assays

A possible association between styrene exposure and chromosomal damage in humans has been the subject of numerous investigations in recent years, particularly in Europe. While these studies have been largely inconclusive, conclusions have sometimes been drawn from them that give  rise to considerable confusion and concern outside the scientific community. In this article, Dr. Preston examines the principal assays for chromosomal analysis and discusses their use for genotoxicity assessment in cellular, animal and human studies. He notes that the better conducted human monitoring studies indicate no difference in aberrations between those exposed to styrene and the control groups who were not exposed.

5. A Critical Review of the Reproductive and Developmental Data on Styrene

Though styrene has sometimes been referred to as a teratogenic (causes malformations) or as a potential human developmental toxicant, the only previous comprehensive review of the data, published in 1981, did not reveal any definite specific effects. Dr. Brown re-reviews the data up to the present, including the unusually large number of Soviet studies. He finds no evidence for teratogenicity in any of the studies and little indication that styrene  can exert any specific developmental or reproductive toxicity. He notes that while initial human studies linked styrene exposure with congenital malformation and spontaneous abortion, these findings were later disproved by subsequent more extensive investigations by the same researchers.

6. Too Many Rodent Carcinogens: Mitogenesis Increases Mutagenesis

These two distinguished researchers, in this most recent paper published in Science, vol. 249, point out that if current progress continues we should understand the causes of the major human cancers by the close of this decade. They anticipate that these discoveries will invalidate many of the assumptions underlying current regulatory policies, particularly the utility and meaning of routine animal cancer tests. They emphasize that too little attention has been paid to the enormous background of natural carcinogens, which have led to the development of layers of natural defenses against toxic chemicals. This means that humans are “well buffered” against toxicity at low doses from both man-made and natural chemicals.

7. Articles Featured in Previous Issues

Published 1991

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1. Spotlight on Risk Assessment: More Art than Science? (George Cruzan, Ph.D., DABT)

2. Tyranny of the Single Number: Harvard Looks at Risk Assessment Reform (John D. Graham, Ph.D., et al.)

Last fall, the White House Office of Management and Budget issued a detailed critique of the risk assessment process used by EPA and other federal agencies, stating that they vastly overstated actual risks and led to serious distortions of public policy and priorities. In March of this year, the Center for Risk Analysis of the Harvard School of Public Health held a two-day invitational workshop on the OMB report for experts in the fields of risk assessment and management. This summary of their discussion points to perceived strengths and weaknesses in the OMB report and recommends several areas for improvement in current risk assessment techniques.

3. Poor Reviews for EPA’s Adipose Tissue Survey…

National Research Council Finds “Fundamental Flaws”
(From the NRC Report, “Monitoring Human Tissues for Toxic Substances,” May, 1991)EPA’s National Human Adipose Tissue Survey, launched in 1967 to study the prevalence of certain toxic substances in human fat, has been frequently cited and often misinterpreted with regard to the human health significance of traces of styrene found in composite fat samples. In 1987, Congress ordered a review of the program by the National Research Council. The Council appointed a nine-member Committee on National Monitoring of Human Tissues, chaired by John C. Bailar III, professor of biostatistics at McGill University School of Medicine, Montreal. The committee’s final report was published in May of this year. The committee found the Adipose Tissue Survey to be “fundamentally flawed” and urged that it be replaced by an improved program that would examine blood samples instead of fat.

A Commentary on the Styrene Measurements
(R.R. Miller, Ph.D., A. Poole, Ph.D. and R.J. Nolan, Ph.D.)

According to the National Adipose Tissue Survey, styrene was found in 100 percent of the composite samples of human fat reported. This fact has frequently been cited – and misinterpreted – as an indication that the health of the American population may be affected from an overexposure to styrene. It has even been suggested that this may be the result of the widespread use of polystyrene food packaging. Prior to the recent publication of the National Research Council study pointing to “fundamental flaws” in the adipose tissue survey (see preceding article), the authors of this article examined the specific data relating to styrene and came to similar conclusions, finding the results of the adipose tissue survey “biologically implausible.”

4. Low Level Exposures to Styrene: A Discussion of Alleged Health Effects (Elizabeth J. Williams)

Environmental critics of plastics in general and polystyrene in particular frequently cite as their source of health concerns an article published by the Los Angeles-based Foundation for Advancements in Science and Education (FASE), titled “Styrene: Health Effects of Low-level Exposure” (vol. 7. no. 2 winter, 1988). A critical review of this article reveals numerous basic flaws, principally its confusion of high-level and low-level exposures. Health effects attributed to low-level exposures by the general public are either unsupported by any scientific data, or cite effects that would be noticed only at levels exceeding those found in the workplace. The article also relies heavily on the EPA National Human Adipose Tissue Survey recently discredited by the National Research Council and other scientists (see preceding articles).

5. The Epidemiology of Styrene…

Studies of Workers in the Reinforced Plastics and Composites Industry (Otto Wong, Ph.D.)A number of epidemiological studies have been conducted to assess the potential carcinogenicity of styrene (see following review). In this article, first published late last year in the British Journal of Industrial Medicine, the author describes one of the more significant of them: a mortality study of nearly 16,000 workers, including nearly 4,000 women, who were exposed to styrene at manufacturing plants in the reinforced plastics and composites industry between the years 1948 and 1977. Thirty manufacturing plants were involved. The study found no excess of any specific cause of death. The ratio of deaths from cancer was slightly lower among these workers than among the population as a whole. The ratio of deaths from leukemia was similar to those in the general population.

A Critical Review of Eight Studies Involving Nearly 50,000 Workers (Gregory G. Bond, Ph.D., et al.)This review examines the eight most recently published epidemiology studies of workers occupationally exposed to styrene. Together, these investigations involved nearly 50,000 employees over a 45-year time period between 1940 and 1986. The studies covered workers in a variety of operations, from boat building to fiberglass panel construction to styrene monomer and styrene-butadiene rubber manufacturing. Workplace environments were all characterized by multiple agent exposures, including a number of known or suspected carcinogens, and some of the earlier styrene exposures were substantial. Nevertheless, the studies showed no overall risk of lymphatic or hematopoietic cancer or the various cancer subtypes to be associated with these workplace exposures to styrene.

6. Clarifying the Carcinogenicity Issue: The Styrene Research Program
(The Science and Technology Task Group of the Styrene Information and Research Center)

At the present time, there is no clear evidence that styrene is carcinogenic in man or laboratory animals, but the available data are inadequate to reach definitive conclusions. This article summarizes the current international research being conducted by the Styrene Information and Research Center, the European Chemical Industry Ecology and Toxicology Center and the International Agency for Research on Cancer to resolve the outstanding issues. Completion of this research program should allow a more thorough understanding of the carcinogenic potential of styrene, as well as the potential human health significance of styrene oxide as an intermediate metabolite of styrene.

Published 1993

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1. Symposium Overview

2. Exposure to Styrene (J.R. Cushman, Ph.D. and R.R. Miller, Ph.D.)

3. Markers of Exposure (G. Cruzan, Ph.D. and F. Ratpan, Ph.D.)

4. Human Cancer Studies (M.G. Ott, Ph.D. and R.C. Leonard, Ph.D.)

“…the body of evidence does not currently support a causal link between styrene exposure and L+H cancer.”

5. Investigation of Styrene Carcinogenicity Using Laboratory Animals (G. Cruzan, Ph.D. and R.C. Leonard, Ph.D.)

“There is no convincing evidence of carcinogenic activity of styrene in animals.”

6. Genotoxicity of Styrene (F. Ratpan, Ph.D., G. Cruzan, Ph.D. and M.G. Ott, Ph.D.)

“…the results of the study indicate that the styrene is a relatively weak SCE inducer in vivo when administered at high doses to rodents…”

7. Metabolism and Dose Estimation (R.R. Miller, Ph.D. and G. Cruzan, Ph.D.)

“Occupational exposure to styrene is very unlikely to result in carcinogenic effects.”

8. Other Health Effects:

I. Reproductive Toxicity (J.R. Cushman, Ph.D. and G. Cruzan, Ph.D.)

“…information is insufficient to alter the conclusion that styrene does not exert any specific developmental or reproductive effect.”

II. Neurotoxicity of Styrene (R.C. Leonard, Ph.D., J.R. Cushman, Ph.D. and M.G. Ott, Ph.D.)

9. Risk Assessment and Risk Management

I. Risk Assessment (R.C. Leonard, Ph.D. and J.R. Cushman, Ph.D.)

“…humans metabolize styrene to styrene oxide at a slower rate than do mice, and that humans also detoxify it more rapidly.”

II. Research Needs for Styrene (G. Cruzan, Ph.D.)

10. Abstracts of Styrene-Related Presentations

Published 1994

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1. Examining the Scientific Basis for a Safe Workplace Exposure Level (A Review of “The Neuroepidemiology of Styrene: A Critical Review of Representative Literature” by Charles S. Rebert and Thomas A. Hall) – R.C. Leonard and L.S. Andrews

2. Styrene Metabolism and Toxicokinetics (R.R. Miller and G. Cruzan)
“Rodents have a greater capacity than humans to form styrene oxide from styrene.”

3. The Determination of Styrene in Selected Foods (D.H. Steele, M.J. Thornburg, J.S. Stanley, R.R. Miller, R. Brooke, J.R. Cushman, and G. Cruzan)

Styrene has been identified as a constituent of a variety of foods, but the methods of determination have varied and questions have been raised about the extent to which styrene occurs in raw agricultural commodities. This study ensured that the food samples analyzed did not contain styrene-based polymers during their collection and handling, to exclude the possibility of migration of styrene into the samples from processing or packaging.

4. An Updated Cohort Mortality Study of Workers Exposed to Styrene in the Reinforced Plastics and Composites Industry (O. Wong, L.S. Trent, and M.D. Whorton)

The SIRC-sponsored cohort mortality study of U.S. reinforced plastics (RP) industry workers has been updated for an additional 12 years, extending follow-up to a period of 42 years from 1948 through 1989.

5. Approach to Health Risk Determination for Priority Substances, Including Styrene, Under the Canadian Environmental Protection Act (M.E. Meek, R. Newhook and V.C. Armstrong)

The article summarizes the Canadian approach to dealing with toxic substances in Canada. The authors are employees of the Environmental Health Directorate, Health Canada, and therefore are well-positioned to provide an explanation. Readers are certain to find the article to be of interest, as styrene is used as the example of how the Canadian approach works in practice.

6. IARC Reevaluation of Styrene (R.R. Miller and J.A. Swenberg)

7. Recommendations for Improving Cancer Risk Assessment (Center for Risk Analysis, Harvard School of Public Health)

Since its creation in 1989, the Center for Risk Analysis of the Harvard University School of Public Health has taken an active role in the debate over methods of risk assessment. The following report from July, 1992 was submitted formally to the U.S. Environmental Protection Agency, the National Academy of Sciences, and the California Environmental Protection Agency, because of their present efforts toward modifying cancer risk assessment guidelines to reflect current scientific knowledge.

8. Letter to the Editor


Published 1997

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1. Styrene Exposure and Color Vision (James E. Sheedy, OD, Ph.D.)

Color vision deficiencies (dyschromatopsia) have been reported in association with occupational exposure to styrene. High exposure levels are associated with color vision deficiency, whereas low exposure levels are not. Styrene-induced color vision deficiencies statistically improve when exposure is decreased. In this article Dr. James Sheedy reviews the literature on these reported effects, noting in his conclusion that research shows that the degree of styrene-induced color vision deficiency is likely not subjectively noticeable.

2. Update on the Research Program of the Styrene Information and Research Center (George Cruzan, Ph.D., DABT)

Styrene is a material with a rich, but often conflicting, database of studies in humans and experimental animals. SIRC continues to sponsor research and ongoing projects, such as the mouse bioassay, in the belief that complete understanding of the data and mechanism will lead to scientifically based regulations.

3. OECD SIDS Process and Styrene: One Observer’s Views (Geoff Granville)

“Another expert assessment has been drafted on styrene … and again there have been differences of opinion.”

4. Risk Assessment Under the EU Existing Substance Regulation (Steve D. Williams)

“The EU Existing Substances Regulation…mandates the collection of information about chemical substances manufactured or imported into Europe. For selected ‘priority chemicals’ this information is used to assess their risks to man and the environment…”

5. Summary of the EU Styrene Draft Risk Assessment by the United Kingdom Health & Safety Executive

“Taken together, animal and human data suggest that styrene does not exhibit carcinogenic activity of significance to human health.”

6. The EPA’s Proposed Guidelines for Carcinogen Risk Assessment: Potential Application to Styrene (C.N. Park, Ph.D. and K.A. Johnson, DVM, Ph.D.)

“The proposed update of the EPA cancer risk assessment guidelines contains a number of changes which could make the risk assessment process more flexible and incorporate more science.”

Published 1998

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1. Environmental Fate and Effects of Styrene (Martin Alexander, Ph.D.)

Styrene is a widely used chemical, and as such is of potential environmental concern. In this article, Dr. Martin Alexander reviews the data on styrene occurrence, reactions, biodegradation, and toxicity. He concludes that styrene is unlikely to cause effects at levels found in the environment.

2. Ecotoxicity Hazard Assessment of Styrene (J.R. Cushman, G.A. Rausina, G. Cruzan, J. Gilbert, E. Williams, M.C. Harrass, J.V. Sousa, A.E. Putt, N.A. Garvey, J.P. St. Laurent, J.R. Hoberg, and M.W. Machado)

3. Review of Styrene as a Potential Endocrine Disruptor (Illinois Environmental Protection Agency), Introduction by John O. Snyder, Jeffrey S. Terry

The Illinois Environmental Protection Agency developed one of the first documents by a regulatroy agency focusing on the issue of endocrine disruptors. SIRC was one of the initial industry groups to ask the agency to more closely examine the data on a specific chemical. That review prompted a scientific forum that examined not only the styrene data, but the issue of endocrine disruption in general.

4. Integrated Risk Information System: An Overview (Chris Bevan, Ph.D.)

“The limitations of IRIS, therefore, are in the absence of exposure assessment and risk characterization.”

Published 2000

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1. Chronic Toxicity/Oncogenicity Study of Styrene in CD rats by Inhalation Exposure for 104 Weeks (George Cruzan, Janette R. Cushman, Larry S. Andrews, Geoffrey C. Granville, Keith A. Johnson, COlin J. Hardy, Derek W. Coombs, Pamela A. Mullins and W. Ray Brown)

There was no evidence that styrene exposure caused treatment-related increases of any tumor type in males or females or in the number of tumor bearing rats in the exposed groups compared to controls. Based on an overall evaluation of eight oncogenicity studies, there is clear evidence that styrene does not induce cancer in rats.

2. Uptake of Styrene in the Upper Respiratory Tract of the CD Mouse and Sprague-Dawley Rat (John B. Morris)

These data provide strong evidence that inspired styrene is metabolized in nasal tissues in the rat and mouse and that a metabolic basis exists for the observed inspired concentration dependence of UE.

3. Mortality From Nonmalignant Diseases of the Respiratory, Genitourinary and Nervous Systems Among Workers Exposed to Styrene in the Reinforced Plastics and Composites Industry in the United States (Otto Wong, Lisa S. Trent)

Mortality from nonmalignant genitourinary diseases, nonmalignant respiratory diseases, and diseases of the nervous system among 15 826 US workers exposed to styrene in the reinforced plastics and composites industry was examined in our investigation. We found no relationship between styrene exposure and any of these causes of death.


Published 2002

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1. Chronic Toxicity/Oncogenicity Study of Styrene in CD-1 Mice by Inhalation Exposure for 104 Weeks (George Cruzan, Janette R. Cushman, Larry S. Andrews, Geoffrey C. Granville, Christopher Bevan, Keith A. Johnson, Colin J. Hardy, Derek W. Coombs, Pamela A. Mullins and W. Ray Brown)

Styrene has a weak genotoxic potential and has caused increased late-occurring tumors in a single organ (lung) of a single species (mouse). The mouse lung has a high incidence of spontaneous tumors.

2. A Review of the Developmental and Reproductive Toxicity of Styrene (Nigel A. Brown, James C. Lamb, Shanna M. Brown, and Barbara H. Neal)

The more complete and better-reported studies show that styrene does not cause developmental toxicity at dose levels that are not maternally toxic… Styrene does not affect fertility or reproductive function. Considerable animal toxicity data on styrene support the conclusion that styrene is neither an endocrine-active substance nor an endocrine disrupter…

3. A Review of Lung Cancer Risk in Occupational Cohorts Exposed to Styrene (Kenneth M. Bodner & Keith A. Johnson, DVM, Ph.D.)

The latest findings from independent studies showed that risk estimates for lung cancer were spread over a narrow range, fell very close to background levels, and demonstrated only inverse trends with styrene exposure… In all, we found no consistent association between human lung cancer and styrene exposure that would indicate a causal relationship.

4. The Styrene Information and Research Center: One Industry’s Approach to Scientific Accountability (Chuck Elkins & Jack Snyder)

The styrene industry is committed to work cooperatively to develop an expanded database on styrene that would be adequate for decision-making and to communicate with governmental agencies, industry members, and the public about these data in a timely fashion to support science-based decision-making about styrene.

Published 2003

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1. Styrene Respiratory Tract Toxicity and Mouse Lung Tumors are Mediated by CYP2F-Generated Metabolites (George Cruzan, Gary P. Carlson, Keith A. Johnson, Larry S. Andrews, Marcy I. Banton, Christopher Bevan, and Janette R. Cushman)

“…styrene respiratory tract toxicity in mice and rats, including mouse lung tumors, are mediated by CYP2F-generated metabolites. The PBPK model predicts that humans do not generate sufficient levels of these metabolites in the terminal bronchioles to reach a toxic level. Therefore, the postulated mode of action for these effects indicates that respiratory tract effects in rodents are not relevant for human risk assessment.”

2. Effects of Inducers and Inhibitors on the Microsomal Metabolism of Styrene to Styrene Oxide in Mice (Gary P. Carlson)

“… the inducibility of styrene metabolism by pyridine and phenobarbital correlated with their effects on styrene-induced hepatotoxicity whereas that of B-naphthoflavone did not. The role of multiple cytochromes P-450 in styrene metabolism was also demonstrated by the inhibitor studies with a large role in noninduced animals for CYP2E1 and, in lung, CYP2F2. The induction studies still suggest though that the strain differences in susceptibility to styrene-induced toxicity may not be explainable on the basis of the conversion of styrene to styrene oxide…”

3. Metabolism of Styrene by Mouse and Rat Isolated Lung Cells (Dawn E. Hynes, Dennis B. DeNicola, and Gary P. Carlson)

“Styrene metabolizing activity was much greater in Clara cells than in type II pneumocytes, which demonstrated essentially no activity. Styrene-metabolizing activity was several-fold higher in the mouse than in rat Clara cells. The more pneumotoxic and genotoxic form, R-SO, was preferentially formed in mice, and S-SO was preferentially formed in rats. These findings indicate the importance of Clara cells in styrene metabolism and suggest that differences in metabolism may be responsible for the greater susceptibility of the mouse to styrene-induced toxicity.”

4. Metabolism of Styrene by Human Liver and Lung (Gary P. Carlson, Nancy A. Mantick, and Mark W. Powley)

“The reason for the lack of metabolism of styrene by human lung, in contrast to reasonably high activity in liver, is not entirely clear. However, since studies in mice suggest that CYP2E1 may be more important in the hepatic metabolism of styrene and CYP2F2 in pulmonary metabolism, it may be a similar case in humans. CYP2F1 in human lung may not be a very efficient cytochrome P-450 in styrene metabolism. Whatever the reason, this would suggest that human lung has little ability to bioactivate styrene to SO and would thus be less susceptible to its toxicity.”

5. Styrene Oxide in Blood, Hemoglobin Adducts, and Urinary Metabolites in Human Volunteers Exposed to C-Styrene Vapors (Gunnar Johanson, Lena Ernstgard, Elisabeth Gullstrand, Agneta Lof, Siv Osterman-Golkar, Carla C. Williams, and Susan C.J. Sumner)

“The aim of the present study was to elucidate the toxicokinetics of inhaled styrene in human volunteers, with particular emphasis on the quantification of SO in blood, and using a nonselective NMR method for analysis of urinary metabolites. The study was undertaken in order to allow quantitative comparisons between rodents and man with respect to SO blood levels and metabolite profiles. Such comparisons are potentially very useful when using animal experimental toxicokinetic and tumor data in human cancer risk assessment for styrene.”

6. The Role of Cytochromes P-450 in Styrene Induced Pulmonary Toxicity and Carcinogenicity (Trevor Green, Alison Toghill, and John R. Foster)

“…the metabolism of styrene by cytochromes P-450 has been shown to be a critical event which results in changes in the mouse lung which are consistent with the subsequent development of cancer. Based on these observations a plausible mode of action for styrene induced mouse lung cancer can be proposed … lower activity in human lung, together with the differences in Clara cell numbers and morphology suggest that styrene will not be metabolised to any measurable extent in human lung. Thus, it seems unlikely, based on the known metabolic capacities of the human lung relative to the mouse lung, that styrene will be either toxic or carcinogenic in the human lung.”

7. The Toxicity of Styrene to the Nasal Epithelium of Mice and Rats: Studies on the Mode of Action and Relevance to Humans (Trevor Green, Robert Lee, Alison Toghill, Susan Meadowcroft, Valerie Lund, and John Foster)

“Whereas cytochrome P-450 metabolism of styrene is similar in rats and mice, the rat is able to metabolise styrene oxide at higher rates than the mouse thus rapidly detoxifying this electrophilic metabolite. Metabolism of styrene to its oxide could not be detected in human nasal tissues in vitro, but the same tissues did have epoxide hydrolase and glutathione S-transferase activities, and were able to metabolise styrene oxide efficiently, indicating that styrene is unlikely to be toxic to the human nasal epithelium.”

8. Quantification of DNA Adducts Formed in Liver, Lungs, and Isolated Lung Cells of Rats and Mice Exposed to C-Styrene by Nose-Only Inhalation (Peter J. Boogaard, Kees P. de Kloe, Brian A. Wong, Susan C.J. Sumner, William P. Watson, and Nico J. van Sittert)

“The overall results of this study demonstrate that DNA adduct formation does not play a significant role in the formation of the lung tumors that were observed in mice chronically exposed to styrene. It is more likely that a nongenotoxic or epigenetic mechanism, possibly caused by a cytotoxic metabolite, is involved in this process.”

9. An Introduction to Physiologically Based Pharmacokinetic Modeling and its Application to Rish Assessment (Harvey J. Clewell, III)

“…PBPK modeling is an important tool for improving the accuracy of human health risk assessments for industrial chemicals in the invironment. The proper use of PBPK modeling can reduce uncertainties that currently exist in risk assessment procedures by providing more scientifically credible extrapolations across species and routes of exposure, and from high experimental doses to potential environmental exposures.”

10. Physiologically Based Pharmacokinetic Modeling of Styrene and Styrene Oxide Respiratory-Tract Dosimetry in Rodents and Humans (Ramesh Sarangapani, Justin G. Teeguarden, George Cruzan, Harvey J. Clewell, Melvin E. Andersen)

“The principle objective of this article was to develop an MOA-based PBPK model for inhaled ST [styrene] that integrates relevant mechanistic and toxicokinetic information and is capable of describing the relationship between exposure and target tissue does of ST and its reactive intermediate SO in rodents and humans … These predictions support a pharmacokinetic basis for species sensitivity in rodents and indicate that humans will be approximately 100-fold less sensitive to the induction of lung tumors following ST exposure than are mice.”

Published 2006

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1. National Toxicology Program (NTP) Center for the Evaluation of Risks to Human Reproduction (CERHR): Monograph on the Potential Human Reproduction and Developmental Effects of Styrene [NTP Brief]

“The NTP concurs with the CERHR Styrene Expert Panel that there is neglible concern for adverse developmental and reproductive effects in humans exposed to styrene, including exposures to the general population and exposures in the workplace. This conclusion is based on the low levels of estimated human exposures to styrene in the general population and in the workplace. No clear evidence of developmental or reproductive toxicity effects in experimental animals has been reported, even at comparatively high doses of styrene.”

2. Two Generation Reproduction Study of Styrene by Inhalation in Crl-CD Rats (George Cruzan, Willem D. Faber, Keith A. Johnson, Linda S. Roberts, Juergen Hellwig, Ed Carney, John T. Yarrington, Donald G. Stump)

“Reproductive performance and offspring postnatal survial prior to weaning were not adversely affected by styrene exposure. Pre-weaning pup weights were unaffected by styrene exposure for the F1 generation.”

3. Developmental Neurotoxicity Study of Styrene by Inhalation in Crl-CD Rats (George Cruzan, Willem D. Faber, Keith A. Johnson, Linda S. Roberts, Juergen Hellwig, Jacques Maurissen, Melissa J. Beck, Ann Radovsky, and Donald G. Stump)

“Based on the results of this study, an exposure level of 50 ppm was considered to be the NOAEL for growth of F2 offspring; an exposure level of 500 ppm was considered to be the NOAEL for F2 developmental neurotoxicity”.

4. Olfactory Function in Workers Exposed to Styrene in the Reinforced-Plastics Industry (Pamela Dalton, Beverly Cowart, Daniel Dilks, Michele Gould, Peter S.J. Lees, Aleksandr Stefaniak, and Edward Emmett)

“The present study found no evidence among a cross-section of reinforced plastics industry workers that current or historical exposure to styrene was associated with impairment of olfactory function. Taken together with anatomical differences between rodent and human airways and the lack of evidence for styrene metabolism in human nasal tissue, the results strongly suggest that at these concentrations, styrene is not an olfactory toxicant in humans.”

5. Exposure Assessment for Study of Olfactory Function in Workers Exposed to Styrene in the Reinforced-Plastics Industry (Peter S.J. Lees, Aleksandr Stefaniak, Edward A. Emmett, and Pamela Dalton)

“Without quantitative measures of exposure, findings and conclusions are of limited usefulness. The use of exposure information in this manner is critical for the development of defensible assessments of the risk of exposure to occupational and environmental agents and, in turn, to the standards setting process.”

6. Neuropsychological Efffects of Styrene Exposure: Review of Literature Published 1990-2003 (Leyla Bagirzadeh, Jeremy Beach, Nicola Cherry, Department of Public Health Sciences, University of Alberta)

“Studies published since 1990 are, in general, of high quality and avoid many of the pitfalls of the earlier studies of neurobehavioral effects. The conclusions drawn by the authors are usually appropriately modest and point to the relatively slight effects that can be attributed to styrene in the populations studied.”

7. The Effect of Styrene Exposure on Color Vision: A Review (Gregory W. Good, Jason J. Nichols)

“Styrene exposure, at high levels, is associated with color vision deficiency. However, the magnitude of these deficiencies is relatively minor, especially relative to congenital color vision defects and it is unlikely that the level of defect would have much functional significance.”

8. Quality of Life and Color Vision: The Significance of Acquired Dyschromatopsias (Jason J. Nichols, Gregory W. Good)

“As the color discrimination losses accompanying styrene exposure are relatively mild, we believe that a study that assessed the significance of styrene-induced color vision deficiency might show little-to-no impairments in quality of life and functional ability.”

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